BACKGROUND:

Prenatal exposure to metabolic disturbances is associated with increased risk of offspring neurodevelopmental impairment and autism spectrum disorder, while little is known about the joint effect of maternal obesity and diabetes. With this study, we aim to assess the joint effect of maternal obesity and diabetes on the risk for offspring psychiatric and mild neurodevelopmental disorders.

METHODS:

Nationwide registries were used to link data of all live births in Finland between 2004 and 2014 (n = 649 043). Cox proportional hazards modeling adjusting for potential confounders was applied to estimate the effect of maternal obesity, pregestational diabetes mellitus (PGDM), and gestational diabetes mellitus, as well as their joint effects, on the outcomes of offspring psychiatric and mild neurodevelopmental diagnoses and offspring prescription of psychotropic drugs.

RESULTS:

Among mothers without diabetes, severely obese mothers had 67% to 88% increased risk of having a child with mild neurodevelopmental disorders (hazard risk ratio [HR] = 1.69; 95% confidence interval [CI] = 1.54–1.86), attention-deficit/hyperactivity disorder or conduct disorder (HR = 1.88; 95% CI = 1.58–2.23), and psychotic, mood, and stress-related disorders (HR = 1.67; 95% CI = 1.31–2.13) compared with mothers with a normal BMI. PGDM implied a further risk increase for all groups of psychiatric diagnoses with onset in childhood or adolescence in mothers with severe obesity. Marked effects were found particularly for autism spectrum disorder (HR = 6.49; 95% CI = 3.08–13.69), attention-deficit/hyperactivity disorder and conduct disorder (HR = 6.03; 95% CI = 3.23–11.24), and mixed disorders of conduct and emotions (HR = 4.29; 95% CI = 2.14–8.60). Gestational diabetes mellitus did not increase the risk highly for these offspring disorders.

CONCLUSIONS:

Maternal PGDM combined with severe maternal obesity markedly increases the risk of several children’s psychiatric and mild neurodevelopmental disorders.

What’s Known on This Subject:

Prenatal exposure to metabolic disturbances was associated with offspring neurodevelopmental impairment and autism spectrum disorder. No study has examined the joint effects of maternal prepregnancy obesity and diabetes on the risk of other offspring psychiatric and mild neurodevelopmental disorders.

What This Study Adds:

The combination of maternal pregestational insulin-treated diabetes (PGDM) and severe obesity was associated with a markedly higher risk for attention- deficit/hyperactivity disorder and conduct disorder, as well as mixed disorders of conduct and emotions, than obesity or diabetes alone.

Maternal prepregnancy obesity is one of the prenatal metabolic risks in humans.1,3 Prenatal exposure to obesity-related metabolic disturbances is associated not only with increased risk of metabolic dysfunction in the offspring4,5 but also increased risk of offspring neurodevelopmental impairment and psychiatric disorders, specifically decreased cognitive performance, autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD).6,8 A long-term impact of maternal prepregnancy obesity on offspring neurodevelopment9,10 has recently been hypothesized to be linked to an altered intrauterine environment owing to increased inflammation,11,13 metabolic stress,14 and lipotoxicity.15 

Authors of studies have suggested that maternal diabetes is also associated with an increased rate of learning difficulties, ASD, and possibly also ADHD in the offspring.16,17 Maternal diabetes is categorized into a diabetes diagnosis any time before the pregnancy (pregestational diabetes mellitus [PGDM]) and diabetes with onset during pregnancy (gestational diabetes mellitus [GDM]). PGDM is known to increase the risk for embryopathy, present in 5% to 10% of the live births of mothers with PGDM, the most common being neural tube defects and cardiovascular malformations. Hyperglycemia during critical morphogenesis periods appears to be a major teratogen16 with downstream events being hyperglycemia-induced hypoxia and oxidative stress followed by apoptosis.16,18 Findings from animal models suggest that epigenetic changes mediate or mark long-term effects of an inflammatory and/or hyperglycemic embryonic environment.19 There are previous reports of maternal PGDM effects also on offspring postnatal neurodevelopment, where cognitive function in particular is well studied and considered normal in offspring from mothers with good glycemic control.16 Less studied is the effect of maternal PGDM on milder neurodevelopmental variations and psychiatric condition in the offspring. There are reports of an association between in utero exposure to PGDM and risk of ASD,20 GDM and ASD,21,23 and between GDM and risk of ADHD.24 Although the maternal PGDM and GDM associations to offspring ASD have been supported by several studies,21,22 the effect size of GDM exposure on ASD is smaller than that of PGDM22 and therefore likely less consistent.25 The combined effects of diabetes and obesity on ASD risk were explored in an attempt to further clarify this; Li et al20 reported that both maternal PGDM and GDM increased the risk for offspring ASD but only in obese mothers. This might reflect a stronger neural effect of exposure to concomitant inflammation, lipotoxicity, metabolic stress, and hyperglycemia than to only hyperglycemia. However, whether there are effects of PGDM and GDM on risk for other offspring psychiatric disorders than ASD is quite unexplored.

Our aim with this study was to assess the risk of maternal pregestational obesity and diabetes, categorized into PGDM or GDM, as well as the combined risk of obesity and PGDM or GDM on the risk for a spectrum of psychiatric and mild neurodevelopmental disorders up to the age of 11 years. To this end, we used nationwide registries in Finland that covered all live births between 2004 and 2014.

All pregnancies ending in live birth in Finland between 2004 and 2014 were identified by using the drugs and pregnancy database26 and included 649 043 births (Table 1). These data stem from the medical birth register (MBR), the register on induced abortions, and the register of congenital malformations, all currently kept at the Finnish National Institute for Health and Welfare (THL). The MBR includes information since 1987 on all live births and stillbirths in Finland with a gestational age of >21 weeks or with a birth weight ≥500 g. Information on maternal and offspring drug purchases was extracted from the Finnish Register on Reimbursement Drugs (RRD) maintained by the National Social Insurance Institution. Prescription-only medicines are sold only in pharmacies, and dispensing requires a prescription issued by a physician or dentist. All Finnish citizens and permanent residents are entitled to reimbursement of prescribed medicine. RRD automatically registers all reimbursed drug prescriptions (anatomic therapeutic chemical [ATC] code) that were dispensed at pharmacies since 1996. All medicines for mothers and offspring were identified from reimbursement of costs for drug purchasing. Maternal and offspring medical diagnoses were obtained from the Finnish Care Registers for Health Care (HILMO). HILMO contains information on all hospital in-patient treatments (since 1969), information on out-patient treatments by physicians in specialized care (since 1998), and covers psychiatric diagnoses well according to validation studies.27 The International Classification of Diseases, 10th Revision (ICD-10) was in routine use over the period between 2004 and 2014.

TABLE 1

Demographic Characteristics of Offspring and Their Mothers

VariablesAll, N = 649 043PGDM, N = 4000GDM, N = 101 696Maternal Obesity, N = 73 559
N (%)N (%)N (%)N (%)
Offspring y of birth     
 2004 57 456 (8.9) 293 (7.3) 9684 (9.5) 4920 (6.7) 
 2005 57 531 (8.9) 307 (7.7) 8909 (8.8) 5295 (7.2) 
 2006 58 765 (9.1) 349 (8.7) 8542 (8.4) 6249 (8.5) 
 2007 58 630 (9.0) 349 (8.7) 8970 (8.8) 6365 (8.7) 
 2008 59 511 (9.2) 325 (8.1) 8737 (8.6) 6520 (8.9) 
 2009 60 489 (9.3) 369 (9.2) 9002 (8.9) 6963 (9.5) 
 2010 61 124 (9.4) 382 (9.6) 9186 (9.0) 7195 (9.8) 
 2011 60 016 (9.2) 371 (9.3) 9694 (9.5) 7422 (10.1) 
 2012 59 622 (9.2) 400 (10.0) 9657 (9.5) 7552 (10.3) 
 2013 58 322 (9.0) 429 (10.7) 9789 (9.6) 7678 (10.4) 
 2014 57 577 (8.9) 426 (10.7) 9526 (9.4) 7400 (10.1) 
Offspring sex     
 Boy 331 845 (51.1) 2025 (50.6) 52 565 (51.7) 37 457 (50.9) 
 Girl 317 198 (48.9) 1975 (49.4) 49 131 (48.3) 36 102 (49.1) 
Any perinatal problem     
 Yes 35 543 (5.5) 1511 (37.8) 7415 (7.3) 9985 (13.6) 
 No 611 453 (94.2) 2472 (61.8) 94 055 (92.5) 63 574 (86.4) 
 Missing 2047 (0.3) 17 (0.4) 226 (0.2) 0 (0.0) 
No. fetuses     
 1 630 498 (97.1) 3892 (97.3) 100 128 (98.5) 71 221 (96.8) 
 2 18 205 (2.8) 105 (2.6) 1556 (1.5) 2304 (3.1) 
 3 336 (0.1) 3 (0.1) 12 (0.0) 34 (0.0) 
 4 4 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 
Mode of delivery     
 Vaginal 485 135 (74.7) 1232 (30.8) 72 899 (71.7) 50 695 (68.9) 
 Instrumental 54 236 (8.4) 265 (6.6) 7846 (7.7) 5103 (6.9) 
 Planned CD 44 070 (6.8) 1239 (31.0) 8440 (8.3) 7096 (9.6) 
 Other CD 65 180 (10.0) 1261 (31.5) 12 478 (12.3) 10 663 (14.5) 
 Missing 422 (0.1) 3 (0.1) 33 (0.0) 2 (0.0) 
Maternal age, y     
 <20 15 179 (2.3) 89 (2.2) 1452 (1.4) 1015 (1.4) 
 20–24 100 493 (15.5) 627 (15.7) 12 316 (12.1) 10 891 (14.8) 
 25–29 205 212 (31.6) 1271 (31.8) 29 454 (29.0) 22 348 (30.4) 
 30–34 205 170 (31.6) 1220 (30.5) 33 048 (32.5) 22 820 (31.0) 
 35–55 122 989 (18.9) 793 (19.8) 25 426 (25.0) 16 475 (22.4) 
Parity     
 0 271 356 (41.8) 1778 (44.5) 36 797 (36.2) 25 635 (34.8) 
 1 218 053 (33.6) 1370 (34.3) 32 995 (32.4) 25 218 (34.3) 
 2 95 403 (14.7) 523 (13.1) 17 510 (17.2) 12 673 (17.2) 
 3 33 124 (5.1) 179 (4.5) 7292 (7.2) 5268 (7.2) 
 4 or more 30 626 (4.7) 148 (3.7) 7054 (6.9) 4753 (6.5) 
 Missing 479 (0.1) 2 (0.1) 48 (0.0) 12 (0.0) 
Mother’s marital status     
 Married 379 442 (58.5) 2264 (56.6) 61 240 (60.2) 42 420 (57.7) 
 Cohabiting 209 742 (32.3) 1318 (33.0) 32 091 (31.6) 24 373 (33.1) 
 Other 57 959 (8.9) 408 (10.2) 8108 (8.0) 6606 (9.0) 
 Missing 1900 (0.3) 10 (0.3) 257 (0.3) 160 (0.2) 
Mother’s country of birth     
 Finland 588 100 (90.6) 3818 (95.5) 91 405 (89.9) 68 162 (92.7) 
 Other 60 943 (9.4) 182 (4.6) 10 291 (10.1) 5397 (7.3) 
Maternal smoking     
 No 535 386 (82.5) 3204 (80.1) 82 430 (81.1) 57 368 (78.0) 
 Stopped in 1 trimester 32 913 (5.1) 236 (5.9) 5769 (5.7) 4663 (6.3) 
 Continued 65 148 (10.0) 460 (11.5) 10 896 (10.7) 9995 (13.6) 
 Missing 15 596 (2.4) 100 (2.5) 2601 (2.6) 1533 (2.1) 
Maternal psychiatric disorders     
 Yes 34 892 (5.4) 349 (8.7) 6392 (6.3) 1910 (2.6) 
 No 614 151 (94.6) 3651 (91.3) 95 304 (93.7) 71 649 (97.4) 
Mother’s diagnoses systemic inflammatory disorders     
 Yes 5737 (0.9) 51 (1.3) 892 (0.9) 753 (1.0) 
 No 643 306 (99.1) 3949 (98.7) 100 804 (99.1) 72 806 (99.0) 
Maternal BMI     
 <18.5 23 061 (3.6) 65 (1.6) 1168 (1.1) 0 (0.0) 
 18.5–24 384 169 (59.2) 1840 (46.0) 33 179 (32.6) 0 (0.0) 
 25–29 134 320 (20.7) 1068 (26.7) 31 536 (31.0) 0 (0.0) 
 30–34 49 812 (7.7) 475 (11.9) 18 568 (18.3) 49 812 (67.7) 
 35 or more 23 747 (3.7) 349 (8.7) 12 363 (12.2) 23 747 (32.3) 
 Missing 33 934 (5.2) 203 (5.1) 4882 (4.8) 0 (0.0) 
VariablesAll, N = 649 043PGDM, N = 4000GDM, N = 101 696Maternal Obesity, N = 73 559
N (%)N (%)N (%)N (%)
Offspring y of birth     
 2004 57 456 (8.9) 293 (7.3) 9684 (9.5) 4920 (6.7) 
 2005 57 531 (8.9) 307 (7.7) 8909 (8.8) 5295 (7.2) 
 2006 58 765 (9.1) 349 (8.7) 8542 (8.4) 6249 (8.5) 
 2007 58 630 (9.0) 349 (8.7) 8970 (8.8) 6365 (8.7) 
 2008 59 511 (9.2) 325 (8.1) 8737 (8.6) 6520 (8.9) 
 2009 60 489 (9.3) 369 (9.2) 9002 (8.9) 6963 (9.5) 
 2010 61 124 (9.4) 382 (9.6) 9186 (9.0) 7195 (9.8) 
 2011 60 016 (9.2) 371 (9.3) 9694 (9.5) 7422 (10.1) 
 2012 59 622 (9.2) 400 (10.0) 9657 (9.5) 7552 (10.3) 
 2013 58 322 (9.0) 429 (10.7) 9789 (9.6) 7678 (10.4) 
 2014 57 577 (8.9) 426 (10.7) 9526 (9.4) 7400 (10.1) 
Offspring sex     
 Boy 331 845 (51.1) 2025 (50.6) 52 565 (51.7) 37 457 (50.9) 
 Girl 317 198 (48.9) 1975 (49.4) 49 131 (48.3) 36 102 (49.1) 
Any perinatal problem     
 Yes 35 543 (5.5) 1511 (37.8) 7415 (7.3) 9985 (13.6) 
 No 611 453 (94.2) 2472 (61.8) 94 055 (92.5) 63 574 (86.4) 
 Missing 2047 (0.3) 17 (0.4) 226 (0.2) 0 (0.0) 
No. fetuses     
 1 630 498 (97.1) 3892 (97.3) 100 128 (98.5) 71 221 (96.8) 
 2 18 205 (2.8) 105 (2.6) 1556 (1.5) 2304 (3.1) 
 3 336 (0.1) 3 (0.1) 12 (0.0) 34 (0.0) 
 4 4 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 
Mode of delivery     
 Vaginal 485 135 (74.7) 1232 (30.8) 72 899 (71.7) 50 695 (68.9) 
 Instrumental 54 236 (8.4) 265 (6.6) 7846 (7.7) 5103 (6.9) 
 Planned CD 44 070 (6.8) 1239 (31.0) 8440 (8.3) 7096 (9.6) 
 Other CD 65 180 (10.0) 1261 (31.5) 12 478 (12.3) 10 663 (14.5) 
 Missing 422 (0.1) 3 (0.1) 33 (0.0) 2 (0.0) 
Maternal age, y     
 <20 15 179 (2.3) 89 (2.2) 1452 (1.4) 1015 (1.4) 
 20–24 100 493 (15.5) 627 (15.7) 12 316 (12.1) 10 891 (14.8) 
 25–29 205 212 (31.6) 1271 (31.8) 29 454 (29.0) 22 348 (30.4) 
 30–34 205 170 (31.6) 1220 (30.5) 33 048 (32.5) 22 820 (31.0) 
 35–55 122 989 (18.9) 793 (19.8) 25 426 (25.0) 16 475 (22.4) 
Parity     
 0 271 356 (41.8) 1778 (44.5) 36 797 (36.2) 25 635 (34.8) 
 1 218 053 (33.6) 1370 (34.3) 32 995 (32.4) 25 218 (34.3) 
 2 95 403 (14.7) 523 (13.1) 17 510 (17.2) 12 673 (17.2) 
 3 33 124 (5.1) 179 (4.5) 7292 (7.2) 5268 (7.2) 
 4 or more 30 626 (4.7) 148 (3.7) 7054 (6.9) 4753 (6.5) 
 Missing 479 (0.1) 2 (0.1) 48 (0.0) 12 (0.0) 
Mother’s marital status     
 Married 379 442 (58.5) 2264 (56.6) 61 240 (60.2) 42 420 (57.7) 
 Cohabiting 209 742 (32.3) 1318 (33.0) 32 091 (31.6) 24 373 (33.1) 
 Other 57 959 (8.9) 408 (10.2) 8108 (8.0) 6606 (9.0) 
 Missing 1900 (0.3) 10 (0.3) 257 (0.3) 160 (0.2) 
Mother’s country of birth     
 Finland 588 100 (90.6) 3818 (95.5) 91 405 (89.9) 68 162 (92.7) 
 Other 60 943 (9.4) 182 (4.6) 10 291 (10.1) 5397 (7.3) 
Maternal smoking     
 No 535 386 (82.5) 3204 (80.1) 82 430 (81.1) 57 368 (78.0) 
 Stopped in 1 trimester 32 913 (5.1) 236 (5.9) 5769 (5.7) 4663 (6.3) 
 Continued 65 148 (10.0) 460 (11.5) 10 896 (10.7) 9995 (13.6) 
 Missing 15 596 (2.4) 100 (2.5) 2601 (2.6) 1533 (2.1) 
Maternal psychiatric disorders     
 Yes 34 892 (5.4) 349 (8.7) 6392 (6.3) 1910 (2.6) 
 No 614 151 (94.6) 3651 (91.3) 95 304 (93.7) 71 649 (97.4) 
Mother’s diagnoses systemic inflammatory disorders     
 Yes 5737 (0.9) 51 (1.3) 892 (0.9) 753 (1.0) 
 No 643 306 (99.1) 3949 (98.7) 100 804 (99.1) 72 806 (99.0) 
Maternal BMI     
 <18.5 23 061 (3.6) 65 (1.6) 1168 (1.1) 0 (0.0) 
 18.5–24 384 169 (59.2) 1840 (46.0) 33 179 (32.6) 0 (0.0) 
 25–29 134 320 (20.7) 1068 (26.7) 31 536 (31.0) 0 (0.0) 
 30–34 49 812 (7.7) 475 (11.9) 18 568 (18.3) 49 812 (67.7) 
 35 or more 23 747 (3.7) 349 (8.7) 12 363 (12.2) 23 747 (32.3) 
 Missing 33 934 (5.2) 203 (5.1) 4882 (4.8) 0 (0.0) 

Perinatal problem was defined as birth before gestational wk 37 or birth wt <2500 g, or small for gestational age, which is a birth wt and/or length >2 SD below the sex- and gestational age–specific reference mean,28 according to the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society.29 PGDM was defined according to prescription of insulin before pregnancy; GDM was defined according to an ICD-10 O24.4 diagnosis. Maternal obesity: only maternal BMI ≥30. CD, cesarean delivery.

Information from the different registers was merged through record linkages by using unique personal identification numbers assigned to all Finnish citizens and permanent residents. Register linkages were conducted as described in the permission from the registers (National Social Insurance Institution and THL). The steering committee of the drugs and pregnancy database and the data protection authority in Finland gave their approval for this study. The registered women and their children were not contacted, and informed consents were not required, according to Finnish regulations.

The data on prepregnancy (pregestational) BMI as recorded at the first prenatal visit (gestational week 7–10) were obtained from the drugs and pregnancy database, originally from MBR. The use of BMI restricted the inclusion to earliest 2004. BMI was calculated as weight in kilograms divided by the square of height in meters and categorized according to the following World Health Organization classification: underweight (BMI <18.5), normal weight (18.5 ≤ BMI < 25), overweight (25 ≤ BMI < 30), obese (30 ≤ BMI < 35), and severely obese (BMI ≥35).

PGDM was identified on the basis of the RRD as insulin-treated diabetes; that is, all PGDM cases were on insulin treatment. GDM was identified on the basis of ICD-10 (O24.4) in HILMO. The presence of a PGDM diagnosis excluded a GDM diagnosis.

Data on psychiatric disorders, as primary or secondary diagnoses, for the offspring and the mothers were obtained from HILMO. For the offspring, the diagnosis groups indicated by the following ICD-10 codes were studied as outcome variables: F80 to F83 (developmental disorders of speech and language, scholastic skills, and motor function), F84 (ASD), F90 to F91 (ADHD and conduct disorders), F92 to F95 (mixed disorders of conduct and emotions, emotional disorders with onset specific to childhood, disorders of social functioning with onset specific to childhood and adolescence, and tic disorders) and F98 (other behavioral and emotional disorders with onset usually occurring in childhood and adolescence), F20 to F45 (psychotic, mood, neurotic and stress related, and somatization disorders), F50 (eating disorders), and F51 (nonorganic sleeping disorders). The grouping of diagnoses was based on symptom similarities and performed to improve the statistical power in the analyses.

Information on prescription of psychotropic drugs to offspring was obtained from the RRD and used as outcome variables in a second model. The following ATC codes were used: N05 (antipsychotics, anxiolytics, hypnotics, and sedatives), N06A (antidepressants), and N06B (psychostimulants and nootropics). From HILMO, we also received information on the mothers’ previous in-patient care caused by mental health disorders before pregnancy (International Classification of Diseases, Eighth Revision: 290–317 during 1969–1986, International Classification of Diseases, Ninth Revision: 290–319 during 1987–1995, and ICD-10: F00–F99 during 1996–2014), which was used as a covariate.

Information on offspring birth year, sex, perinatal problems and offspring birth weight according to gestational age, number of fetuses, mode of delivery, maternal age at delivery, parity, family situation, mother’s country of birth, and maternal smoking were obtained from the drugs and pregnancy database. Data on mothers’ diagnoses related to systemic inflammatory disorders (ICD-10: M30–M36 during 1996–2014) were used as primary or secondary diagnoses.

Cox proportional hazards modeling was used to estimate the effect of the exposures maternal prepregnancy obesity, PGDM, and GDM (the latter 2 stratified by BMI categories) on the outcomes offspring psychiatric diagnosis and prescription of psychotropic drug (sensitivity analysis). For maternal BMI, the strata overweight, obese, and severely obese were compared with those with BMI <25. Births to underweight mothers (BMI <18.5) were included in the reference group because there was no detectable effect of underweight on the risk for the offspring psychiatric diagnoses. Covariates were adjusted for as indicated in Tables 2 and 3. Hazard risk ratios (HRs) with 95% confidence intervals (CIs) were reported as measures of effect size. All statistical analyses were performed by using SAS version 9.3 (SAS Institute, Inc, Cary, NC).

TABLE 2

HRs for Offspring Psychiatric Disorders in Relation to Maternal Obesity and Diabetes

Diabetes Categories Stratified by BMIAny F, N = 34 892F80–F83, N = 17 923F84, N = 2346F90–F91, N = 5263F92–F95, N = 5301F98, N = 8506F20–F45, N = 2928F50, N = 279F51, N = 2219
HR95% CIHR95% CIHR95% CIHR95% CIHR95% CIHR95% CIHR95% CIHR95% CIHR95% CI
No PGDM, no GDM                   
 Normal 1.00 — 1.00 — 1.00 — 1.00 — 1.00 — 1.00 — 1.00 — 1.00 — 1.00 — 
 Overweight 1.08 1.04–1.11 1.11 1.06–1.15 1.15 1.03–1.29 1.15 1.06–1.24 0.85 0.78–0.93 1.01 0.95–1.07 1.19 1.07–1.32 1.00 0.71–1.41 1.08 0.96–1.21 
 Obese 1.31 1.24–1.37 1.46 1.37–1.56 1.28 1.06–1.55 1.44 1.28–1.63 0.98 0.86–1.12 1.14 1.03–1.26 1.58 1.36–1.85 0.81 0.43–1.54 1.04 0.85–1.26 
 Severely obese 1.45 1.35–1.56 1.69 1.54–1.86 1.25 0.92–1.70 1.88 1.58–2.23 1.15 0.94–1.41 1.17 0.99–1.37 1.67 1.31–2.13 0.89 0.33–2.41 1.04 0.76–1.43 
PGDM                   
 Normal 1.17 0.99–1.39 1.14 0.90–1.44 0.54 0.20–1.44 1.46 0.98–2.19 0.95 0.58–1.55 1.01 0.72–1.43 1.12 0.58–2.17 2.71 0.85–8.64 1.03 0.49–2.16 
 Overweight 1.24 1.00–1.54 1.45 1.11–1.90 0.44 0.11–1.74 1.52 0.90–2.58 0.94 0.49–1.81 1.09 0.71–1.68 1.10 0.46–2.66 — — 2.33 1.21–4.52 
 Obese 1.69 1.25–2.28 1.22 0.76–1.97 3.64 1.63–8.16 1.00 0.32–3.10 0.95 0.31–2.96 1.92 1.14–3.26 3.08 1.28–7.43 3.94 0.55–28.54 2.38 0.89–6.36 
 Severely obese 2.97 2.23–3.96 3.11 2.13–4.54 6.49 3.08–13.69 6.03 3.23–11.24 4.29 2.14–8.60 3.31 1.99–5.50 2.06 0.52–8.27 — — 1.69 0.42–6.78 
GDM                   
 Normal 1.12 1.07–1.17 1.11 1.04–1.19 1.06 0.88–1.28 1.15 1.01–1.30 0.99 0.87–1.12 1.18 1.07–1.29 1.17 0.99–1.38 1.36 0.84–2.18 1.20 1.01–1.44 
 Overweight 1.17 1.12–1.23 1.23 1.15–1.31 1.27 1.06–1.52 1.16 1.02–1.32 1.04 0.92–1.18 1.12 1.02–1.24 1.26 1.07–1.49 0.60 0.30–1.23 0.96 0.78–1.18 
 Obese 1.40 1.32–1.48 1.59 1.48–1.72 1.56 1.26–1.93 1.64 1.42–1.88 1.17 1.01–1.37 1.28 1.13–1.44 1.44 1.18–1.76 0.91 0.43–1.95 0.79 0.59–1.05 
 Severely obese 1.66 1.55–1.77 1.85 1.70–2.02 1.37 1.04–1.81 2.15 1.84–2.52 1.49 1.26–1.78 1.37 1.19–1.58 1.67 1.32–2.11 1.44 0.67–3.07 0.83 0.59–1.17 
Diabetes Categories Stratified by BMIAny F, N = 34 892F80–F83, N = 17 923F84, N = 2346F90–F91, N = 5263F92–F95, N = 5301F98, N = 8506F20–F45, N = 2928F50, N = 279F51, N = 2219
HR95% CIHR95% CIHR95% CIHR95% CIHR95% CIHR95% CIHR95% CIHR95% CIHR95% CI
No PGDM, no GDM                   
 Normal 1.00 — 1.00 — 1.00 — 1.00 — 1.00 — 1.00 — 1.00 — 1.00 — 1.00 — 
 Overweight 1.08 1.04–1.11 1.11 1.06–1.15 1.15 1.03–1.29 1.15 1.06–1.24 0.85 0.78–0.93 1.01 0.95–1.07 1.19 1.07–1.32 1.00 0.71–1.41 1.08 0.96–1.21 
 Obese 1.31 1.24–1.37 1.46 1.37–1.56 1.28 1.06–1.55 1.44 1.28–1.63 0.98 0.86–1.12 1.14 1.03–1.26 1.58 1.36–1.85 0.81 0.43–1.54 1.04 0.85–1.26 
 Severely obese 1.45 1.35–1.56 1.69 1.54–1.86 1.25 0.92–1.70 1.88 1.58–2.23 1.15 0.94–1.41 1.17 0.99–1.37 1.67 1.31–2.13 0.89 0.33–2.41 1.04 0.76–1.43 
PGDM                   
 Normal 1.17 0.99–1.39 1.14 0.90–1.44 0.54 0.20–1.44 1.46 0.98–2.19 0.95 0.58–1.55 1.01 0.72–1.43 1.12 0.58–2.17 2.71 0.85–8.64 1.03 0.49–2.16 
 Overweight 1.24 1.00–1.54 1.45 1.11–1.90 0.44 0.11–1.74 1.52 0.90–2.58 0.94 0.49–1.81 1.09 0.71–1.68 1.10 0.46–2.66 — — 2.33 1.21–4.52 
 Obese 1.69 1.25–2.28 1.22 0.76–1.97 3.64 1.63–8.16 1.00 0.32–3.10 0.95 0.31–2.96 1.92 1.14–3.26 3.08 1.28–7.43 3.94 0.55–28.54 2.38 0.89–6.36 
 Severely obese 2.97 2.23–3.96 3.11 2.13–4.54 6.49 3.08–13.69 6.03 3.23–11.24 4.29 2.14–8.60 3.31 1.99–5.50 2.06 0.52–8.27 — — 1.69 0.42–6.78 
GDM                   
 Normal 1.12 1.07–1.17 1.11 1.04–1.19 1.06 0.88–1.28 1.15 1.01–1.30 0.99 0.87–1.12 1.18 1.07–1.29 1.17 0.99–1.38 1.36 0.84–2.18 1.20 1.01–1.44 
 Overweight 1.17 1.12–1.23 1.23 1.15–1.31 1.27 1.06–1.52 1.16 1.02–1.32 1.04 0.92–1.18 1.12 1.02–1.24 1.26 1.07–1.49 0.60 0.30–1.23 0.96 0.78–1.18 
 Obese 1.40 1.32–1.48 1.59 1.48–1.72 1.56 1.26–1.93 1.64 1.42–1.88 1.17 1.01–1.37 1.28 1.13–1.44 1.44 1.18–1.76 0.91 0.43–1.95 0.79 0.59–1.05 
 Severely obese 1.66 1.55–1.77 1.85 1.70–2.02 1.37 1.04–1.81 2.15 1.84–2.52 1.49 1.26–1.78 1.37 1.19–1.58 1.67 1.32–2.11 1.44 0.67–3.07 0.83 0.59–1.17 

F80 to F83 include developmental disorders of speech and language, scholastic skills, and motor function; F84 includes ASD; F90 to F91 include ADHD and conduct disorders; F92 to F95 include mixed disorders of conduct and emotions, emotional disorders with onset specific to childhood, disorders of social functioning with onset specific to childhood and adolescence, and tic disorders; F98 includes other behavioral and emotional disorders with onset usually occurring in childhood and adolescence; F20 to F45 include psychotic disorders, mood disorders, neurotic and stress-related disorders, and somatization disorders; F50 includes eating disorders; F51 includes nonorganic sleep disorders. The analyses were adjusted for offspring birth year, sex, perinatal problems (yes or no), where “yes” was birth wt <2500 g or gestational age <37 week, or small birth wt according to gestational age according to Finnish sex-specific standards,28,29 number of fetuses (4 groups), cesarean delivery (yes or no), maternal age group at delivery, parity (5 groups), unmarried mother at birth (yes or no), mother’s country of birth (Finland or other), maternal smoking (yes or no), maternal psychiatric disorder (yes or no), maternal systemic inflammatory disease (yes or no). —, not applicable.

Of the 649 043 births, the prepregnancy BMI was normal for 59.2%, whereas 20.7% of births had maternal overweight, 7.67% had obesity, and 3.66% had severe obesity. In addition, for 0.62% (n = 4000) of the births, the mother had PGDM, and for 15.7% (n = 101 696) of the births, the mother had GDM. Among the offspring, 5.4% (n = 34 892) of the children were diagnosed with a psychiatric disorder between 2004 and 2014, that is up to the age of 11 years for the oldest children. Therein, we identified 17 923 (2.8%) with developmental disorders of speech and language, scholastic skills, motor function (ICD-10: F80–F83); 2346 (0.36%) with ASD (F84)30; 5263 (0.81%) with ADHD or conduct disorder (F90–F91)31; 5301 (0.82%) with mixed disorders of conduct and emotions with childhood onset (F92–F95); 8506 (1.31%) with other behavioral and emotional disorders (F98); 2928 (0.45%) children with a psychotic, mood, neurotic or stress-related, or somatization disorder (F20–F45); 279 (0.043%) with eating disorders; and, finally, 2219 (0.34%) with sleep disorders. Additionally, a total of 13 436 (2.1%) children had been prescribed a psychotropic medication during the period between 2004 and 2014, including antipsychotics, hypnotics, and anxiolytics (N05; 9445 cases); antidepressants (N06A; 334 cases); and stimulants (N06B; 4613 cases). Additional descriptive characteristics of mothers and their offspring are shown in Table 1.

Table 2 shows the relationship for maternal obesity, PGDM, and GDM to the risk of offspring psychiatric and mild neurodevelopmental disorders up to the age of 11 years, after adjusting for potential confounders. Firstly, among mothers without any type of diabetes, there were, to varying degrees, associations between higher maternal BMI and increased risk for the following neurodevelopmental and psychiatric disorder categories in the ICD-10: F80 to F83, F90 to F91, and F20 to F45 in offspring. The hazard ratio for these F-diagnosis categories was 67% to 88% increased for offspring to the mothers with severe obesity. Thus, severely obese mothers had an increased risk of having a child with F80 to F83 (developmental disorders of speech, language, motor, and scholastic skills; HRseverely obese = 1.69; 95% CI = 1.54–1.86), F90 to F91 (ADHD, conduct disorder; HRseverely obese = 1.88; 95% CI = 1.58–2.23), and F20 to F45 (psychosis and mood and anxiety disorders; HRseverely obese = 1.67; 95% CI = 1.31–2.13) compared with mothers with a BMI <25. Secondly, maternal PGDM implied an additionally increased risk for offspring neurodevelopmental and psychiatric disorder. For the combined group of any studied offspring F-diagnosis, PGDM implied a twofold increased risk for F-diagnosis among severely obese mothers with PGDM compared with severe obesity only (HRPGDM = 2.97; 95% CI = 2.23–3.96; HRno diabetes = 1.45; 95% CI = 1.35–1.56). Marked effects were found particularly for ASD and ADHD and/or conduct disorder. Mothers with PGDM and severe obesity had a sixfold higher risk of having a child with ASD (HR = 6.49; 95% CI = 3.08–13.69, Fig 1) or ADHD and/or conduct disorder (HR = 6.03; 95% CI = 3.23–11.24, Fig 2) compared with normal weight mothers without PGDM. In fact, PGDM implied an overrepresentation of all groups of F-diagnoses with onset in childhood or adolescence (F80–F98) in mothers with severe obesity, with the category F92 to F95 also revealing markedly increased risk (mixed disorders of emotions and conduct, disorders of social function, and tics; HR = 4.29; 95% CI = 2.14–8.60, Fig 3). In addition, PGDM in combination with ordinary obesity associated with increased offspring risk for ASD (HR = 3.64; 95% CI = 1.63–8.16). Also, the diagnosis group F20 to F45 (nonjuvenile psychosis and mood and anxiety disorders) were overrepresented in offspring to mothers with PGDM and obesity (HR = 3.08; 95% CI = 1.28–7.43), a twofold risk relative to those without PGDM (HR = 1.58; 95% CI = 1.36–1.85). Maternal GDM, on the other hand, had only a borderline statistically significant influence on the risk for psychiatric disorders (for mothers with severe obesity, HRgdm = 1.66; 95% CI = 1.55–1.77; HRno diabetes = 1.45, 95% CI = 1.35–1.56). Sex-specific analyses for ASD, ADHD and/or conduct disorder, and F92 to F95 revealed that, of the cases, 79.4%, 80.2%, and 67.3%, respectively, were boys and that the HRs for obesity and diabetes on these diagnoses were similar comparing boys and girls (Supplemental Tables 4 and 5). In addition, because cases with diagnoses of ASD or F92 to F95 were found in birth cohorts between 2004 and 2013 and cases with ADHD and/or conduct disorder in birth cohorts between 2004 and 2012, a sensitivity analysis was performed excluding birth year 2014 for ASD and F92 to F95 and birth years 2013 and 2014 for ADHD and/or conduct disorder; the HRs were similar (Supplemental Table 6) to those when the birth cohorts 2013 and 2014 were included (Table 2). Finally, a sensitivity analysis in which the underweight mothers (pregestational BMI <18.5) were excluded (Supplemental Table 7) revealed HRs similar to those in which underweight mothers were included in the normal BMI group (Table 2).

FIGURE 1

Adjusted HR and 95% CI for ASD in offspring stratified for maternal obesity, PGDM, and GDM. The models were adjusted for offspring birth year, sex, small birth weight according to gestational age, number of fetuses, cesarean delivery, maternal age at delivery, parity, mother’s marital status, mother’s country of birth, maternal smoking, maternal psychiatric disorder, and maternal systemic inflammatory disease.

FIGURE 1

Adjusted HR and 95% CI for ASD in offspring stratified for maternal obesity, PGDM, and GDM. The models were adjusted for offspring birth year, sex, small birth weight according to gestational age, number of fetuses, cesarean delivery, maternal age at delivery, parity, mother’s marital status, mother’s country of birth, maternal smoking, maternal psychiatric disorder, and maternal systemic inflammatory disease.

Close modal
FIGURE 2

Adjusted HR and 95% CI for ADHD in offspring stratified for maternal obesity, PGDM, and GDM. The models were adjusted for offspring birth year, sex, small birth weight according to gestational age, number of fetuses, cesarean delivery, maternal age at delivery, parity, mother’s marital status, mother’s country of birth, maternal smoking, maternal psychiatric disorder, and maternal systemic inflammatory disease.

FIGURE 2

Adjusted HR and 95% CI for ADHD in offspring stratified for maternal obesity, PGDM, and GDM. The models were adjusted for offspring birth year, sex, small birth weight according to gestational age, number of fetuses, cesarean delivery, maternal age at delivery, parity, mother’s marital status, mother’s country of birth, maternal smoking, maternal psychiatric disorder, and maternal systemic inflammatory disease.

Close modal
FIGURE 3

Adjusted HR and 95% CI for the ICD-10 psychiatric disorder categories of F80 to F83, F92 to F95, and F98 in offspring stratified for maternal obesity and PGDM. The models were adjusted for offspring birth year, sex, small birth weight according to gestational age, number of fetuses, cesarean delivery, maternal age at delivery, parity, mother’s marital status, mother’s country of birth, maternal smoking, maternal psychiatric disorder, and maternal systemic inflammatory disease. Categories F80 to F88 include developmental disorders of speech and language, scholastic skills, and motor function; F92 to F95 include mixed disorders of conduct and emotions, emotional disorders with onset specific to childhood, disorders of social functioning with onset specific to childhood and adolescence, and tic disorders; F98 includes other behavioral and emotional disorders with onset usually occurring in childhood and adolescence.

FIGURE 3

Adjusted HR and 95% CI for the ICD-10 psychiatric disorder categories of F80 to F83, F92 to F95, and F98 in offspring stratified for maternal obesity and PGDM. The models were adjusted for offspring birth year, sex, small birth weight according to gestational age, number of fetuses, cesarean delivery, maternal age at delivery, parity, mother’s marital status, mother’s country of birth, maternal smoking, maternal psychiatric disorder, and maternal systemic inflammatory disease. Categories F80 to F88 include developmental disorders of speech and language, scholastic skills, and motor function; F92 to F95 include mixed disorders of conduct and emotions, emotional disorders with onset specific to childhood, disorders of social functioning with onset specific to childhood and adolescence, and tic disorders; F98 includes other behavioral and emotional disorders with onset usually occurring in childhood and adolescence.

Close modal

For a second, but likely less sensitive, measure of offspring psychiatric disorders, we used prescription of psychotropic medication including the ATC groups N05 (antipsychotics, hypnotics, and anxiolytics), N06A (antidepressants), and N06B (stimulants). Table 3 reveals that both increased maternal prepregnancy BMI and PGDM were associated with increased prescription of psychotropic medication to offspring, after adjusting for potential confounders. As above, offspring to mothers with PGDM and severe obesity had the highest signal of psychiatric disorder here indicated by prescription of any of N05, N06A, and N06B. There was a marked increase in prescription of N05, N06A, or N06B among offspring to severely obese mothers with PGDM (HR = 4.54; 95% CI = 2.89–7.13) compared with among offspring to severely obese mother without PGDM (HR = 1.69; 95% CI = 1.51–1.90). Both N05 and N06B prescriptions were each overrepresented among offspring to severely obese mothers with PGDM (HRN05 = 3.71; 95% CI = 2.10–6.54; HRN06B = 6.20; 95% CI = 2.95–13.03) compared with when mothers were severely obese without PGDM (HRN05 = 1.53; 95% CI = 1.33–1.77; HRN06B = 2.28; 95% CI = 1.92–2.72). The offspring N06A prescriptions, however, were too few to estimate effects. Presence of maternal GDM had no effect on offspring prescription of psychotropic medication.

TABLE 3

HRs for Offspring Psychiatric Disorders in Relation to Their Childhood Psychotropic Medications

Diabetes Categories Stratified by BMIAny Medication, N = 13 436N05, N = 9445N06A, N = 334N06B, N = 4613
HR95% CIHR95% CIHR95% CIHR95% CI
No PGDM, no GDM         
 Normal 1.00 — 1.00 — 1.00 — 1.00 — 
 Overweight 1.25 1.19–1.31 1.23 1.16–1.30 0.74 0.52–1.06 1.31 1.20–1.42 
 Obese 1.41 1.31–1.53 1.35 1.23–1.48 0.45 0.20–1.01 1.71 1.50–1.93 
 Severely obese 1.69 1.51–1.90 1.53 1.33–1.77 0.85 0.32–2.28 2.28 1.92–2.72 
PGDM         
 Normal 1.66 1.29–2.13 1.25 0.88–1.76 1.16 0.16–8.35 2.25 1.56–3.26 
 Overweight 1.39 0.98–1.99 1.26 0.81–1.95 1.92 0.27–13.90 1.82 1.05–3.14 
 Obese 1.81 1.05–3.12 1.50 0.75–3.01 — — 2.28 0.94–5.49 
 Severely obese 4.54 2.89–7.13 3.71 2.10–6.54 20.90 5.11–85.49 6.20 2.95–13.03 
GDM         
 Normal 1.12 1.04–1.21 1.06 0.97–1.17 1.03 0.63–1.69 1.23 1.08–1.41 
 Overweight 1.20 1.11–1.30 1.20 1.09–1.31 0.90 0.53–1.51 1.23 1.07–1.40 
 Obese 1.41 1.28–1.55 1.22 1.08–1.37 1.30 0.73–2.33 1.93 1.67–2.23 
 Severely obese 1.69 1.51–1.89 1.38 1.19–1.59 1.88 1.00–3.56 2.55 2.17–3.00 
Diabetes Categories Stratified by BMIAny Medication, N = 13 436N05, N = 9445N06A, N = 334N06B, N = 4613
HR95% CIHR95% CIHR95% CIHR95% CI
No PGDM, no GDM         
 Normal 1.00 — 1.00 — 1.00 — 1.00 — 
 Overweight 1.25 1.19–1.31 1.23 1.16–1.30 0.74 0.52–1.06 1.31 1.20–1.42 
 Obese 1.41 1.31–1.53 1.35 1.23–1.48 0.45 0.20–1.01 1.71 1.50–1.93 
 Severely obese 1.69 1.51–1.90 1.53 1.33–1.77 0.85 0.32–2.28 2.28 1.92–2.72 
PGDM         
 Normal 1.66 1.29–2.13 1.25 0.88–1.76 1.16 0.16–8.35 2.25 1.56–3.26 
 Overweight 1.39 0.98–1.99 1.26 0.81–1.95 1.92 0.27–13.90 1.82 1.05–3.14 
 Obese 1.81 1.05–3.12 1.50 0.75–3.01 — — 2.28 0.94–5.49 
 Severely obese 4.54 2.89–7.13 3.71 2.10–6.54 20.90 5.11–85.49 6.20 2.95–13.03 
GDM         
 Normal 1.12 1.04–1.21 1.06 0.97–1.17 1.03 0.63–1.69 1.23 1.08–1.41 
 Overweight 1.20 1.11–1.30 1.20 1.09–1.31 0.90 0.53–1.51 1.23 1.07–1.40 
 Obese 1.41 1.28–1.55 1.22 1.08–1.37 1.30 0.73–2.33 1.93 1.67–2.23 
 Severely obese 1.69 1.51–1.89 1.38 1.19–1.59 1.88 1.00–3.56 2.55 2.17–3.00 

Psychotropic medications were defined according to the following ATC classification system: antipsychotics, anxiolytics, hypnotics, and sedatives (ATC groups N05); antidepressants (ATC group N06A); stimulants (ATC group N06B). The analyses were adjusted for offspring birth year, sex, perinatal problems (yes or no), where “yes” was birth wt <2500 g or gestational age <37 wk, or small birth wt according to gestational age according to Finnish sex-specific standards,28,29 number of fetuses (4 groups), cesarean delivery (yes or no), maternal age group at delivery, parity (5 groups), unmarried mother at birth (yes or no), mother’s country of birth (Finland or other), maternal smoking (yes or no), maternal psychiatric disorder (yes or no), maternal systemic inflammatory disease (yes or no). PGDM was defined according to prescription of insulin before pregnancy; GDM was defined according to an ICD-10 O24.4 diagnosis. —, not applicable.

In this large prospective population-based cohort study, we provide evidence of an increased risk for different pediatric psychiatric and mild neurodevelopmental disorders by joint effects of maternal obesity and PGDM. To our knowledge, this is the first study used to explore a joint effect of maternal obesity and diabetes, stratified in PGDM and GDM, on the risk of a wide spectrum of psychiatric and mild neurodevelopmental disorders in offspring. We demonstrate that maternal prepregnancy obesity was associated with a slightly increased risk of offspring’s psychiatric and mild neurodevelopmental disorders, but the risk effects were most pronounced when mothers had both maternal PGDM and severe obesity. This pattern of risk was observed for children diagnosed particularly with ASD and ADHD and/or conduct disorder but also those with most of the other studied neurodevelopmental and psychiatric disorders with onset in childhood or adolescence (F80–83, F92–F95, and F98). These joint effects of severe obesity and PGDM might reflect a stronger neural effect of exposure to long-term concomitant inflammation, lipotoxicity, metabolic stress, and hyperglycemia than that of metabolic stress and hyperglycemia (PGDM only).11,16,18 GDM, however, did not increase the risk highly for these offspring disorders. This might reflect milder in utero metabolic disturbances, adequate GDM treatment, as well as timing of the GDM (unavailable in our study) as the vulnerability period was recently suggested to be the first 26 gestational weeks.21 

Specifically, we found that mothers with PGDM and severe obesity had a >6 times higher risk of giving birth to a child developing ASD, with a 95% CI of 3.1–13.7, whereas PGDM and obesity implied an HR for ASD of 3.6 (95% CI = 1.6–8.2) compared with nondiabetic mothers with normal weight. These risks are comparable to that of the previous BMI-stratified study of 2734 children including 102 with ASD born to obese or severely obese mothers in Boston, Massachusetts (HRASD = 3.91 [95% CI = 1.76–8.68]).20 We did not find any clear effects of GDM on ASD risk. Li et al,20 however, reported an effect on ASD risk also of GDM in obese or severely obese mothers (HRASD = 3.04 [95% CI = 1.21–7.63]). Likewise, a meta-analysis detected effects of both maternal PGDM and GDM on offspring ASD risk without considering BMI (RRpoint estimates of 1.7–2.2 for PGDM and 1.4–1.5 for GDM).22 Similar risks for ASD were found also later among mothers with type 2 diabetes mellitus (DM) (HRASD <1.5) and first trimesters-GDM (HRASD <1.8).21 Differences in findings between reports20,22,25 may depend on that screening procedures, diagnostic criteria, and treatment guidelines for GDM. We also found a sixfold increase in risk for offspring AHDH and/or conduct disorder when mothers had PGDM and severe obesity but no clear effect of GDM on ADHD, compared with that of nondiabetic mothers with normal weight. Whereas Li et al20 reported no effect of maternal PGDM or GDM on risk for ADHD in normal-weight or obese mothers, Nomura et al24 proposed, from a small study (n = 212), an increased risk for ADHD symptoms in offspring exposed to a combination of GDM and low socioeconomic status (SES).16,28 Thus, different maternal SES and BMI distributions, possibly interdependent, may explain discrepancies in the effect of maternal diabetes on offspring ADHD between studies. In our study, we not only stratified for BMI but also adjusted for SES through smoking and marital status, which correlated highly with more sophisticated measures of SES.

Although the association between maternal diabetes and offspring psychiatric disorders other than ASD is previously unexplored, it is well known that maternal obesity is associated with an increased risk of offspring neurodevelopmental impairment and psychiatric disorders, specifically decreased cognitive performance, ASD, and ADHD.6,8 In line with previous studies, our study supports an increased risk of offspring’s psychiatric disorders associated with maternal prepregnancy obesity. Among the largest previous studies on this topic6 is a Swedish population-based cohort study (n = 673 632 births) in which authors reported a dose-dependent increase in ADHD symptoms in children as maternal prepregnancy BMI increased from overweight to obese, with effect sizes (HRADHD = 1.7) similar to ours after adjusting for measured covariates.7 An Australian prospective cohort (n = 2785 births) revealed that higher maternal prepregnancy BMI was associated with an increased risk of internalizing problems (including withdrawal and depression) after adjusting for confounders.29 Authors of a cohort study including >1500 Australian adolescents reported that increase in maternal prepregnancy BMI increased the odds of eating disorders (anorexia, bulimia, and binge eating) in offspring.24 

Finally, we performed a sensitivity analysis estimating the risk for psychotropic medication by the exposures maternal prepregnancy obesity and diabetes. The hazard ratios observed supported our findings from the F-diagnosis–based analyses.

Our study has some limitations. First, whereas the oldest birth year cohort could be followed-up for 11 years (until 2014), those born at later birth years were followed-up for a shorter time, reducing the sample size of later onset disorders. Second, offspring disorders were grouped (eg, F20–F45) to avoid too small group sizes. Third, CIs of the effect sizes for outcome diagnoses were wide but overlapped with that of outcome psychotropic medication and previous studies. Fourth, PGDM was defined on the basis of reimbursement for insulin prescription. Although insulin is used to treat primarily type 1 DM, also a minor proportion of severe type 2 DM may be treated with insulin. Young adults in Finland were recently reported to have almost similar nationwide prevalence of type 1 DM as type 2 DM.32 Fifth, maternal BMI was available from only 1 time point, so risk of change in gestational BMI on psychiatric disorders could not be studied. Missing BMI data were due to the recent clinical implementation of the registration of BMI at prenatal visit. Sixth, although we adjusted for maternal in-patient psychiatric disorders, potential residual confounding from genetic predisposition, such as data for maternal and paternal out-patient psychiatric conditions, were unavailable. In addition, a recent article revealed that suboptimal maternal cholesterol levels may increase the risk of ADHD in offspring.33 Thus, the recent emerging factors such as maternal dyslipidemia is also worth considering in future studies.

The combination of maternal pregestational insulin-treated diabetes and severe obesity was associated with greater risk for a wide variety of children’s psychiatric and mild neurodevelopmental disorders than either obesity or diabetes alone. Further studies are required to explore the biological mechanisms by which maternal diabetes and obesity may influence this long-term mental and behavioral health.

ADHD

attention-deficit/hyperactivity disorder

ASD

autism spectrum disorder

ATC

anatomic therapeutic chemical

CI

confidence interval

DM

diabetes mellitus

GDM

gestational diabetes mellitus

HILMO

Finnish Care Registers for Health Care

HR

hazard risk ratio

ICD-10

International Classification of Diseases, 10th Revision

MBR

medical birth register

PGDM

pregestational diabetes mellitus

RRD

Finnish Register on Reimbursement Drugs

SES

socioeconomic status

THL

Finnish National Institute for Health and Welfare

Dr Lavebratt conceptualized the study, designed the study, and interpreted the data; Drs Norstedt and Schalling conceptualized the study; Dr Gissler designed the study and performed the statistical analyses; Mr Kong interpreted the data and drafted the manuscript; and all authors provided critical inputs on the result interpretation, critically reviewed the manuscript, and approved the final manuscript as submitted.

FUNDING: Supported by the National Institute for Health and Welfare: Drugs and Pregnancy project (Dr Gissler), the Swedish Research Council (Dr Lavebratt), the regional agreement on medical training and clinical research between Stockholm County Council and Karolinska Institutet Stockholm County Council (Dr Lavebratt), the China Scholarship Council (www.csc.edu.cn; Mr Kong), and the Swedish Brain Foundation (Dr Lavebratt).

We thank Dr Anna-Maria Lahesmaa-Korpinen, THL National Institute for Health and Welfare for excellent register assistance.

1
Devlieger
R
,
Benhalima
K
,
Damm
P
, et al
.
Maternal obesity in Europe: where do we stand and how to move forward?: a scientific paper commissioned by the European Board and College of Obstetrics and Gynaecology (EBCOG).
Eur J Obstet Gynecol Reprod Biol
.
2016
;
201
:
203
208
[PubMed]
2
Yan
J
.
Maternal pre-pregnancy BMI, gestational weight gain, and infant birth weight: a within-family analysis in the United States.
Econ Hum Biol
.
2015
;
18
:
1
12
[PubMed]
3
Santangeli
L
,
Sattar
N
,
Huda
SS
.
Impact of maternal obesity on perinatal and childhood outcomes.
Best Pract Res Clin Obstet Gynaecol
.
2015
;
29
(
3
):
438
448
[PubMed]
4
Brisbois
TD
,
Farmer
AP
,
McCargar
LJ
.
Early markers of adult obesity: a review.
Obes Rev
.
2012
;
13
(
4
):
347
367
[PubMed]
5
Penfold
NC
,
Ozanne
SE
.
Developmental programming by maternal obesity in 2015: outcomes, mechanisms, and potential interventions.
Horm Behav
.
2015
;
76
:
143
152
[PubMed]
6
Edlow
AG
.
Maternal obesity and neurodevelopmental and psychiatric disorders in offspring.
Prenat Diagn
.
2017
;
37
(
1
):
95
110
[PubMed]
7
Chen
Q
,
Sjölander
A
,
Långström
N
, et al
.
Maternal pre-pregnancy body mass index and offspring attention deficit hyperactivity disorder: a population-based cohort study using a sibling-comparison design.
Int J Epidemiol
.
2014
;
43
(
1
):
83
90
[PubMed]
8
Gardner
RM
,
Lee
BK
,
Magnusson
C
, et al
.
Maternal body mass index during early pregnancy, gestational weight gain, and risk of autism spectrum disorders: results from a Swedish total population and discordant sibling study.
Int J Epidemiol
.
2015
;
44
(
3
):
870
883
[PubMed]
9
Van Lieshout
RJ
,
Taylor
VH
,
Boyle
MH
.
Pre-pregnancy and pregnancy obesity and neurodevelopmental outcomes in offspring: a systematic review.
Obes Rev
.
2011
;
12
(
5
):
e548
e559
[PubMed]
10
Huang
L
,
Yu
X
,
Keim
S
,
Li
L
,
Zhang
L
,
Zhang
J
.
Maternal prepregnancy obesity and child neurodevelopment in the collaborative perinatal project.
Int J Epidemiol
.
2014
;
43
(
3
):
783
792
[PubMed]
11
Denison
FC
,
Roberts
KA
,
Barr
SM
,
Norman
JE
.
Obesity, pregnancy, inflammation, and vascular function.
Reproduction
.
2010
;
140
(
3
):
373
385
[PubMed]
12
Bilbo
SD
,
Tsang
V
.
Enduring consequences of maternal obesity for brain inflammation and behavior of offspring.
FASEB J
.
2010
;
24
(
6
):
2104
2115
[PubMed]
13
Huleihel
M
,
Golan
H
,
Hallak
M
.
Intrauterine infection/inflammation during pregnancy and offspring brain damages: possible mechanisms involved.
Reprod Biol Endocrinol
.
2004
;
2
(
1
):
17
[PubMed]
14
Heerwagen
MJ
,
Miller
MR
,
Barbour
LA
,
Friedman
JE
.
Maternal obesity and fetal metabolic programming: a fertile epigenetic soil.
Am J Physiol Regul Integr Comp Physiol
.
2010
;
299
(
3
):
R711
R722
[PubMed]
15
Jarvie
E
,
Hauguel-de-Mouzon
S
,
Nelson
SM
,
Sattar
N
,
Catalano
PM
,
Freeman
DJ
.
Lipotoxicity in obese pregnancy and its potential role in adverse pregnancy outcome and obesity in the offspring.
Clin Sci (Lond)
.
2010
;
119
(
3
):
123
129
[PubMed]
16
Ornoy
A
,
Reece
EA
,
Pavlinkova
G
,
Kappen
C
,
Miller
RK
.
Effect of maternal diabetes on the embryo, fetus, and children: congenital anomalies, genetic and epigenetic changes and developmental outcomes.
Birth Defects Res C Embryo Today
.
2015
;
105
(
1
):
53
72
[PubMed]
17
Gardener
H
,
Spiegelman
D
,
Buka
SL
.
Prenatal risk factors for autism: comprehensive meta-analysis.
Br J Psychiatry
.
2009
;
195
(
1
):
7
14
[PubMed]
18
Chauhan
A
,
Chauhan
V
,
Brown
WT
,
Cohen
I
.
Oxidative stress in autism: increased lipid peroxidation and reduced serum levels of ceruloplasmin and transferrin–the antioxidant proteins.
Life Sci
.
2004
;
75
(
21
):
2539
2549
[PubMed]
19
Bianco-Miotto
T
,
Craig
JM
,
Gasser
YP
,
van Dijk
SJ
,
Ozanne
SE
.
Epigenetics and DOHaD: from basics to birth and beyond.
J Dev Orig Health Dis
.
2017
;
8
(
5
):
513
519
[PubMed]
20
Li
M
,
Fallin
MD
,
Riley
A
, et al
.
The association of maternal obesity and diabetes with autism and other developmental disabilities.
Pediatrics
.
2016
;
137
(
2
):
e20152206
[PubMed]
21
Xiang
AH
,
Wang
X
,
Martinez
MP
, et al
.
Association of maternal diabetes with autism in offspring.
JAMA
.
2015
;
313
(
14
):
1425
1434
[PubMed]
22
Xu
G
,
Jing
J
,
Bowers
K
,
Liu
B
,
Bao
W
.
Maternal diabetes and the risk of autism spectrum disorders in the offspring: a systematic review and meta-analysis.
J Autism Dev Disord
.
2014
;
44
(
4
):
766
775
[PubMed]
23
Lyall
K
,
Munger
KL
,
O’Reilly
ÉJ
,
Santangelo
SL
,
Ascherio
A
.
Maternal dietary fat intake in association with autism spectrum disorders.
Am J Epidemiol
.
2013
;
178
(
2
):
209
220
24
Nomura
Y
,
Marks
DJ
,
Grossman
B
, et al
.
Exposure to gestational diabetes mellitus and low socioeconomic status: effects on neurocognitive development and risk of attention-deficit/hyperactivity disorder in offspring.
Arch Pediatr Adolesc Med
.
2012
;
166
(
4
):
337
343
[PubMed]
25
Daraki
V
,
Roumeliotaki
T
,
Koutra
K
, et al
.
Effect of parental obesity and gestational diabetes on child neuropsychological and behavioral development at 4 years of age: the Rhea mother-child cohort, Crete, Greece.
Eur Child Adolesc Psychiatry
.
2017
;
26
(
6
):
703
714
[PubMed]
26
Artama
M
,
Gissler
M
,
Malm
H
,
Ritvanen
A
;
Drugs and Pregnancy Study Group
.
Nationwide register-based surveillance system on drugs and pregnancy in Finland 1996-2006.
Pharmacoepidemiol Drug Saf
.
2011
;
20
(
7
):
729
738
[PubMed]
27
Sund
R
.
Quality of the Finnish hospital discharge register: a systematic review.
Scand J Public Health
.
2012
;
40
(
6
):
505
515
[PubMed]
28
Sankilampi
U
,
Hannila
M-L
,
Saari
A
,
Gissler
M
,
Dunkel
L
.
New population-based references for birth weight, length, and head circumference in singletons and twins from 23 to 43 gestation weeks.
Ann Med
.
2013
;
45
(
5–6
):
446
454
[PubMed]
29
Clayton
PE
,
Cianfarani
S
,
Czernichow
P
,
Johannsson
G
,
Rapaport
R
,
Rogol
A
.
Management of the child born small for gestational age through to adulthood: a consensus statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society.
J Clin Endocrinol Metab
.
2007
;
92
(
3
):
804
810
[PubMed]
30
Hinkka-Yli-Salomäki
S
,
Banerjee
PN
,
Gissler
M
, et al
.
The incidence of diagnosed autism spectrum disorders in Finland.
Nord J Psychiatry
.
2014
;
68
(
7
):
472
480
[PubMed]
31
Atladottir
HO
,
Gyllenberg
D
,
Langridge
A
, et al
.
The increasing prevalence of reported diagnoses of childhood psychiatric disorders: a descriptive multinational comparison.
Eur Child Adolesc Psychiatry
.
2015
;
24
(
2
):
173
183
[PubMed]
32
Lammi
N
,
Blomstedt
PA
,
Moltchanova
E
,
Eriksson
JG
,
Tuomilehto
J
,
Karvonen
M
.
Marked temporal increase in the incidence of type 1 and type 2 diabetes among young adults in Finland.
Diabetologia
.
2008
;
51
(
5
):
897
899
[PubMed]
33
Ji
Y
,
Riley
AW
,
Lee
LC
, et al
.
A prospective birth cohort study on maternal cholesterol levels and offspring attention deficit hyperactivity disorder: new insight on sex differences.
Brain Sci
.
2017
;
8
(
1
):
3
[PubMed]

Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

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