Effect of iodine supplementation in pregnancy on neurocognitive development on offspring in iodine deficiency areas: a systematic review

Machamba, Almeida A. L.; Azevedo, Francilene M.; Fracalossi, Karen O.; Franceschini, Sylvia do C. C.

doi:10.20945/2359-3997000000376

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Review • Arch. Endocrinol. Metab. 65 (3) • May-Jun 2021 • https://doi.org/10.20945/2359-3997000000376 linkcopy

Effect of iodine supplementation in pregnancy on neurocognitive development on offspring in iodine deficiency areas: a systematic review

Authorship SCIMAGO INSTITUTIONS RANKINGS

Objective: To investigate the effect of iodine supplementation during gestation on the neurocognitive development of children in areas where iodine deficiency is common.

Materials and methods: Based on the PRISMA methodology, we conducted the search for articles in the PubMed, LILACS and Scopus databases, between March and April 2020, without limitation of dates. We used descriptors in English, Portuguese, and Spanish, without filters. Four clinical trials and four cohort articles were included in the review.

Results: The maximum supplementation was 300 μg of potassium iodide per day. The Bayley scale and Children’s Communication Checklist-Short were used to assess neurodevelopment in children. There was no significant improvement in the children’s mental development index and behavioural development index in the supplemented group; however, the psychomotor development index (PDI) showed improvement in the poorer gross motor skills. We found differences in the response time to sound in the supplemented group living in mild deficiency areas.

Conclusion: Daily supplementation with iodine can improve poor psychomotor development of children living in mild to moderate iodine deficiency areas. Thus, it is necessary to perform further studies to assess the effect of supplementation on neurodevelopment before, during and after gestation in mild to moderate iodine deficiency areas.

Keywords
Potassium iodide; cognition; child; pregnant woman

Author/Year	Methodology			Main results
Author/Year	Children by type of mother’s supplementation	Study design	Skills assessed	Main results
Murcia et al., 2011 (²⁷)	Spain <100 μg/day of KI (n = 169) 100-149 μg/day (n = 298) ≥150 μg/day (n = 222) Maternal MUIC: NA	Study: Cohort CA: 11-16 months GA: < 12th weeks NA	Bayley Scales 1^st ed. (¹⁶)	Mild iodine deficiency areas
			Mental development	↑ in the KI group (≥150 μg), compared to the KI group (<100 and between 100-149 μg)
			Psychomotor development	↑ in the KI group (≥150 μg), compared to the KI group (<100 and between 100-149 μg) ↓ 5,2 scores and ↑ 1,8 odds of a PDI < 85 in the KI group (≥150 μg/day).*
Rebagliato et al., 2013 (²⁹)	Spain <100 μg/day of KI 100–149 μg/day ≥150 μg/day Maternal UIC in both group: 102 (71-169) µg/L	Study: Cohort CA: 12-30 months GA: NA	Bayley Scales 1^st ed. (¹⁶)	Mild iodine deficiency areas
			Mental development	↑ odds in the KI group (≥150 μg), compared to KI groups (<100 and 100-149 μg) ↓ score in KI group (≥150 μg).
			Psychomotor development	↑ odds in the KI group (≥150 μg), compared to KI groups (<100 and 100-149μg) ↓ score in KI group (≥150 μg).
Markhus et al., 2018 (²⁵)	Norway 175 µg/day of KI (n = 155) Placebo (n = 658) 851 pregnant women Maternal UIC: 92 (56-200) µg/L in supplemented group, 77 (50-120) µg/L in control.	Study: Cohort CA: 6 and 18 months GA: 16-26th week	Bayley Scales 3^rd ed. (¹⁸)	Mild iodine deficiency areas
			Mental development	↑ in the treated group compared to the placebo group
			Psychomotor Development	↑ in the treated group compared to the placebo group
			Behavior	↓ in the treated group compared to the placebo group
			Verbal IQ (WPPSI – III)	↑ in the treated group compared to the placebo group
Abel et al., 2019 (²⁸)	Oslo, Norway 175 µg/day of KI (n = 14,665) Placebo (n = 24,806) 39,471 pregnant women Maternal UIC: 83 (43-138) µg/L L in supplemented group, 59 (32-101) µg/L in control	Study: Cohort CA: 36 and 96 months GA: 1-22th week	CCC-S and CCC-2 (²⁰,²¹)	Mild iodine deficiency areas
			Language skillsa	↑ in the treated group compared to the placebo group
			Reading skillsa	↓ in the treated group compared to the placebo group
			Writing skillsa	↓ in the treated group compared to the placebo group*
			Mapping test Readingb	↓ in the treated group compared to the placebo group*
			Mapping test mathematicsb	↓ in the treated group compared to the placebo group*
			Special educationb	↓ in the treated group compared to the placebo group*
Velasco et al., 2009 (²⁴)	Spain 300 µg/day of KI (n = 133) Placebo (n = 61) Maternal MUIC: 263.0 ± 120.8 µg/L in supplementation, in control: 87.6 ± 62.1 µg/L	Study: Non-randomized controlled trial CA: 3-18 months GA: 8^th to 12th week until lactation	Bayley Scales 2^nd ed. (¹⁷)	Mild to Moderate iodine deficiency areas
			Mental development	↑ in the treated group, compared to the control group.
			Psychomotor Development	↑ in the treated group, compared to the control group.*
			Behavior	↑ in the treated group, compared to the control group.*
Santiago et al., 2013 (²⁶)	Spain Iodized salt (n = 38) 200 µg of KI (n = 55) 300 µg (n = 38) Maternal MUIC: NA	Study: Randomized controlled trial	Bayley Scales 3^rd ed. (¹⁸)	Mild iodine deficiency areas
		Study: Randomized controlled trial	Mental development	↑ in the control group, compared to the KI group (200 μg), compared to 300
		CA: 6-18 months GA: 10th week	Psychomotor Development	↑ in the control group, compared to the KI group (200 μg), compared to 300
Zhou et al, 2015 (³¹)	New Zealand and Australia 150 μg/day KI (n = 27) Placebo (n = 26) Maternal MUIC: 200 µg/L in supplementation and 150 µg/L in control	Study: Randomized controlled trial CA: 18 months GA: 20th week	Bayley Scales 3^rd ed. (¹⁸)	Mild to Moderate iodine deficiency areas
			Mental development	↑ in the placebo group, compared to the treated group.
			Psychomotor Development	↑ in the placebo group, compared to the treated group.
			Behavior	↑ in the placebo group, compared to the treated group.
Gowachirapant et al., 2017 (³⁰)	Thailand and India 200 µg/day of KI (n = 303) Placebo (n = 312) 832 pregnant women (T0) Maternal MUIC: NA	Study: Randomized controlled trial CA: 12 and 24 months GA: 14th week CA: 60 and 72 months GA: 14th week	Bayley Scales 3^rd ed. (¹⁸)	Mild iodine deficiency areas
			Mental development	↑ in the placebo group, compared to the treated group*
			Psychomotor Development	↔ between groups
			Behavior	↔ between groups
			Sound response time (T).	↑ in the treated group compared to the placebo group*
			Verbal IQ (WPPSI – III)	↑ in the treated group compared to the placebo group
			IQ performance (WPPSI – III)	↑ in the treated group compared to the placebo group
			IQ reasoning (WPPSI – III)	↑ in the treated group compared to the placebo group

Reference	Reason for exclusion
A review of the iodine status of UK pregnant women and its implications for the offspring	Is revision
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Can multi-micronutrient food fortification improve the micronutrient status, growth, health, and cognition of schoolchildren? A systematic review	Is revision
Consequences of iodine deficiency and excess in pregnant women: an overview of current knowns and unknowns	Not iodine
Dietary micronutrients are associated with higher cognitive function gains among primary school children in rural Kenya	Not iodine
Does prenatal micronutrient supplementation improve children’s mental development? A systematic review	Is revision
Driving Policy Change to Improve Micronutrient Status in Women of Reproductive Age and Children in Southeast Asia: The SMILING Project.	Is revision
Effect of iron-, iodine-, and β-carotene-fortified biscuits on the micronutrient status of primary school children: A randomized controlled trial	Not pregnant
Effect of micronutrient supplement on health and nutritional status of schoolchildren: Study design	Not pregnant
Effects of iodine supplementation during pregnancy on child growth and development at school age	Supplementation in child
Effects of maternal iodine nutrition and thyroid status on cognitive development in offspring: A pilot study	Not supplementation
Effects of nutrients (in food) on the structure and function of the nervous system: Update on dietary requirements for brain. Part 1: Micronutrients	Not iodine
Effects of nutritional interventions during pregnancy on infant and child cognitive outcomes: A systematic review and meta-analysis	Is revision
Feeding the brain – The effects of micronutrient interventions on cognitive performance among school-aged children: A systematic review of randomized controlled trials	Is revision
Food ingredients and cognitive performance	Not iodine
Growth, development and differentiation: A functional food science approach	Not iodine
Hypothyroxinemia and pregnancy	Not child neurodevelopment
Impact of iodine supplementation in mild-to-moderate iodine deficiency: Systematic review and meta-analysis	Is revision
Iodine as essential nutrient during the first 1000 days of life	Not pregnant
Iodine deficiency and iodine prophylaxis in pregnancy	Is revision
Iodine deficiency in pregnancy and the effects of maternal iodine supplementation on the offspring: a review.,	Is revision
Iodine deficiency in pregnancy, infancy and childhood and its consequences for brain development,	Is revision
Iodine fortification of foods and condiments, other than salt, for preventing iodine deficiency disorders.	Not supplementation
Iodine intake from supplements and diet during pregnancy and child cognitive and motor development: The INMA Mother and Child Cohort Study.	Not intervention
Iodine Nutrition During Pregnancy: Past, Present, and Future.	Is revision
Iodine nutrition in pregnancy and lactation.	Is revision
Iodine plus n-3 fatty acid supplementation augments rescue of postnatal neuronal abnormalities in iodine-deficient rat cerebellum,	Not human
Iodine supplementation improves cognition in iodine-deficient schoolchildren in Albania: A randomized, controlled, double-blind study	Supplementation in child
Iodine supplementation improves cognition in mildly iodine-deficient children	Supplementation in child
Iodine supplementation in pregnancy and its effect on child cognition	Not child neurodevelopment
Iodine: it’s important in patients that require parenteral nutrition.	Not supplementation
Iron deficiency and cognitive functions	Not iodine
Malnutrition, brain development, learning, and behavior,	Not iodine
Maternal iodine status is associated with offspring language skills in infancy and toddlerhood.	Not iodine
Micronutrient adequacy and morbidity: Paucity of information in children with cerebral palsy.	Not iodine
Micronutrient interventions on cognitive performance of children aged 5-15 years in developing countries.	Is revision
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Neurocognitive outcomes of children secondary to mild iodine deficiency in pregnant women,	Not child neurodevelopment
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Nutrition and brain development in early life,	Not iodine
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Nutrition and neurodevelopment in children: Focus on NUTRIMENTHE project,	Not iodine
Nutritional deficiencies and later behavioral development,	Not supplementation
Overall child development: Beyond pharmacological iodine supplementation	Is revision
Prevention and control of iron deficiency anemia amongst young children,	Not iodine
Promoting early child development with interventions in health and nutrition: A systematic review	Is revision
Role of iodine-containing multivitamins during pregnancy for children and brain function: protocol of an ongoing Randomized controlled trial: the SWIDDICH study.,	Not child neurodevelopment
Suggested use of sensitive measures of memory to detect functional effects of maternal iodine supplementation on hippocampal development,	Not in human
Summary of the public affairs committee symposium at the teratology society 2011 annual meeting: The thyroid and iodine: Impacts on pregnancy and child health	Not article
Systemic endocrinopathies (thyroid conditions and diabetes): impact on postnatal life of the offspring.	Not supplementation
Teratology public affairs committee position paper: Iodine deficiency in pregnancy	Not supplementation
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The Assessment of Cognitive Performance in Children: Considerations for Detecting Nutritional Influences,	Not iodine
The Effect of Intermittent Antenatal Iron Supplementation on Maternal and Infant Outcomes in Rural Viet Nam: A Cluster Randomized Trial	Not iodine
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Mild-to-moderate gestational iodine deficiency processing disorder”,2019	Review
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WITHDRAWN: Iodine supplementation for preventing iodine deficiency disorders in children. Nov. 2018	Review
	62

Author/ Year	Dosage	Supplementation interval	Form of supplementation
Velasco et al., 2009²⁴	300 µg/day of iodine	≤13^th week of pregnancy to lactation	Potassium iodide (KI)
Murcia et al., 2011²⁷	<100 µg/day	≤13^th week of pregnancy to delivery	Different supplementary sources of iodine
	100–149 µg/day
	≥150 µg/day
Santiago et al., 2013²⁶	200 µg/day	≤10^th week of pregnancy to delivery	KI
Santiago et al., 2013²⁶	300 µg/day	≤10^th week of pregnancy to delivery	KI
Rebagliato et al., 2013²⁹	<100 μg/day of KI	≤13^th week of pregnancy to delivery	KI or vitamin/mineral preparations containing iodine
	100– 149 μg/day
	≥150 μg/day
Zhou et al., 2015³¹	150 μg/day	≤20^th week of pregnancy to delivery	KI
Gowachirapant et al., 2017³⁰	200 µg/day	≤14^th week of pregnancy to delivery	KI
Markhus et al., 2018²⁵	150 – 200 µg/day	≤26^th week of pregnancy to delivery	Different supplementary sources of iodine
Abel et al., 2019²⁸	NA	Week 0-26 before pregnancy	Different supplementary sources of iodine
		GW: 0–12
		GW: 12–22

Trial	Iodine Status of region	Mental development (MDI)	Psychomotor development (PDI)	Behaviour development (BDI)	Sound response time (T).	Verbal IQ (WPPSI – III)	IQ performance (WPPSI – III)	IQ reasoning (WPPSI – III)
Velasco et al., 2009(²⁴)	Maternal MUIC during pregnancy (last third trimester): MUIC 263.0 ±120.8 µg/L iodine (n=133) > control 87.6 ± 62.1 µg/L (n=31, Iodine in breast milk: within 3.6 ± 2.9 months of lactation, intake 1.8 ± 1.2 µg/100 mL, in 300 µg/day of supplemented group (n = 67), vs. 1.4 ± 0.6 µg/100 mL, without supplement in control group (n=21). Infant MUIC: 203.5 ± 150.6 µg/L iodine, in 300 µg/day supplemented group (n= 75) > control 114.6 ± 60.9 µg/L iodine (n= 30) Southern of Spain (Malaga and Osuna in Andaluzia state) is areas of mild to moderate iodine deficiency and iodine deficiency in pregnant	Infant: NA	Maternal intake of 300 µg/day, that were breastfeeding compared with without group (n= 19) associated with a 6.1+0,9 point high in PDI with control. High PDI in child was associated also with lower FT4 in third trimester of pregnancy in mother in supplemented group (r: 0.50; P <0.0001).	Mother intake 300 µg/day of iodine in supplements as compared with the control group was seems more in agreement with for the following items: To reaction to the mother, Odds reaction: 4.3 (CI 95%; 1.69 –10.86, P <0.05), Cooperation, Odds reaction: 17.29 (CI 95%; 2.00 –148.86) 0.009 22.45, P<0.008), activity, Odds reaction: 8.55 (CI 95%; 1.64–44.44, P<0.01), and producing sounds by banging, Odds reaction: 9.00 (CI 95%; 2.66 –30.44) (P <0.001).	NA	NA	NA	NA
Murcia et al., 2011 (²⁷)	Maternal MUIC during pregnancy: NA. Infant MUIC.: NA Valencia, is north of Spain,there does not know of iodine situation. But recently evidence (INNA Project) showed an increased risk of raised thyroid stimulating hormone (TSH) during the first half of pregnancy for women who consumed iodine supplements, because in some years ago there were iodine deficiency	Infant: NA	Maternal intake of ≥150 mcg/day, compared with <100 mcg/day, of iodine from supplements was associated with a 5.2- point decrease in PDI (95% confidence interval: -8.1, -2.2) and a 1.8-fold increase in the odds of a PDI <85 (95% confidence interval: 1.0, 3.3)	NA	NA	NA	NA	NA
Santiago et al., 2013 (²⁶)	Maternal MUIC during pregnancy: NA MUIC least 1 year before becoming pregnancy: 177.1 + 82.3 µg/L in 200 µg group (n=55) and 222.0 +85.5 µg/L in 300 µg/L in supplemented group (n=38), with control 130.2 + 64.8 µg/L (n=38) Iodine in breast milk: Not diff. in groups but all is >100 µg/L: in treatment groups is high intake: 2.4·+1.2 µg/100ml in 200 µg group, 2.2+1.5 µg/100ml in 300 µg group, that in control group: 1.4+0.9µg/100ml Infant MUIC: NA Objective of this study was assessment iodine intake and their consequences in health in area with iodine deficiency	Maternal supplementation with 200 or 300 µg/day was related with lower PDI than the iodized salt group (NA). The results showed that the age at which this psychometric test was performed correlated significantly with a scales MDS (r 0·93,P,0·001) and the PDS (r 0·90, P,0·0001), but not with indices (MDI and DPI). The showing a age to be important factor of measured its testes.		NA	NA	NA	NA	NA
Rebagliato et al., 2013 (²⁹)	Maternal MUIC during pregnancy: Median in three municipality of Valencia, in both groups is Asturias 102 (71–169) µg/L (n = 412) Gipuzkoa 169 (108–284) µg/L (n = 548) Sabadell 90 (52–148) µg/L (n = 559) Infant MUIC: NA In Asturias and Gipuzkoa is iodine sufficiency areas and Sabadell is several. But the supplementation iodine program is implemented in both because the author wanted to see effect of neurodevelopment on infant in sufficiency and deficiency iodine consumer.	A negative association of iodine supplementation with low development. No difference with groups, site of study and user of iodized salt or supplement. But consumption during pregnancy of 150 μg/day or more of iodine was related to a decrease in Psychomotor development score, although only significantly so in Asturias less than 85 (OR = 1.7, 95% CI: 1.1, 2.6).		NA	NA	NA	NA	NA
Zhou et al., 2015 (³¹)	Maternal MUIC during pregnancy 3rd trimester: 200 µg/L in supplemented group > (n=27), with 150 µg/L (n=26) in control Iodine in breast milk: 6 weeks after birth was 1.1 (0.8–1.5) μg/100ml in both groups. 150 µg/day of KI (n=29) for supplemented group, with without iodine supplements in control (n=30) Infant MUIC: NA Australia and New Zeland are moderate iodine deficiency areas.	Infant: NA	Infant: NA	Infant: NA	NA	NA	NA	NA
Gowachirapan et al., 2017 (³⁰)	Maternal MUIC during pregnancy: NA 200 µg/day of KI group (n=303) Placebo (n=312) Infant MUIC: NA In INNA Study, the authors found in a sample of women from the Valencia region, an iodine-sufficient areas, that maternal consumption of multivitamins containing iodine was related to lower psychomotor achievement of their infants at 1 year of age.	All the scores in the primary outcomes were higher in mean in the placebo than in the intervention group (not significant).			Infant: no diff iodine vs. control (n=unclear, means not presented)	Infant: A negative association of iodine supplementation with expressive language (BSID) at 1 year in the first one	Infant: NA	Infant: no congenital goitre was found in either group
Markhus, M. W., 2018 (²⁵)	Maternal MUIC during pregnancy 1^st trimester: Median 92 (56,200) µg/L in supplemented group (n=658) > and 77 (50,120) µg/L in control (n=155). In total: 79% of women had a MUIC < 150 µg/L and 28% < 50 µg/L. 175 µg/day of KI (n=155) for supplemented group, with without iodine supplements in control (n=658). Infant MUIC: NA	Infant: NA	Supplementation with 150 µg/day was associated with poorer gross motor skills, standardized beta = - 0.18 (95% CI = -0.33, - 0.03, p = 0.02).	NA	NA	Infant: NA But women having a low MUIC in pregnancy (50> but <100 µg/L) was significantly associated with poorer skills in language domains (receptive and expressive) in infancy and toddlerhood.	NA	NA
Abel M.H. al., 2018 (²⁸)	Maternal MUIC during pregnancy 1st and 2nd trimester: Median 83 (43, 138) µg/L in supplemented group (n= 14,665) > and 59 (32, 101) µg/L in control (n= 24,806). 175 µg/day of KI (n=14,665) for supplemented group, with without iodine supplements in control (n=24,806). Infant MUIC: NA	NA The results are consistent in demonstrating no beneficial effects of iodine supplement use in pregnancy. Not have any associations between maternal use of iodine-containing supplements and child outcomes. But in sample, 6.9% of the 8year old were granted special education at school. According to the mother, 28% had suboptimal or low score on the mandatory mapping test in school in reading, and 18% had suboptimal or low score in mathematics.			NA	NA But in control: Materna iodine intake was associated with child language skills at age 3 years. children with mild to moderate language delay at 3 years (3.1%) scored on average 1.2 SD higher on the language score (CCC-S) at 8 years (95% CI 1.1, 1.3), and those with severe language delay at 3 years (0.7%) scored 2.8 SD higher (95% CI 2.3, 3.2). Higher scores at 8 years indicated poorer language skills.	NA	NA

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[TFN1] MUIC: median urinary iodine concentration; NA: not available; GA: gestational age at the beginning of supplementation; Ed.: edition; KI: potassium iodide; n: sample number; T0: initial time; PDI: Psychomotor Development Index; T.: test; WPPSI-III: 3rd ed Primary Intelligence Scale; IQ: intelligence quotient; CA: Child’s age in the test application; NA: not applicable;

[TFN2] ^a
standardized beta;

[TFN3] ^b
odds ratio.

[TFN4] ^*
Results with statistical significance.

[TFN4a] ^↑
increased;

[TFN4b] ^↓
reduced;

[TFN4c] ^↔
no difference.