The association of maternal diabetes with attention deficit and hyperactivity disorder in offspring: a meta-analysis

Figures & data

Figure 1 Flow diagram of the identification of the eligible studies.

Table 1 Basic information of the included studies

Study	Ethnicity	Study design	Exposed/case	Unexposed/control	Diabetes diagnosis	ADHD diagnosis	Effect size	Confounder adjustment
Bytoft et al, 2017^Citation19	C	A prospective nationwide cohort from Denmark	Adolescents with mothers who had T1D during 1993–1997 (n=269)	Gender, age, and SES matched background individuals (n=293)	GDM, data from Danish Diabetes Association	Self-reported use of ADHD medication	RR: 14.16, 95% CI: 0.80–250.08	No adjustment
Nielsen et al, 2017^Citation12	C	A Danish cohort based on nationwide register systems	Exposed children born in Denmark from 1990 to 2007 (n=190)	All unexposed children born in Denmark from 1990 to 2007 (n=983,490)	T1D, ICD-8 code 249 and ICD-10 code E10	Psychiatric admission or outpatient care for a diagnosis of ADHD (ICD code F90.x+ F98.8)	RR: 1.36, 95% CI: 1.17–1.56	Age, gender, the interaction of gender with age, and parental history of psychiatric admission
Daraki et al, 2017^Citation20	C	A part of prospective pregnancy cohort from Greece	Exposed children had neurodevelopment assessment at 4 years of age from Oct 2011 to Jan 2013 (n=56)	All unexposed children had neurodevelopment assessment at 4 years of age from October 2011 to January 2013 (n=716)	GDM screen between 24 and 28 weeks of gestation according to criteria proposed by ADA (2008)	Standardized child scale	RR: 10.18; 95% CI: 0.22–473.43	Child gender, maternal age, origin, education, parity, smoking and pre-pregnancy BMI
Nomura et al, 2012^Citation10	C	A cohort study from New York	Exposed children at 6 years of age (n=21)	Unexposed children at 6 years of age (n=191)	GDM, face-to-face interview	Semi-structured child psychiatric interview	RR: 2.20; 95% CI: 1.00–4.82	No adjustment
Li et al, 2014^Citation11	A	A hospital-based cohort study from China	Children exposed to maternal diabetes and hypertension (n=302)	Children unexposed to maternal diabetes and hypertension (n=668)	GDM, blood and oral glucose tolerance test	Standardized child scale	RR: 1.86; 95% CI: 1.27–2.73	No adjustment
Ji et al, 2018^Citation13	C	A retrospective cohort study based on Swedish register system	Exposed children born in Denmark from 1970 to 2012 (n=15,615)	Matched control subjects (n=1,380,829)	T1D, ICD-8 code 250, ICD-9 code 250 and ICD-10 code E10	ICD-9 code 314 and ICD-10 code F90	HR: 1.35; 95% CI: 1.18–1.55	Year of birth, gender, parental history of ADHD, education, income, small for gestational age, maternal smoking, and low Apgar score
Schmitt and Romanos 2012^Citation21	C	A case control study based on German nationwide survey	Children with ADHD (n=660)	Children without ADHD (n=12,828)	Self-reported physician diagnosed GDM	Medical or psychological exam reported in standardized interview	OR: 1.91; 95% CI: 1.21–3.01	Age, gender, SES, maternal smoking, breastfeeding, atopic eczema, and perinatal health problems
Hegvik et al, 2018^Citation14	C	A cross-sectional study based on a Norwegian cohort	Children with ADHD during 2004–2015 (n=63,721)	All remaining individuals (n=2,436,397)	T1D, ICD-10 code E10 or ICPC T89	ADHD medication	OR: 1.00; 95% CI: 0.84–1.20	Age and maternal education
Instanes et al, 2017^Citation8	C	A population-based nested case-control study based on longitudinal Norwegian registers	Children with ADHD during 2004–2012 (n=47,944)	All remaining individuals (n=2,274,713)	PGDM, data from registry system	ADHD medication	T1D: OR: 1.5; 95% CI: 1.2–1.9; T2D: OR: 1.1; 95% CI: 0.7–1.8	Age, parity, maternal age, education, marital status, ADHD medication, birth weight, and gestation age

Abbreviations: A, Asian; ADA, American Diabetes Association; ADHD, attention deficit hyperactivity disorder; BMI, body mass index; C, Caucasian; GDM, gestational diabetes mellitus; ICD, International Classification of Diseases; ICPC, International Classification of Primary Care; PGDM, pregestational diabetes mellitus; RR, risk ratio; SES, socioeconomic status; T1D, type 1 diabetes; T2D, type 2 diabetes.

Table 2 Quality of the included studies

Study	Selection score	Comparability score	Outcome score	Total score	Quality
Bytoft et al, 2017^Citation19	4	2	3	9	High
Nielsen et al, 2017^Citation12	3	2	3	8	High
Daraki et al, 2017^Citation20	4	2	3	9	High
Nomura et al, 2012^Citation10	4	2	3	9	High
Li et al, 2014^Citation11	3	0	2	5	Moderate
Ji et al, 2018^Citation13	3	2	3	8	High
Schmitt and Romanos, 2012^Citation21	4	2	2	8	High
Hegvik et al, 2018^Citation14	3	2	3	8	High
Instanes et al, 2017^Citation8	4	2	2	8	High

Table 3 Evaluation of overall quality levels using the GRADE approach

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Case	Control	Relative (95% CI)	Absolute
Association between maternal diabetes and ADHD (case-control study)
3	Observational studies	No serious risk of bias	Seriousa	No serious indirectness	No serious imprecision	Very strong associationb	2531/112,325 (2.3%)	5,53/472,393 (0.12%) 1.99%	RR 1.20 (0.96–1.49)	0 more per 1,000 (from 0 fewer to 1 more) 4 more per 1,000 (from 1 fewer to 10 more)	⋆⋆⋆⋆ Moderate	Critical
Association between maternal diabetes and ADHD (cohort study)
6	Observational studies	No serious risk of bias	No serious inconsistency	No serious indirectness	No serious imprecision	Reporting biasc Very strong associationb	2,372/16,453 (14.4%)	1,159/23,661 (4.9%) 0.52%	RR 1.40 (1.27–1.54)	20 more per 1,000 (from 13 more to 26 more) 2 more per 1,000 (from 1 more to 3 more)	⋆⋆⋆⋆ Moderate	Critical
Association between GDM and ADHD (better indicated by lower values)
4	Observational studies	No serious risk of bias	No serious inconsistency	No serious indirectness	No serious imprecision	Reporting biasd Very strong associationb	782	984,642	–	ES 2.00 higher (1.42–2.81 higher)	⋆⋆⋆⋆ Moderate	Important

Notes:

a Significant heterogeneity (I²=76.5%) was observed among the included studies.

b A large sample size was observed among the included studies.

c Publication bias was identified according to Egger’s test (t=6.56, P=0.003).

d Publication bias was identified regarding this analysis.

Abbreviations: ADHD, attention deficit hyperactivity disorder; ES, effect size; GDM, gestational diabetes mellitus; RR, risk ratio.

Figure 2 Main results of the meta-analyses.

Notes: (A) Data combination of case-control studies; (B) sensitivity analysis on case-control studies; (C) data combination of cohort studies; and (D) sensitivity analysis on cohort studies. Weights are from random-effects analysis.
Abbreviations: ES, effect size; GDM, gestational diabetes mellitus; T1D, type 1 diabetes; T2D, type 2 diabetes.

Table 4 Main results of the meta-analyses

Analysis	No of subjects	Statistical model	Data pooling			Heterogeneity		Publication bias		Sensitivity analysis
			Effect size	t-value	P-value	I^2 (%)	P-value	t-value	P-value
Overall OR	4,836,263	Random	1.20 (0.96–1.49)	1.62	0.105	76.5	0.002	1.67	0.194	Stable
Overall RR	2,382,640	Fixed	1.40 (1.27–1.54)	6.89	<0.001	31.8	0.197	6.56	0.003	Stable
GDM RR	985,984	Fixed	2.00 (1.42–2.81)	4.00	<0.001	0.0	0.446	4.99	0.038	Stable
GDM in Caucasian RR	985,014	Fixed	2.64 (1.26–5.56)	2.56	0.011	0.0	0.369	3.30	0.187	Stable

Abbreviations: GDM, gestational diabetes mellitus; RR, risk ratio.

Figure 3 Meta-analyses of the subjects from (A) mothers with GDM or (B) Caucasian mothers with GDM.

Abbreviations: ES, effect size; GDM, gestational diabetes mellitus.

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