Table 2.

Observational studies investigating the effect of maternal thyroid dysfunction during pregnancy on child psychopathology.

	First author (year)	Design and Subjects	Thyroid Function			Psychopathology		Results
			Biomarkers	Dysfunction	GA at assessment	Assessment	Age at assessment
Maternal hypothyroidism (subclinical or overt)	Andersen (2014b)	Retrospective; N = 542 100, all live-born singletons born between 1980 and 1990 in Denmark	-	Hospitaldiagnosed or treated hypothyroidism before 1996 (N = 3979) (information obtained from DNHR and DNPR)	-	Prescription of anxiolytics, antipsychotics, and antidepressants at least twice (information obtained from DNPR)	15- 31 years	Maternal hypothyroidism was associated with an increased risk of prescription of anxiolytics and antipsychotics (adjusted hazard ratio (aHR) 1.23 and 1.22 respectively).
	Päkkilä (2014)	Longitudinal; N = 5131 mother child-pairs (Northern Finland Birth Cohort 1986)	TSH, fT4, TPO-Ab	TSH > 3.1 mU/l (first trimester) or TSH > 3.5 mU/l	Mean (SD) = 10.7 (2.8) weeks GA	Rutter B2 scale (teacher-rated); combined ADHD symptoms defined as total Rutter B2 scores of ≥9 and 3 or more points from ADHD questions	8 years	In general, there were no significant differences in the odds of ADHD symptoms in children born to mothers with high and normal serum TSH, but girls had a 1.4-fold odds of combined ADHD symptoms with every natural log increase in maternal TSH.
Maternal hypothyroxinemia	Modesto (2015)	Longitudinal; N = 3873 mother-child pairs (Generation R cohort)	TSH, fT4, TPO-Ab	fT4 < 5th percentile and TSH < 2.5 mU/l (n = 127)	Mean (SD) = 13.6 (1.9) weeks GA	CPRS-R:S	Mean (SD) = 8.1 (0.2) years	Children of hypothyroxinemic women had higher scores on the ADHD index (7% increase) but not on the Oppositional scale compared to nonexposed children.
	Roman (2013)	Longitudinal; N = 4039 mother-child pairs (Generation R cohort)	TSH, fT4, TPO-Ab	fT4 < 10th percentile and TSH < 2.5 mU/l (n =295)/ fT4 < 5th percentile and TSH < 2.5 mU/l (n = 136)	Mean (SD) = 13. 4 (1.9) weeks GA	PDP subscale of the CBCL 1½ -5, SRS; probable autism defined by a PDP score > 98th per- centile and SRS score in the top 5% of the sample (n = 81)	6 years	Severe maternal hypothyroxinemia (fT4 < 5th percentile) was associated with an increased risk of having a probable autistic child (adjusted Odds Ratio (aOR) = 3.89) and with higher scores on the PDP and SRS
	Vermiglio (2004)	Longitudinal; N = 27 mother- child 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	fT4 < 2.5th percentile and TSH < 4 mU/l	5-10 weeks GA, 11-14 weeks GA, and 18-20 weeks GA	ADHD (diagnosis based on DSM-IV)	18-36 months and 8-10 years	Maternal hypothyroxinemia occurred in eight (50%) of the women from area A and only transiently in one woman from area B; seven of the eight hypothyroxinemic mothers from area A had children diagnosed with ADHD; 11 of the 16 children from area A were diagnosed with ADHD whereas none from area B were affected.
Maternal thyroid autoimmunity	Ghassabian (2012)	Longitudinal; N = 3139 mother-child pairs (Generation R cohort)	TSH, fT4, TPO-Ab	TPO-Ab > 100 mU/l (n = 147)	Mean (SD) = 13.5 (1.8) weeks GA	CBCL 1½ -5	Mean (SD) = 34 (1) months	Elevated titers of TPOAbs in mothers were associated with externalizing problems in children (OR = 1.64), in particular with ADHD problems (OR = 1.77); maternal TSH was also associated with children’s externalizing problems (B = 0.18 per SD of TSH).
Maternal iodine deficiency	Van Mil (2012)	Longitudinal; N = 1156 mother-child pairs (Generation R cohort)	Urinary iodine	Iodine:creatinine ratio < 10th percentile (48.6– 136.1 mg/g creatinine, n = 117)	Median (range) = 13.2 (10.2 – 17.6) weeks GA	BRIEF-P	4 years	Low maternal urinary iodine was associated with deficits in inhibition, working memory and global executive functioning in the children.
Multiple or undefined thyroid dysfunction	Andersen (2014a)	Retrospective; N = 857 014, all live-born singletons born between 1991 and 2004 in Denmark	-	Hospital- diagnosed or treated hypothyroidism (N = 18 011) (information obtained from DNHR and DNPR)	-	Diagnosis of ADHD or ASD (information obtained from DNHR and DPCR)	3 years onwards	Maternal hypothyroidism diagnosed and treated after the birth of the child increased the risk of ASD (aHR 1.34); paternal thyroid dysfunction was not associated with an increased risk for any of these disorders.
	Ghassabian (2011)	Longitudinal; N = 3736 mother-child pairs (Generation R cohort)	TSH, fT4, T4	-	Mean (SD) = 13.3 (1.7) weeks GA	CBCL 1½ -5	1 ½ and 3 years	Maternal TSH levels were positively associated with combined externalizing scores at 1 ½ and 3 years (B = 0.22 per SD of TSH), particularly on attention deficit/hyperactivity (B = 0.08 per SD of TSH) and oppositional defiant subscales (B = 0.08 per SD of TSH); T4 and fT4 were not associated with an increased risk for behavioral problems.
	Yau (2014)	Retrospective; N = 272 children born in Orange County, CA between 2000 and 2001	TSH	-	15-19 weeks GA	Diagnosis of ASD (n = 78, information obtained from medical records) or developmental delay (n = 45, defined as Mullen Scales of Early Learning and Vineland Adaptive Behavior Scales composite score <70)	3 – 4 years	Maternal mid-pregnancy TSH levels were inversely associated with ASD risk in the child (aOR = 0.33) as well as risk of developmental delay (aOR = 0.09).

Abbreviations. ADHD = Attention Deficit/ Hyperactivity Disorder, ASD = Autism Spectrum Disorders, BRIEF-P = Behavior Rating Inventory of Executive Function for Preschoolers, CBCL 1 ½ -5 = Child Behavior Checklist for Toddlers, CPRS-R:S = Conners’ Parent Rating Scale– Revised Short Form, DNHR = Danish National Hospital Register, DNPR = Danish National Prescription Registry, DPCR = Danish Psychiatric Central Register, DSM-IV = Diagnostic and Statistical Manual of Mental Disorders- Version IV, PDP = Pervasive Developmental Problems, SRS = Social Responsiveness Scale.