Introduction: Iodine is an essential trace element for the human body and a necessary raw material for the production of thyroid hormones. Thyroid hormones are crucial for fetal brain development. To ensure that the fetus receives sufficient thyroid hormones, pregnant women's iodine requirements increase. This is due to two main factors: increased synthesis of thyroid hormones, increased glomerular filtration rate leading to increased urinary iodine loss, and the transfer of some iodine to the fetus through the placenta. All of these factors contribute to increased iodine consumption. Therefore, we need to pay attention to iodine nutrition during pregnancy.
Severe iodine deficiency is rare in Europe, but mild to moderate iodine deficiency remains common. Severe iodine deficiency during pregnancy can significantly affect the health of both mother and child, causing goiter, hypothyroidism, and intellectual disability in offspring—this is undeniable. However, current research on the impact of mild to moderate iodine deficiency on the neurodevelopment of offspring has yielded inconsistent conclusions. Therefore, researchers conducted a meta-analysis on the relationship between iodine nutritional status during pregnancy and children's IQ, and explored the susceptible period for the impact of iodine deficiency during pregnancy on neurodevelopment.
Research related information
This study included three cohort studies: the Generation R study in the Netherlands, the INMA study (INfancia y Medio Ambiente Project) in Spain, and the ALPAC study (Avon Longitudinal Study of Parents and Children) in the UK. All mother-child pairs in these studies included urinary iodine levels and creatinine concentrations during pregnancy, as well as intelligence scores (IQ scores) of their offspring.
Individuals with multiple pregnancies, those who have undergone assisted reproductive technologies, and those with thyroid disorders or taking medications that interfere with thyroid function were excluded. The study was approved by the medical ethics committee, and informed consent was obtained from participants and their parents and/or guardians.
Iodine status in pregnant women: Urine samples were collected and stored at -20°C for analysis of urinary iodine and creatinine, with standardized measurements across laboratories. For pregnant women with multiple urine samples, the earliest sample was selected for iodine status assessment. The urinary iodine/creatinine ratio (UI/Creat) was ultimately used as a measure of iodine status. Data with UIC > 500 ug/L and/or UI/Creat > 700 ug/g were excluded. Finally, based on WHO standards, the iodine status of pregnant women was divided into three groups according to the UI/Creat index: 1) Iodine deficiency < 150 ug/g; 2) Iodine adequacy 150-500 ug/g; 3) Iodine excess ≥ 500 ug/g.
Thyroid function in pregnant women: TSH and free thyroxine (FT4) levels were measured, and thyroid antibodies (TPOAb) were also detected. In the Generation R and ALSAC studies, a TPOAb titer of ≥60 IU/mL and ≥6 IU/mL, respectively, were used to determine antibody positivity.
Nonverbal and verbal IQ scores: In the Generation R study, nonverbal IQ was assessed using the Snijders Oomen Nonverbal Intelligence Test, with a mean age of 5.9 years at the time of assessment. Parents were also surveyed. Verbal IQ was assessed using the McArthur Communicative Development Inventory, with a mean age of 1.5 years at the time of assessment. In the INMA study, both nonverbal and verbal IQ were assessed using the McCarthy Scales of Children's Abilities, with a mean age of 4.6 years. In the ALSAC study, both nonverbal and verbal IQ scores were assessed using the Wechsler Intelligence Scale for Children, with a mean age of 8.6 years at the time of assessment. Children with IQ scores <50 or >150 were considered outliers and excluded.
Statistical analysis: Potential confounding variables in this study included maternal age, education level (low, medium, high), race/country of birth, parity, gestational body mass index, and smoking status during pregnancy (never smoked, started smoking until pregnancy was confirmed, or continued smoking during pregnancy). Finally, multiple linear regression analysis was used, with a p-value of 0.05 defined as statistically significant.
Research Results
Based on the inclusion and exclusion criteria, a total of 6180 mother-child pairs were ultimately included in this study. The median UIC (UI/Creat) levels were: Generation R (214 ug/g, adequate intake), INMA (152 ug/g, mild deficiency), and ALSAC (124 ug/g, moderate deficiency). The median gestational age for iodine status determination were: Generation R 13.1 weeks (12.1, 14.8), INMA 13.0 weeks (12.4, 14.1), and ALSAC 12.0 weeks (8.0, 16.0).
Nonverbal IQ: A one-step analysis of the aggregated data revealed a linear positive correlation between UI/Creat and the average nonverbal IQ score, but the correlation was not statistically significant (P=0.052).
Using a two-step approach and a random-effects meta-analysis of specific populations, both UI/Creat values <150ug/g and UI/Creat values ≥500ug/g were correlated with nonverbal IQ scores, with values of -0.6 (95% CI: -1.7~0.4) and -1.1 (95% CI: -4.2~2.0), respectively. The group analysis showed that UI/Creat values were not directly related to nonverbal IQ scores.
Language IQ: Using the one-step method, a clear curve relationship was observed between UI/Creat values and language IQ scores (see Figure 2, P < 0.001). Except for the Generation R study, language IQ in preschool children was positively correlated with iodine nutrition during pregnancy. Using the two-step method, neither UI/Creat values < 150 ug/g nor UI/Creat values ≥ 500 ug/g showed a significant correlation with language IQ scores, with values of -0.6 (95% CI: -1.3–0.1) and -0.6 (95% CI: -2.6–1.4), respectively.
Ultimately, iodine nutrition during pregnancy (UI/Creat ratio) was only positively correlated with verbal IQ. A UI/Creat ratio <150 ug/g was not associated with lower nonverbal IQ scores (-0.6, 95% CI: -1.7–0.4, P=0.246), nor with lower verbal IQ scores (-0.6, 95% CI: -1.3–0.1, P=0.082). Statistical analysis indicated that the correlation between UI/Creat ratio and verbal IQ was only observed in pregnant women at 14 weeks of gestation.
discuss
Fetal brain development is susceptible to mild to moderate iodine deficiency, especially in the first trimester. During this period, the fetus relies entirely on the placenta to transport thyroid hormones to support critical brain development processes; therefore, iodine status should be monitored from the time of conception. However, there is currently no evidence that iodine supplementation in pregnant women with mild to moderate iodine deficiency is beneficial for children's neurodevelopment. More research is needed to confirm this, and trials should begin in early pregnancy, or even earlier, to explore the optimal intervention period.
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