Table 1.

Observational studies investigating the effect of maternal thyroid dysfunction during pregnancy on child neurocognitive and psychomotor outcomes.

	First author (year)	Design and Subjects	Thyroid Function			Neurobehavioral Outcome		Results
	First author (year)	Design and Subjects	Biomarkers	Dysfunction	GA at assessment	Test	Age at assessment
*Maternal* *hypothyroxinemia*	Craig (2012)	Longitudinal; N = 198 mother- child pairs	TSH, fT4	fT4 < 3^rd percentile and TSH < 3.5 mU/l (n = 99)	2^nd trimester	Bayley Scales of Infant Development (MDI and PDI)	2 years	Children of hypothyroxinemic mothers did not have significantly lower scores on any of the Bayley subscales.
	Finken (2013)	Longitudinal; N = 1765 mother-child pairs (ABCD cohort)	TSH, fT4	fT4 < 10^th percentile (n = 175)	Median (range) = 90 (83 - 100) days (12.9 weeks GA)	Amsterdam Neuropsychological Tasks (ANT)	Mean (SD) = 5.7 (0.5)	Maternal hypothyroxinemia was associated with reduced performance in the baseline speed reaction time task (41.3 ms slower) but not in other tasks; children exposed to maternal hypothyroidism, i.e. fT4 < 10th percentile and TSH > 90th percentile (n = 44) had a 71.3 ms slower response speed.
	Ghassabian (2014a)	Longitudinal; N = 3727 mother-child pairs (Generation R cohort)	TSH, fT4, TPO-Ab	fT4 < 5^th percentile and TSH < 2.5 mU/L (n = 129)	Mean (SD) = 13.5 (2.0) weeks GA	SON-R 2 ½ - 7 (non- verbal intelligence)	Mean (SD) = 6.2 (0.5) years	Children of mothers with hypothyroxinemia had an IQ 4.3 points lower than controls.
	Henrichs (2010)	Longitudinal; N = 3659 mother-child pairs (Generation R cohort)	TSH, fT4	fT4 < 10^th percentile and TSH < 1 SD above the gestational age- specific mean (mild hypothyroxi- nemia, n = 311)/ fT4 < 5^th percentile and TSH < 1 SD above the gestational age- specific mean (severe hypothyroxinemia, n = 157)	Mean (SD) = 13.3 (1.7) weeks GA	MCDI (verbal development); LDS (verbal development); PARCA (nonverbal cognitive development)	18 months (MCDI) and 30 months (LDS, PARCA)	Both mild and severe maternal hypothyroxinemia were associated with a higher risk of expressive language delay across all ages (OR 1.4 and 1.8 respectively); severe hypothyroxinemia was also associated with a higher risk of nonverbal cognitive delay (OR 2.0); continuous fT4 levels were negatively associated with language delay at 30 months.
	Julvez (2012)	Longitudinal; N = 1761 mother-child pairs	TSH, fT4	fT4 < 10^th percentile/ fT4 < 5^th percentile/ fT4 < 2.5^th percentile	Median (range) = 13 (8 – 20) weeks GA	Bayley Scales of Infant Development (MDI and PDI)	Median (range) 14 (11 – 23) months	Children of mothers with fT4 < 5^th percentile had significantly lower MDI scores (3.4 points); self- reported pre-pregnancy thyroid disorder without medical treatment was also associated with lower MDI scores (5.5 points).
	Kooistra (2006)	Longitudinal; N = 204 mother- child pairs	TSH, fT4	fT4 < 10^th percentile at 12 weeks GA, TSH not elevated (n = 108)	12, 24 and 32 weeks GA	Neonatal Behavioral Assessment Scale	3 weeks	Infants of women with hypothyroxinemia at 12 weeks gestation had significantly lower scores on the orientation index compared with controls but not on other subscales; maternal TSH and fT4 later in pregnancy were not significant predictors of newborn performance.
	Pop (1999)	Longitudinal; N = 220 mother- child pairs	TSH, fT4, TPO-Ab	fT4 < 10^th percentile at 12 weeks/ fT4 < 5^th percentile	12 and 32 weeks GA	Bayley Scales of Infant Development (MDI and PDI)	10 months	Children of women with fT4 < 5^th and fT4 < 10^th percentile had significantly lower PDI scores (14.1 and 7.4 points respectively); levels at 32 weeks were not associated with MDI or PDI; continuous fT4 was positively correlated with PDI scores.
	Pop (2003)	Longitudinal; N = 125 mother- child pairs	TSH, fT4	fT4 < 10^th percentile and TSH < 2 mU/l at 12 weeks GA (n = 63)	12, 24 and 32 weeks GA	Bayley Scales of Infant Development (MDI and PDI)	1 and 2 years	Children of hypothyroxinemic women at 12 weeks GA had significantly lower PDI and MDI scores at both 1 and 2 years of age (all between 8 and 10 points lower); children of mothers whose fT4 levels decreased further over pregnancy had the lowest scores; continuous fT4 levels at 12 weeks GA were positively associated with PDI and MDI scores.
	Suarez-Rodriguez (2012)	Longitudinal; N = 70 mother- child pairs	TSH, fT4	fT4 < 10^th percentile and TSH < 5 mU/l (n = 37)	37 weeks GA	McCarthy Scales of Children’s Abilities	38 – 60 months	Children of hypothyroxinemic mothers had a significantly lower score on the general cognitive index (6.1 points) and on perceptual-manipulative and memory subscales.
*Maternal* *hypothyroidism* *(subclinical or* *overt)*	Haddow (1999)	Longitudinal; N = 186 mother- child pairs	TSH, T4, fT4, TPO-Ab	TSH > 98^th percentile, partly treated (n = 62)	2^nd trimester	WISC; Test of Language Development; PIAT-R (reading recognition and comprehension); Conners’ Continuous Performance Test (sustained vigilance, attention); Developmental Test of Visual-Motor Integration (visual perception, fine motor skills); grooved pegboard test (visual–motor coordination)	7 – 9 years	Children from hypothyroid mothers performed less well on all tests, but only Conners’ Continuous Performance Test and the word discrimination subscale of the Test of Language Development reached significance; children from mothers whose hypothyroidism was untreated showed significantly lower performance on most tests, specifically their mean IQ score on the WISC was 7 points lower, and 19 % had an IQ score of 85 or lower as compared to 5% of the control children.
	Klein (2001)	Longitudinal; N = 172 mother- child pairs	TSH, T4, fT4, TPO-Ab	TSH ≥ 99.85^th percentile (group 3, n = 20), and TSH >98^th and <99.85^th percentile (group 2, n = 28)	Mean = 17 weeks GA	WISC	Mean (SD) = 8 (0.5) years	Children from mothers with the highest TSH concentrations had significantly lower IQ scores than controls (mean (SD) 107 (13) vs. 97 (14)) and a significantly higher incidence of IQs of 1 SD or more below the control mean (adjusted OR 4.7); children of mothers with TSH >98^th and < 99.85^th percentile had intermediate scores but did not differ significantly from the other two groups; continuous measures of TSH showed a significant negative association with IQ score.
	Murcia (2011)	Longitudinal; N = 691 mother- child pairs	TSH, urinary iodine	TSH > 4 mU/l (n = 24)	Mean (SD) = 12.4 (0.66) weeks GA	Bayley Scales of Infant Development (MDI and PDI)	11 – 16 months	Children of mothers with TSH > 4 mU/l had an increased risk of a PDI score < 85 (OR 3.5) but not MDI.
*Maternal thyroid* *autoimmunity*	Pop (1995)	Longitudinal; N = 230 mother- child pairs	TSH, fT4, fT3, TPO-Ab	TPO-Ab > 100 U/ml but euthyroid	32 weeks GA	McCarthy Scales of Children’s Abilities	Mean (SD) = 4.8 (0.3) years	Children of euthyroid women with elevated TPO-Ab titers had significantly lower scores on four of the six subscales, in particular on the general cognitive index (10.5 points).
*Maternal iodine* *deficiency*	Bath (2013)	Longitudinal; N = 1040 mother-child pairs (ALSPAC cohort)	Urinary iodine	Urinary iodine < 150 μg/l (n = 646)	Median (range) = 10 (9 – 12) weeks GA	WISC (abbreviated), Neale Analysis of Reading Ability	8 years (WISC) and 9 years (Neale)	Children of mothers with low iodine levels had a significantly higher risk for suboptimum cognitive outcomes (i.e. scores in the bottom quartile) on the subscales verbal IQ, reading accuracy, and reading comprehension; mean total IQ was also significantly lower in these children (3.4 points).
*Maternal iodine* *deficiency*	Ghassabian (2014b)	Longitudinal; N = 1525 mother-child pairs (Generation R cohort)	Urinary iodine	Urinary iodine < 150 μg/g cre- atinine (n = 188)	Mean (SD) = 13.28 (1.85) weeks GA, range 6.07– 17.93 weeks	SON-R 2 ½ - 7 (non- verbal intelligence), receptive subtest of the Taaltest voor Kinderen (language comprehension)	Mean (SD) = 6.0 (0.3) years	After adjustment for possible confounders, there was no relation between maternal low UIC and children’s non-verbal IQ or language comprehension.
*Multiple or* *undefined thyroid* *dysfunction*	Chevrier (2011)	Longitudinal; N = 287 mother- child pairs	TSH, T4, fT4	-	Mean (SD) = 26.9 (3.4) weeks GA	Bayley Scales of Infant Development (MDI and PDI), PLS, WPPSI, McCarthy Scales of Children’s Abilities, Woodcock- Johnson Test of Cognitive Ability, WRAVMA, KCPT, PPVT	6 (Bayley, PLS), 12 (Bayley, PLS), 24 (Bayley), and 60 months (WPPSI, McCarthy, Woodcock- Johnson, WRAVMA, KCPT, PPVT)	Maternal T4 and fT4 levels were not significantly associated with any child outcome; Increasing maternal TSH was related to better performance on the MDI and on the auditory comprehension subscale of the PLS at 12 months.
	Costeira (2011)	Longitudinal; N = 86 mother- child pairs from a mildly iodine- deficient area	TSH, T4, fT4, T3, fT3, urinary iodine	TSH > 90th percentile/ T4, fT4, T3, or fT3 < 10th percentile/ urinary iodine <50 μg/l	12, 24 and 32 weeks gestation	Bayley Scales of Infant Development (MDI and PDI)	12, 18 and 24 months	Low urinary iodine concentrations in the first and third trimester were associated with lower MDI scores at (18 and) 24 months and lower PDI scores at 18 months; fT4 < 10^th percentile in the first trimester was associated with lower PDI scores at 18 and 24 months and with an increased OR of 2.1 for having a child mildly or significantly delayed (PDI < 84).
	Grau (2015)	Longitudinal; N = 455 mother- child pairs (N = 289 at follow- up)	TSH, fT4, fT3, TPO-Ab, urinary iodine	fT4 < 10^th percentile and TSH < 5 mU/l (subgroup 1, n = 47) / fT4 > 10^th percentile, urinary iodine < 150 μg/l or TPO-Ab positive (subgroup 2, n = 369)	End of first and end of second trimester	Brunet-Lezine scale; WISC	Mean (SD) = 1.08 (0.03) years (Brunet-Lezine) and 7.3 (0.25) years (WISC)	Maternal hypothyroxinemia and continuous fT4 was not associated with scores on the Brunet-Lezine scale or the WISC.
	Li (2010)	Longitudinal; N = 213 mother- child pairs	TSH, T4, fT4, TPO-Ab	TSH > 97.5th percentile, T4 and fT4 normal, TPO- Ab negative (subclinical hypothyroidism, n = 18) / T4 < 2.5^th percentile, TSH and fT4 normal, TPO-Ab negative (hypothyroxinemia , n = 19) / TPO-Ab > 50 U/ml, TSH, T4 and fT4 normal (elevated TPO-Ab, n = 34)	16 – 20 weeks GA	Bayley Scales of Infant Development (MDI and PDI)	25 – 30 months	Children of women from all three case groups had significantly lower scores on the MDI (8.9 – 10.5 points) and the PDI (7.5 – 10 points); the three risk factors (increased TSH, decreased T4, elevated TPO-Ab) were independently associated with lower intellectual and motor development.
	Oken (2009)	Longitudinal; N = 500 mother- child pairs	TSH, T4, TPO-Ab	TSH > 2.5 mU/l / TPO-Ab > 2 U/ml	Mean 10.2 weeks GA	VRM, PPVT, WRAVMA	6 months (VRM) and 3 years (PPVT, WRAVMA)	Maternal thyroid function was not associated with child cognitive test scores.
	Pharoah (1984)	Longitudinal; N = 20 mother-child pairs from a severly iodine- deficient area	T4, T3	-	Any time during index pregnancy	PDCT, Pegboard, peg transfer, bead threading	Mean (range) = 11.3 (10.3 – 11.9) years	Maternal T4 was positively associated with test scores on PDCT and the three motor performance tasks (but not T3).
	Vermiglio (2004)	Longitudinal; N = 27 motherchild pairs (n = 16 from a moderately iodine-deficient area A and n = 11 from an iodine-sufficient area B)	TSH, fT4, T4, fT3, T3, TBG, T4/TBG ratio	-	5-10 weeks GA, 11-14 weeks GA, and 18-20 weeks GA	WISC	8-10 years	The children’s IQ score was positively related to maternal FT4 (r = .56) and inversely related to maternal TSH values (r = −.63) at midgestation, when both area A and B were combined.
	Williams (2012)	Longitudinal; N = 143 mothers and their N = 166 children born preterm	TSH, T4, fT4, TPO-Ab, Tg- Ab	-	At delivery	McCarthy Scales of Children’s Abilities	5.5 years	Each mU/l increment of maternal TSH level at delivery was associated with significant decrements in the general cognitive index (3.2 points) and the verbal and perceptual performance subscales; each pmol/l decrease in fT4 was associated with significant increments in the general cognitive index (1.5 points), quantitative subscale and motor scale; maternal T4 levels were not associated with the McCarthy Scales.

Abbreviations. KCPT = Conner’s Kiddie Continuous Performance Test; LDS = Language Development Survey; MCDI = MacArthur Communicative Development Inventory; MDI = Mental Development Index; PARCA = Parent Report of Children’s Abilities; PDCT = Pacific Design Construction Test; PDI = Psychomotor Development Index; PIAT-R = Peabody Individual Achievement Test, revised; PLS = Preschool Language Scale; PPVT = Peabody Picture Vocabulary Test; SON-R 2 ½ - 7 = Snijders-Oomen Niet-verbale intelligentie test, revisie; VRM = Visual Recognition Memory Test; WISC = Wechsler Intelligence Scale for Children; WPPSI = Wechsler Preschool and Primary Scale of Intelligence; WRAVMA = Wide Range Assessment of Visual Motor Ability