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I just wanted to give you a quick heads up! Other then that, very good blog! Way cool! Some very valid points! Among the many central micronutrients in this regard is vitamin B9 folate , which in its synthetic form is known as folic acid. Due to the rapid neuronal proliferation during pregnancy, the achievement of sufficient folate levels through a regular diet is challenging.
In Norway, there is no mandatory fortification of food products with folate. Hence, daily use of folic acid tablets or multivitamins containing folic acid is recommended to women 1 month before planned pregnancy and until 12 weeks of gestation 3.
The current percentage of women in Norway taking folic acid supplements before pregnancy is Regarding multivitamin supplements, the percentage of women taking multivitamins before pregnancy is The recommendation of maternal folic acid use is primarily built on evidence for the prevention of neural tube defects in infants 6 , but folate appears to have preventive effects also on other adverse pregnancy outcomes 7 — 9.
The need for folate increases during pregnancy because of increased demands from the fetus and rapid neuronal proliferation 10 , If folate deficiency during early pregnancy can cause neural tube defects, it may also cause milder forms of fetal neural impairments that could be expressed as decreased motor function 9. A possible mechanism is the level of myelinization, which has been proposed as an expression of the functional maturity of the brain and thus linked to motor development However, maternal folate status during pregnancy and its impact on offspring motor function remains inconsistent or insufficiently examined 8 , 9.
A limitation in previous studies is the use of global screening instruments as outcome measures and not thorough clinical assessments. Due to the divergent findings from previous research; the aim of the present study was to examine maternal folic acid-containing supplement use before and during pregnancy and its association with both clinical assessments and parent reports on infant motor function.
Our predefined hypothesis was that infants born by mothers who did take folic acid-containing supplements either as folic acid tablets or folic acid-containing multivitamins or both either before or during pregnancy would be associated with higher scores in motor function compared to infants of mothers who did not use any of these supplements in pregnancy.
We conducted a prospective, observational study of infants aged 3—18 months. Infants were recruited by public health nurses during regular well-baby check-ups in primary care in Norway. All infants aged 3—18 months were eligible for inclusion. Excluded were infants with parents not speaking and understanding a Scandinavian or English language.
Clinical assessments of motor function according to the Infant Motor Profile IMP 20 were standardized for all participants and conducted at the public health care centers or in the infant's home by a specialist in pediatric physiotherapy KMT. Assessments were video-recorded and scored shortly after the assessment.
Mothers received a written invitation and signed informed consent before enrolment. MBRN is a national health registry that has collected information on pregnancies, births, and maternal and child health in Norway since Data on maternal characteristics before and during pregnancy are collected through standardized notification forms by the attending health care personnel during delivery Data on supplement use are reported by the pregnant woman and health care personnel in connection with routine pregnancy health check-ups.
All multivitamins available in Norway contain folic acid 4. Due to the different doses of folic acid in multivitamins and folic acid tablets, we also categorized the women by supplement type i. Information on the exact timing of initiation, frequency, or duration of supplement use was not available. The outcome variables were assessed once when infants were between 3 and 18 months old with the clinical tool IMP and the parent-reported ASQ The IMP is a clinical tool with norm references from 1, Dutch infants IMP consists of a total score and five domain scores: variation, adaptability, symmetry, fluency, and performance.
Variation is defined as the presence of a broad repertoire of motor behavior, while adaptability is the ability to select the best fitting motor strategy in each situation The domain symmetry indicates whether the infant has a prevailing asymmetry, or if asymmetric, stereotyped postures are present.
Fluency denotes spatial and temporal flow in movement, paying particular attention to the velocity of movements. The performance domain relates to the achievement of motor milestones. The IMP assessment provides a continuous score from 0 to in each domain, with indicating optimal motor function. The IMP domains adaptability and performance are age-dependent This means that with increasing age and increased movement experience, the infant will learn to adapt its movements in the specific context and increase its motor skills.
Hence, the scores corresponding to a given percentile value in these domains will increase by increasing age. Psychometric properties of IMP are documented in several studies 24 — In addition, two studies on predictive validity confirmed that IMP scores throughout infancy assessed at 4, 10, and 18 months were predictive of cognitive, behavioral, and neurological function at 4 and 9 years in a low-risk population 28 , A clinical study comparing two physiotherapeutic interventions suggested a clinically relevant change in IMP score to be 7.
The ASQ-2 is a worldwide used parent-reported instrument containing domains of gross and fine motor function, communication, personal and social skills, and problem-solving skills. Each domain provides a five-point interval score between 0 and 60, where 60 indicates optimal skills The reliability and validity of the questionnaire are supported by evidence 21 and recommended for developmental screening by the American Academy of Pediatrics AAP Due to the scope of this study, we only analyzed the parent reports on infant gross- and fine motor skills.
Other variables not considered as confounding factors included for description purposes only were maternal prepregnancy body mass index BMI , gestational age GA , infant birth weight, head circumference, and APGAR score at 5 min. GA was expressed as completed age of gestation in weeks and based on second-trimester ultrasound measurement, or if ultrasound data was missing, on the first day of the last menstrual period. Women who reported supplement use before pregnancy only were placed in category 2.
In an additional analysis, we incorporated supplement use as an ordered variable according to four increasing folic acid doses i. To estimate the association of exposure variables with each of the domains of IMP and the gross- and fine motor domains of ASQ-2, we used linear regression models. To account for unequal variability of the outcome variables across the range of supplement use groups, we further used robust variance estimation of regression coefficients.
Additionally, a sensitivity analysis excluding preterm infants was performed. Due to the age-dependency in IMP total score and the IMP domains adaptability and performance, the different scores should be considered in relation to the age of the infants. As our sample has an age range from 3 to 18 months, it is relevant to also examine the age-specific association between folic acid-containing supplements and motor function. Hence, in a supplemental analysis, we divided our study sample into three age groups: 1: infants aged 3—6 months, 2: infants aged 7—12 months, and 3: infants aged 13—18 months.
The associations of folic acid-containing supplements with IMP and ASQ-2 scores were estimated for each age group using linear regression models with robust standard error estimation. Maternal and infant clinical characteristics are provided in Table 1.
Of the infants boys and girls recruited in this study, infants were term-born [mean gestational age for the total sample was About half of the infants Only small differences in GA and corrected age at assessment were found between the exposure groups. One infant had missing data on ASQ-2 due to an incomplete questionnaire. Mean age for the mothers was 31 years SD 4. In general, there was a high mean score, indicating a more or less optimal motor function for the majority of infants Table 2.
No difference between term-born and preterm infants was found for the IMP total and domain scores. Overall, Of the latter women, eight women reported using folic acid-containing supplements before pregnancy only. The overall use of multivitamin tablets before and during pregnancy was The number of women using only multivitamins and not folic acid before and during pregnancy was Overall, no significant associations were found between folic acid-containing supplement use and IMP domain scores in the total sample.
No significant association was found for the infant age group 13—18 months Supplementary Table 1. Table 3. Associations of folic acid-containing supplement use with motor function. Regarding the remaining domains, no associations of supplement use with motor function were found. Further, no significant associations were found in separate analyses for the three age groups Supplementary Table 1. Table 4. Dose-response associations of folic acid use with motor function.
No associations were found between folic acid-containing supplement use and the gross and fine motor domains of ASQ. Adjusting for maternal age, marital status, and parity did not influence the results, nor did the strength of the associations change markedly when women were grouped by the dose of folic Table 4 or when infants were grouped by age in months Supplementary Table 1.
We examined whether the use of maternal folic acid-containing supplements before and during pregnancy affected motor function in infancy. In our study, we did not find any support for our predefined hypothesis about a positive association between folic acid-containing supplement use and increased motor function in offspring up to 18 months. This association remained strongest for infants aged 7—12 months, but the mean difference was below the clinically relevant difference Further, the additional analysis of a dose-response association did not reveal any significant or clinically relevant differences.
Our findings support the null findings from some of the previously mentioned studies 16 , 17 , but the evidence is mixed. The inconsistent findings are likely to be caused by differences in design, sample selection, and study size, statistical methods as well as different measures of exposure and assessment of motor function.
Motor function is not a fixed construct, and it can be problematic to compare the results of studies using different outcome measures. Previous epidemiological studies have utilized global developmental assessment batteries as outcome measures.
Even though they are recommended as screening instruments 31 and parent reports have been found predictive of developmental delays 33 , these instruments usually contain few items on gross and fine motor function. Consequently, minor impairments may not be detected. Hence, this may be a reason for discrepancies between studies investigating motor function. Although we know that motor trajectories between term-born and preterm infants are somewhat different 34 , and the term-born infants in our sample had higher ASQ-2 scores, excluding preterm infants from our sample did not affect the outcome of the linear regression analysis.
Despite the good psychometric characteristics of the ASQ-2 and IMP 21 , 24 — 27 , the long-term implications of any relationship with folic acid-containing supplement use, are uncertain. Previous studies contained participants up to 5 years of age 14 , 15 , 17 , while our sample only included infants up to 18 months. Hence, any possible later consequences could thus not be discovered. Although IMP shows good predictive validity 28 , 29 , instability in motor assessment scores can be found in both high-risk, and low-risk infants 35 , Future studies should, therefore, consider conducting endpoint assessments in older infants.
As to the statistical analysis, we checked normality of residuals for all regression models using histograms and Q-Q plots. The strongest deviations from the normal distribution were found for the IMP domain scores fluency and symmetry. In our population, nearly all infants had close to perfect scores of fluency and symmetry, leaving a strong ceiling effect for these outcomes.
Accordingly, the estimated difference in fluency and symmetry between compared groups should be interpreted with caution. A strength of our study is the prospective design providing accuracy of data collection regarding exposure, endpoints, and confounders.
In contrast to case-control studies, the exposure status is collected ahead of the outcome, thus avoiding recall bias. Further, the prospective design also offers the possibility to examine several outcomes. In our study, we combined both parent reports of general development and a thorough clinical assessment of motor function. The scope of our study was motor function, but it could also be relevant to examine the other domains of ASQ-2 communication, problem-solving skills, and personal and social skills in relation to supplement use in a future study.
Finally, a large number of variables from the MBRN were available. Accordingly, we were able to evaluate and account for several potential confounding variables. It is, however, also possible that our findings were influenced by unmeasured confounding factors. The relationship between maternal education and offspring motor function is inconclusive 37 — 39 , but maternal education is recognized as a strong predictor of folic acid use, along with planned pregnancy 32 and maternal lifestyle 16 , Unfortunately, these variables are not registered in the MBRN but should be included in future research.
We cannot know whether our findings would be different if we had access to these variables, but it would be relevant in order to describe the sample, thus enabling a comparison with other study samples. Some limitations should be noted. The main concern is that we lack accurate measures of plasma folate concentration. Further, we acknowledge that not only folic acid, but a broad specter of nutrients is essential for the developing brain both during gestation and postpartum.
In our study, the dose-response analysis did not reveal any differences, but the results could also be affected by the inaccuracy in exposure measurement.
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