Iodine nutrition in pregnancy, maternal thyroid function and child neurodevelopment - Results from the Norwegian Mother and Child Cohort Study
Doctoral thesis, Peer reviewed
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Bakgrunn: Mild- til moderat jodmangel er utbredt blant unge kvinner, gravide og ammende i Norge og i mange andre land. Jod inngår i stoffskiftehormonene som dannes i skjoldbruskkjertelen (thyreoidea), og disse er særlig viktige i hjernens utvikling hos foster og barn. Alvorlig jodmangel i fosterlivet påvirker hjernens utvikling negativt, mens det er mindre kunnskap om konsekvenser av mild- til moderat jodmangel. Enkelte observasjonsstudier og dyrestudier indikerer at selv mildere former for mangel kan gi varig redusert nevrokognitiv utvikling, f.eks. lavere IQ. Det er også manglende kunnskap om effekt av å ta kosttilskudd med jod i svangerskapet i befolkninger med mild- til moderat jodmangel. Mål: Å bruke data fra Den norske mor og barn-undersøkelsen (MoBa) til å undersøke sammenhengen mellom mors jodinntak i svangerskapet og hjernens utvikling hos barn. Materiale og metode: Studien inkluderer deltakere i MoBa, en prospektiv kohortundersøkelse der deltakere ble rekruttert fra hele landet i første del av svangerskapet i årene 1999-2008. Inklusjonskriterier var enkeltfødsel og ingen rapportert bruk av stoffskiftemedisiner i svangerskapet. Eksponeringer var mors jodinntak i svangerskapet beregnet ut fra et validert matvarefrekvensskjema (i bruk fra mars 2002) og mors bruk av kosttilskudd i svangerskapsuke 0-22 (ja/nei og tid for oppstart av tilskudd). Utfall var mors thyreoideafunksjon i svangerskapet (n=2910), mål for barnets utvikling ved tre år (n=48,297) og åtte års (n=39,471) og barnets risiko for ADHD-diagnose (n=77,164). Regresjonsanalyse ble brukt for å undersøke assosiasjoner kontrollert for kovariater. Resultater: Et lavt jodinntak fra kost i svangerskapet (tilsvarende lavere inntak enn anbefalt for ikke-gravide: 150 μg/dag) var assosiert med endringer i mors nivåer av thyreoideahormoner og at barnet fikk redusert språkutvikling, dårligere finmotorikk, mer atferdsproblemer og ADHD-symptomer, dårligere skoleprestasjoner og hadde økt sannsynlighet for å motta spesialundervisning. Mors jodinntak var ikke signifikant assosiert med barnets grovmotorikk eller risiko for ADHD-diagnose. Det ble ikke funnet evidens for gunstige effekter av å ta jodtilskudd i svangerskapet. Å starte å ta jodtilskudd i første trimester var assosiert med økt risiko for atferdsproblemer, ADHD-symptomer og ADHD-diagnose, men ikke med de andre utfallene. Konklusjon: Resultatene understøtter at mild- til moderat jodmangel i svangerskapet er assosiert med redusert nevrokognitiv utvikling hos barn. Effektene var generelt små, men omfattet en betydelig andel av populasjonen og er derfor likevel relevante. Tilskudd med jod i svangerskapet ser ikke ut til å kunne kompensere for et lavt langtidsinntak av jod fra kost.Background: Iodine is an essential micronutrient through being an integral part of the thyroid hormones synthesized in the thyroid gland. Thyroid hormones are important in regulating nerve cell- and brain development. Suboptimal iodine nutrition can affect thyroid function and consequently also foetal brain development, and the first trimester is identified as a particularly vulnerable time window. Although great effort has been made during the last decades to eradicate iodine deficiency (ID), mild-to-moderate ID remains one of the most common nutritional deficiencies worldwide. The World Health Organization (WHO) estimates that ID is the most common cause of preventable impaired cognitive development, and up to 50% of babies born in Europe today are estimated to be at risk. Severe ID has detrimental effects on brain development, but less is known about the potential impact of mild-to-moderate ID and about what is the optimal range of iodine intake in pregnancy. Studies have indicated that the optimal range is narrow. A high iodine intake can also affect thyroid function negatively. In areas of ID, WHO recommends iodine supplements for women of childbearing age, pregnant and lactating women until salt iodization is implemented. In severe ID, iodine supplements are effective in preventing thyroid dysfunction and child impairments, but in mild-to-moderate ID studies show conflicting results. Aim: The aim of this project was to take full advantage of the potential within the Norwegian Mother and Child Cohort Study (MoBa) (within the frames of a Ph.D.-project) to explore the association between maternal iodine intake and child neurodevelopment in a population characterized with mild-to-moderate ID in pregnant women. Specifically, we aimed to explore if maternal iodine intake from food was associated with maternal thyroid function in pregnancy (plasma thyroid hormones and antibodies) and with child neurodevelopment up to age 8 years (language, motor, behaviour problems, school performance, special educational services, symptoms of attention deficit/hyperactivity disorder (ADHD), and ADHD diagnosis). A second aim was to explore the potential impact of maternal use of iodine containing supplements on the same outcome measures. Material and methods: The study sample included participants in the Norwegian Mother and Child Cohort Study (MoBa) recruited in pregnancy, all over Norway in 1999-2008. Inclusion criteria were singleton pregnancy, no reported use of thyroid medication in pregnancy, available data on exposure(s) and outcome(s). Maternal habitual iodine intake was calculated based on an extensive and validated food frequency questionnaire (FFQ, in use from 2002) covering the first half of pregnancy. Outcomes included maternal thyroid function in pregnancy (n=2910), measures of child neurodevelopment at 3 years (n=48,297) and 8 years (n=39,471), and child risk of ADHD diagnosis (n=77,164). Associations were explored by multivariable regression analysis controlling for confounding factors. Results The median calculated habitual iodine intake from food was 121 μg/day (IQR: 89, 161 μg/day)1, and the majority of the participants did not reach the recommended intake of iodine in pregnancy2. UIC was measured in a subsample of women (n=2910, mean gestational week 18.5, SD: 1.3), and median UIC was 59 μg/L in non-users of iodine supplements and 98 μg/L in current iodine supplement users. Both groups were well below what is considered adequate by WHO (i.e. median ≥150 μg/L). UIC in the subsample of 8 year old children (n=279) indicated adequate iodine status in the children (i.e. median UIC ≥100 μg/L; median UIC was 110 μg/L, IQR: 79, 155 μg/L). UIC, but not iodine from food by the FFQ, was inversely associated with maternal thyroid hormones (plasma free thyroxine (FT4) and free triiodothyronine (FT3)) in gestational week 18. A recent introduction of an iodine supplement (within the last 5 weeks) was associated with lower FT4. A low maternal iodine intake from food (below ~150 μg/day) was associated with poorer language skills at 3 and 8 years, poorer fine-motor skills at 3 years, with more behaviour problems at 3 years and ADHD-symptoms at 8 years, with poorer reading and writing skills at 8 years, and with increased likelihood of child receiving special educational services at 8 years. It was not associated with gross motor skills at 3 years or child ADHD diagnosis registered in the Norwegian Patient Registry (NPR) by Dec. 2015. There was no evidence of beneficial effects of maternal use of an iodine-containing supplement in the first half of pregnancy. Introducing an iodine-containing supplement in the first trimester was associated with more behaviour problems at 3 years, ADHD symptoms at 8 years, and ADHD diagnosis in the NPR, but not with the other outcomes on neurodevelopment. Conclusion: Overall, the results from MoBa indicate that mild-to-moderately insufficient iodine intake in pregnancy (less than ~150 μg/day) was associated with changes in maternal thyroid function, poorer child cognitive development, and more child behaviour problems. 1 All singleton pregnancies in MoBa with data from the food frequency questionnaire (n=84,327). 2 Recommended iodine intake for pregnant women varies and ranges from 175 μg/day in the Nordic recommendations to 250 μg/day in the WHO recommendations. There was no evidence of beneficial effects of maternal use of iodine-containing supplements. Initiating iodine supplement use might lead to a temporary inhibition of thyroid hormone production/release in mild-to-moderate ID which potentially can affect neurodevelopment negatively. This was indicated for child behaviour problems, including ADHD, when supplement use was initiated in the first trimester. Impact: Preventing even mild-to-moderate ID in women of childbearing age seems critical to secure optimal foetal brain development. Prevention by taking iodine supplementation initiated in pregnancy might be too late, and can potentially cause a transient inhibition of the thyroid function. Effective prevention strategies should therefore aim to secure an optimal iodine status in all women of reproductive age. ID is easily preventable, yet it remains an important risk factor for impaired neurodevelopment. Given the relatively high prevalence of mild-to-moderate ID in Norwegian pregnant women (69% in MoBa had iodine intake from food <150 μg/day), results from this study suggests that ID is an important risk factor for impaired neurodevelopment in children born in Norway and that actions to prevent ID are urgently needed. For the purpose of prevention, it is important to gain knowledge about what intake is needed to secure an optimal foetal brain development while at the same time not aiming too high putting pregnant women and also other groups of the population at risk of iodine excess. The results of this study does not support either an increased recommended intake of iodine in pregnancy or recommending pregnant women with mild-to-moderate ID to take iodinecontaining supplements. However, more research is needed to elucidate this.