Mantel

Original Investigation | Psychiatry
Analysis of Neurodevelopmental Disorders in Offspring of Mothers

With Eating Disorders in Sweden
Ängla Mantel, MD, PhD; Anne K. Örtqvist, MD, PhD; Angelica Lindén Hirschberg, MD, PhD; Olof Stephansson, MD, PhD
Abstract Key Points

Question Are children of mothers with
IMPORTANCE Despite indices of impaired neurodevelopment in children of mothers with eating
eating disorders at increased risk of
disorders, it remains unclear whether these children are at increased risk of developing
developing neuropsychiatric diseases?
neuropsychiatric diseases.
Findings In this nationwide cohort
OBJECTIVE To evaluate the association between maternal eating disorders, whether preexisting or study of 52 878 children, including 8813
ongoing during pregnancy, and offspring neuropsychiatric disease risk. children born to women with an eating
disorder and 44 065 matched children
DESIGN, SETTING AND PARTICIPANTS This population-based prospective cohort study used the born to women without an eating
Swedish Medical Birth Registry and identified singleton births registered between from January 1, disorder, maternal eating disorder was
1990, and December 31, 2012. Children of exposed mothers with eating disorders were matched with significantly associated with attention-
comparator children of mothers without diagnoses of eating disorders. To adjust for unmeasured deficit/hyperactivity disorder and
shared familial factors, a cluster of exposed children with full maternal cousin comparators was autism-spectrum disorder in offspring.
identified. Follow-up was completed on December 31, 2017. Data were analyzed from August 31,
Meaning These findings highlight the
2020, to April 30, 2021.
importance of clinical awareness and
intensified support to women with
EXPOSURES Maternal eating disorder diagnosis.
eating disorders and their children and
for future research efforts to identify
MAIN OUTCOMES AND MEASURES All children were followed up from 1 year of age for autism
underlying mechanisms of the
spectrum disorder (ASD) and from 3 years of age for attention-deficit/hyperactivity disorder (ADHD).
association.
The relative risk of ASD and ADHD was assessed among exposed children, stratified by eating
disorder subtype and ongoing vs previous disease, adjusted for potential confounders, including
parental socioeconomic status and comorbidities. + Supplemental content
Author affiliations and article information are
RESULTS Among the 52 878 children included in the analysis, maternal eating disorder exposure (n listed at the end of this article.
= 8813) was associated with an increased risk of ADHD (hazard ratio [HR] for anorexia nervosa, 1.42
[95% CI, 1.23-1.63]; HR for bulimia nervosa, 1.91 [95% CI, 1.43-2.54]; and HR for unspecified eating
disorder, 2.00 [95% CI, 1.72-2.32]) and ASD (HR for anorexia nervosa, 2.04 [95% CI, 1.58-2.63]; HR
for bulimia nervosa, 2.70 [95% CI, 1.68-4.32]; and HR for unspecified eating disorder, 1.95 [95% CI,
1.49-2.54]). After adjustment for parental confounders, the risk of ADHD remained significantly
increased, whereas the risk of ASD in children to mothers with bulimia nervosa was no longer
significant. Ongoing anorexia nervosa was associated with a significantly higher risk of ADHD (HR,
2.52 [95% CI, 1.86-3.42]) and ASD (HR, 3.98 [95% CI, 2.49-6.27]) compared with previous disease
(HRs, 1.26 [95% CI, 1.06-1.48] and 1.81 [95% CI, 1.38-2.38], respectively). Results based on the family
cluster were similar to those of the main analysis for maternal exposure to anorexia nervosa and
bulimia nervosa.
CONCLUSIONS AND RELEVANCE These findings suggest that children born to mothers with eating
disorders, in particular disorders that were active during pregnancy, were at increased risk of
developing ADHD and ASD. The association could not be fully explained by parental psychiatric
(continued)
Open Access. This is an open access article distributed under the terms of the CC-BY License.
JAMA Network Open. 2022;5(1):e2143947. doi:10.1001/jamanetworkopen.2021.43947 (Reprinted) January 18, 2022 1/13
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JAMA Network Open | Psychiatry Neurodevelopmental Disorders in Offspring of Mothers With Eating Disorders in Sweden
Abstract (continued)
comorbidities, and among children of mothers with anorexia nervosa and bulimia nervosa, it could
not be explained by unmeasured familial confounding.
JAMA Network Open. 2022;5(1):e2143947. doi:10.1001/jamanetworkopen.2021.43947
Introduction
Eating disorders are complex and severe psychiatric disorders characterized by an irrational fear of
obesity in combination with weight-controlling behaviors resulting in physical complications and
impaired psychosocial function.1 Nine of 10 individuals affected by eating disorder are women, and
the incidence is highest in adolescence and early adulthood,2 signifying the importance to
understand how the course of eating disorders is affected by pregnancy and vice versa, and not least
how it affects the future health of children of mothers with eating disorders.3 The disease course is
chronic for approximately one-third of women with anorexia nervosa and bulimia nervosa,4 and
pregnancy constitutes a vulnerable time period that might be associated with an increased risk of
relapse among women with a history of an eating disorder.5,6 In fact, both ongoing and previous
maternal eating disorders have been associated with an increased risk of several pregnancy and
neonatal complications.5,7-11
In addition to the direct effect on the fetal growth and development, the intrauterine
environment presumably influences health during childhood and throughout life.12,13 Precise
mechanisms and interactions are poorly defined, but it is assumed that intrauterine environmental
exposures, including nutritional factors, affect neurodevelopment and immune maturation. Thus,
hypothetically, children of mothers with eating disorders might be prone to develop specific
conditions, including neurodevelopmental disorders. According to a few studies,14,15 children of
mothers with an eating disorder are at increased risk of impaired neuropsychiatric and cognitive
development and behaviors indicative of psychiatric diseases. Importantly, these previous studies
are heterogenous in nature and therefore difficult to compare. Moreover, exposures and outcomes
have typically been identified using questionnaires, inventories, or clinical interviews, making them
prone to recall bias, and information on potential confounders is generally not available. The aim of
this study was to investigate the association between maternal eating disorders and risk of
neurodevelopmental disorders in the children using large-scale population-based Swedish health
care registers.
Methods
This cohort study was approved by the Swedish Ethical Review Authority, which waived the need for
informed consent owing to use of pseudonymized data. The study followed the Strengthening the
Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
Study Setting, Data Sources, and Study Base

The study setting was the Swedish health care system, and data sources used are described in detail
in the eMethods and eFigure 1 in the Supplement. We used the Swedish Medical Birth Registry and
identified 2 296 074 of 2 363 437 singleton births (98.6%) with valid information on maternal and
child personal identification numbers16 from January 1, 1990, to December 31, 2012, which made up
the study base from which exposed children and matched unexposed comparator children were
identified (Figure 1). Using the personal identification number, information from the Swedish
Medical Birth Registry was linked with information from several national health registers to identify
exposures, outcomes, and other covariates of interest. We obtained data from the National Patient
Register, including information on inpatient and outpatient care, and the Cause of Death Register,

which stores information on diseases or cause of death according to International Classification of

Diseases, Ninth Revision (ICD-9), and International Statistical Classification of Diseases and Related
Health Problems, Tenth Revision (ICD-10). We also retrieved information from the Prescribed Drug
Register, including information on all dispensed prescriptions using Anatomical Therapeutic
classifications (ATC), the Education Register, the Multigeneration Register, and the Total Population
Register.
Exposed Cohorts and Matched Comparators

Within the study base, 3 cohorts of exposed children were identified. Maternal eating disorder
exposure was stratified into the subtypes anorexia nervosa, bulimia nervosa, and unspecified eating
disorder and defined as (1) a maternal eating disorder diagnosis registered at least twice (anorexia
nervosa, ICD-9 307B and ICD-10 F50.0 and F50.1; bulimia nervosa, ICD-10 F50.2 and F50.3;
unspecified eating disorder, ICD-9 307F and ICD-10 F50-9) in the Patient Register or (2) 1 main
diagnosis in inpatient care before delivery date. Participants diagnosed before 9 years of age (and no
registered diagnoses thereafter) were excluded to avoid misclassification of pediatric feeding
disorders. Eating disorder status was further divided into ongoing disease, defined as at least 1 visit
listing the specific diagnosis during the pregnancy or within 1 year before estimated conception, or
previous eating disorder, defined as a last registered diagnosis more than 1 year before estimated
conception.
All exposed children were matched with 5 comparator children, free of any maternal eating
disorder exposure, based on maternal age at delivery, sex, and birth year. To adjust for unmeasured
shared familial factors, we used the Multigeneration Register and identified a cluster of all exposed
children with at least 1 exposure-discordant full maternal cousin (Figure 1).
Figure 1. Flowchart of Study Population Generation
2 363 467 Births with a valid PIN in the Swedish Medical Birth
Registry from January 1, 1990, to December 31, 2012
67 363 Multiple births excluded (2.9%)
2 296 104 Remaining births
10 277 Women with any prior eating

disorder diagnosis excluded (0.4%)
Multigeneration register
1412 Children with ≥1 full 4047 Children born to

maternal cousin mothers with anorexia
nervosa
2878 Exposure-discordant
full maternal cousins
327 Children with ≥1 full 1185 Children born to Matching factors; 1:5 2 285 827 Children born to
maternal cousin mothers with bulimia maternal age, birth mothers free of
nervosa year, and sex eating disorders;
potential controls
3581 Children born to mothers

1228 Children with ≥1 full
with unspecified eating
maternal cousin
disorders
PIN indicates personal identification number.

Outcomes and Follow-up

Based on the generally accepted minimal attained age for diagnosis of respective outcome, the
follow-up started at different index ages depending on the specific outcome. Autism spectrum
disorder (ASD) was defined as at least 2 registered diagnoses (ICD-9 299 and ICD-10 F84.0, F84.1,
F84.3, or F84.5) in the patient register during the follow-up period, and follow-up started at the index
age of 1 year. Attention-deficit/hyperactivity disorder (ADHD) was defined as at least 2 registered
diagnoses in the Patient Register (ICD-9 314 and ICD-10 F90) and/or dispensed prescription of ADHD-
specific pharmacotherapy (amphetamine [ATC N06BA01], dexamphetamine [ATC N06BA02],
methylphenidate hydrochloride [ATC N06BA04], atomoxetine hydrochloride [ATC N06BA09], and
lisdexamfetamine dimesylate [ATC N06BA12]) in the Prescribed Drug Register. The follow-up for
ADHD started at the index age of 3 years. All children who died or migrated from Sweden before the
index age were excluded from analyses. The follow-up started at the index age and ended at the
point of outcome, December 31, 2017, death, or migration from Sweden. For the full maternal cousin
cluster, the follow-up ended at point of outcome, death, migration from Sweden, or the minimal
attained age (from index age to December 31, 2017) within the cluster.
Covariates
Data on baseline pregnancy, delivery, and neonatal characteristics were obtained from the Swedish
Medical Birth Registry and categorized as described in eTable 1 in the Supplement. Via the
Multigeneration Register, we identified the personal identification number of the biological father for
98.1% to 99.0% of children. Data on maternal and paternal educational level were retrieved from
the Educational Register as a proxy for socioeconomic status. For all mothers and fathers, a history of
psychiatric (anxiety, depressive disorder, ADHD, or ASD), alcohol abuse, or substance abuse
disorders was defined as a registered diagnosis in the Patient Register before the delivery date (ICD-9
and ICD-10 codes specified in eTable 2 in the Supplement).
Statistical Analysis
Data were analyzed from August 31, 2020, to April 30, 2021. The exposed children of mothers with
eating disorders were compared with the matched unexposed comparator children of mothers
without eating disorders. We calculated crude incidence rates by dividing the number of respective
outcome-events during follow-up with the corresponding person-time at risk presented as number
of events per 1000 person-years. We used multivariable Cox proportional hazards regression models
with robust standard variance estimates to obtain hazard ratios (HRs) as a measurement of the
association between each maternal eating disorder subtype and offspring risk of the respective
outcome. The proportional hazard assumption was assessed by inspecting cumulative incidence
curves (eFigure 4 in the Supplement). The model was adjusted stepwise for confounders selected on
the a priori hypothesized association with maternal eating disorder and neurodevelopmental
disorder (eFigure 3 in the Supplement).16 Adjustments were made for matching factors, parental
(maternal and paternal) educational level, paternal age at birth, maternal smoking status, and
parental anxiety disorder, depressive disorder, ADHD, ASD, and alcohol or substance abuse disorder
before the delivery date. Covariates with missingness were accounted for using complete case
analysis. Stratum-specific HRs were calculated and presented for ongoing vs previous maternal
eating disorder.
To investigate the potential effect of shared unmeasured genetic and environmental factors, we
performed a stratified Cox proportional hazards regression model in the cluster of exposed children
and their full maternal cousin comparators accounting for 12.5% of the genetic background. Only
exposure-discordant full maternal cousin comparators were included in the analyses, and by design
only outcome-discordant comparators contributed to the estimate.
Given the overlap of maternal eating disorder subtypes that, as expected, was most prominent
for unspecified eating disorder (eFigure 2 in the Supplement), a sensitivity analysis was performed
among children exposed to a maternal unspecified eating disorder without any overlap with anorexia

nervosa and/or bulimia nervosa. We also repeated main analyses stratified by sex and by birth
cohorts. Data were analyzed using SAS software, version 9.4 (SAS Institute Inc).
Results
Study Population and Baseline Characteristics
Figure 1 summarizes the study population generation and Table 1 summarizes the baseline
characteristics of study participants (52 878 children). Swedish law does not allow data on race and
ethnicity. The mean maternal (SD) age at delivery was 29.2 (5.1) years among mothers with anorexia
nervosa and matched comparators, 29.6 (4.9) years among mothers with bulimia nervosa and
matched comparators, and 28.9 (5.3) years among mothers with unspecified eating disorder and
matched comparators. Among 4047 mothers with anorexia nervosa, 417 (10.3%) had ongoing
disease during pregnancy, as did 803 of 3581 (22.4%) of mothers with unspecified eating disorder
and 339 of 1185 (28.6%) of mothers with bulimia nervosa. Underweight (body mass index [calculated
as weight in kilograms divided by height in meters squared], <18.5) was more frequent among
mothers with anorexia nervosa (341 of 4047 [8.4%]) and unspecified eating disorder (201 of 3581
[5.6%]) compared with the matched comparator of group mothers (433 of 20 235 [2.1%] and 427 of
17 905 [2.4%], respectively). Children of mothers with eating disorders were more often firstborn
(mothers with anorexia nervosa, 51.9%; mothers with unspecified eating disorder, 53.1%; and
mothers with bulimia nervosa, 54.9%) compared with their matched comparators (range,
45.8%-47.9%). Maternal smoking, in particular before pregnancy, was more common among
exposed children (range, 20.5%-26.2%) compared with their matched comparators (range,
17.1%-18.7%). Preterm birth was more common among exposed children (range, 6.3%-8.0%)
compared with their matched unexposed comparator children (range, 4.7%-4.9%) (Table 1).
Parental Educational Level and Psychiatric Comorbidity Status

Parental educational level and psychiatric comorbidities are presented in Table 2. Except for a higher
frequency of an educational level of greater than 12 years of schooling among mothers with anorexia
nervosa (2176 of 4047 [53.8%]) vs comparators (9681 of 20 235 [47.8%]), there were no major
differences in educational level among mothers and fathers of exposed children compared with
those of nonexposed children. All groups of mothers with eating disorders had a higher
co-occurrence of psychiatric comorbidities. Likewise, although with a smaller difference in absolute
numbers, fathers of exposed children had a higher co-occurrence of most psychiatric comorbidities
(Table 2).
The Offspring Risk of ADHD

During a mean (SD) follow-up time of 9.7 (5.5) years, there was an overall 40% increased risk of
ADHD (crude HR, 1.42 [95% CI, 1.23-1.63]) among children of mothers with anorexia nervosa. The risk
decreased to 27% (fully adjusted HR, 1.26 [95% CI, 1.06-1.50]) after additional adjusting for parental
educational level and psychiatric comorbidities. Stratification revealed a higher risk among children
to mothers with ongoing anorexia nervosa during pregnancy (crude HR, 2.52 [95% CI, 1.86-3.42];
fully adjusted HR, 1.59 [95% CI, 1.08-2.33]) compared with children of mothers with previous
anorexia nervosa for whom adjusted HRs were no longer significantly increased (fully adjusted HR,
1.15 [95% CI, 0.95-1.40]). Children of mothers with bulimia nervosa and an unspecified eating
disorder were also at increased risk of ADHD during a mean (SD) follow-up of 6.8 (3.0) years and 8.7
(5.3) years, respectively (crude HR among children exposed to maternal bulimia nervosa, 1.91 [95%
CI, 1.43-3.18]; crude HR among children exposed to maternal unspecified eating disorder, 2.00 [95%
CI, 1.72-2.32]). Hazard ratios remained significantly increased after adjusting for parental educational
level and psychiatric comorbidities (fully adjusted HRs, 1.51 [95% CI, 1.04-2.17] and 1.51 [95% CI,
1.23-1.85], respectively). Stratification of bulimia nervosa into ongoing vs previous disease did not
reveal any significant difference in crude estimate, whereas adjusted estimates were attenuated and

Table 1. Maternal Pregnancy, Delivery, and Neonatal Characteristics of Exposed Children of Mothers With Eating Disorder and Their Matched Comparatorsa
Maternal anorexia nervosa Maternal bulimia nervosa Maternal unspecified eating disorder
Characteristic Exposed Unexposed comparator Exposed Unexposed comparator Exposed Unexposed comparator
Ongoing diseaseb 417/4047 (10.3) NA 339/1185 (28.6) NA 803/3581 (22.4) NA
Maternal age, y
Mean (SD) 29.2 (5.1) 29.2 (5.1) 29.6 (4.9) 29.6 (4.9) 28.9 (5.3) 28.9 (5.3)
<20 88/4047 (2.2) 440/20 235 (2.2) 16/1185 (1.4) 80/5925 (1.3) 89/3581 (2.5) 445/17 905 (2.5)
20-25 937/4047 (23.2) 4685/20 235 (23.2) 234/1185 (19.7) 1170/5925 (19.7) 932/3581 (26.0) 4660/17 905 (26.0)
26-30 1362/4047 (33.7) 6810/20 235 (33.7) 440/1185 (37.1) 2200/5925 (37.1) 1197/3581 (33.4) 5985/17 905 (33.4)
31-35 1179/4047 (29.1) 5895/20 235 (29.1) 356/1185 (30.0) 1780/5925 (30.0) 947/3581 (26.4) 4735/17 905 (26.4)
>35 481/4047 (11.9) 2405/20 235 (11.9) 139/1175 (11.7) 695/5925 (11.7) 416/3581 (11.6) 2080/17 905 (11.6)
BMI
Median (IQR) 21.2 (19.6-23.1) 23.5 (21.4-26.5) 22.9 (20.9-25.6) 23.7 (21.5-26.7) 22.2 (20.4-24.8) 23.5 (21.4-26.6)
<18.5 341/4047 (8.4) 433/20 235 (2.1) 41/1185 (3.5) 132/5925 (2.2) 201/3581 (5.6) 427/17 905 (2.4)
18.5-25.0 2715/4047 (67.1) 11 082/20 235 (54.8) 680/1185 (57.4) 3315/5925 (55.9) 2148/3581 (60.0) 9805/17 905 (54.8)
25.1-30.0 304/4047 (7.5) 4270/20 235 (21.1) 206/1185 (17.4) 1382/5925 (23.3) 497/3581 (13.9) 3833/17 905 (21.4)
>30.0 54/4047 (1.3) 2001/20 235 (9.9) 105/1185 (8.9) 636/5925 (10.7) 216/3581 (6.0) 1780/17 905 (9.9)
Missing 633/4047 (15.6) 2449/20 235 (12.1) 153/1185 (12.9) 460/5925 (7.8) 519/3581 (14.5) 2060/17 905 (11.5)
Parity
Median (IQR) 1.7 (1.0-2.0) 1.8 (1.0-2.0) 1.0 (1.0-2.0) 2.0 (1.0-2.0) 1.7 (0.9) 1.8 (1.0)
1 2101/4046 (51.9) 9273/20 235 (45.8) 650/1185 (54.9) 2748/5925 (46.4) 1900/3581 (53.1) 8567/17 905 (47.8)
2 1296/4046 (32.0) 7385/20 235 (36.5) 372/1185 (31.4) 2178/5925 (36.8) 1123/3581 (31.3) 6415/17 905 (35.8)
3 433/4046 (10.7) 2604/20 235 (12.9) 113/1185 (9.5) 708/5925 (11.9) 401/3581 (11.2) 2095/17 905 (11.7)
>3 216/4046 (5.3) 973/20 235 (4.8) 50/1185 (4.2) 291/5925 (4.9) 157/3581 (4.4) 828/17 905 (4.6)
Smoking
First antenatal visit 433/4047 (10.7) 1870/20 235 (9.2) 119/1185 (10.0) 429/5925 (7.2) 468/3581 (13.1) 1645/17 905 (9.2)
Missing 208/4047 (5.1) 994/20 235 (4.9) 48/1185 (4.1) 232/5925 (3.9) 152/3581 (4.2) 906/17 905 (5.1)
Before pregnancy 663/4047 (16.4) 2992/20 235 (14.8) 297/1185 (25.1) 969/5925 (16.4) 758/3581 (21.2) 2793/17 905 (15.6)
Missing 806/4047 (19.9) 3944/20 235 (19.5) 51/1185 (4.3) 262/5925 (4.4) 116/3581 (3.2) 2973/17 905 (16.6)
Mode of delivery
Vaginal 3130/3996 (78.3) 15 458/19 980 (77.4) 880/1173 (75.0) 4557/5903 (77.2) 2664/3524 (75.6) 13 729/17 690 (77.6)
Assisted vaginal 272/3996 (6.8) 1520/19 980 (7.6) 93/1173 (7.9) 419/5903 (7.1) 245/3524 (7.0) 1369/17 690 (7.7)
Emergency cesarean 251/3996 (6.3) 1482/19 980 (7.4) 85/1173 (7.2) 493/5903 (8.3) 243/3524 (6.9) 1353/17 690 (7.6)
delivery
Planned cesarean 343/3996 (8.6) 1520/19 980 (7.6) 115/1173 (9.8) 434/5903 (7.3) 372/3524 (10.5) 1239/17 690 (7.0)
delivery
Preterm birthc
All 324/4047 (8.0) 992/20 235 (4.9) 75/1185 (6.3) 282/5925 (4.7) 268/3581 (7.5) 853/17 905 (4.8)
Moderate 277/4047 (6.8) 866/20 235 (4.3) 64/1185 (5.4) 246/5925 (4.1) 222/3581 (6.2) 704/17 905 (3.9)
Very 32/4047 (0.8) 82/20 235 (0.4) 8/1185 (0.7) 23/5925 (0.4) 32/3581 (0.9) 104/17 905 (0.6)
Extreme 15/4047 (0.4) 44/20 235 (0.2) 3/1185 (0.3) 13/5925 (0.2) 14/3581 (0.4) 45/17 905 (0.3)
GW for GAd
Appropriate 3809/4038 (94.3) 18 957/20 171 (94.0) 1113/1182 (94.2) 5597/5918 (94.6) 3353/3569 (93.9) 16 787/17 860 (94.0)
Small 158/4038 (3.9) 549/20 171 (2.7) 41/1182 (3.5) 149/5918 (2.5) 117/3569 (3.3) 528/17 860 (3.0)
Large 71/4038 (1.8) 665/20 171 (3.3) 28/1182 (2.4) 172/5918 (2.9) 99/3569 (2.8) 545/17 860 (3.1)
Microcephalye 75/4047 (1.9) 287/20 235 (1.4) 26/1185 (2.2) 94/5925 (1.6) 76/3581 (2.1) 286/17 905 (1.6)
Missing 149/4047 (3.7) 679/20 235 (3.3) 41/1185 (3.5) 144/5925 (2.4) 116/3581 (3.2) 556/17 905 (3.1)
Apgar score <7 at 5 57/4047 (1.4) 213/20 235 (1.1) 15/1185 (1.3) 72/5925 (1.2) 57/3581 (1.6) 193/17 905 (1.1)
min
Missing 18/4047 (0.4) 121/20 235 (0.6) 7/1185 (0.6) 27/5925 (0.5) 37/3581 (1.0) 89/17 905 (0.5)
c
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by Preterm defined as before gestational week 37 plus 0 days; moderate, gestational
height in meters squared); GA, gestational age; GW, gestational weight; NA, not week 32 plus 0 days to 36 plus 6 days; very, gestational week 28 plus 0 days to 31 plus
applicable. 6 days; and extreme, before gestational week 28 plus 0 days.
a d
Unless otherwise indicated, data are expressed as number/total number (%) of Appropriately defined as GW of −2 to +2 SDs for GA; small, GW below −2 SDs for GA;
participants. and large, GW above +2 SDs for GA.
b e
Diagnosis of the eating disorder during pregnancy or within 1 year before conception. Defined as head circumference at birth below −2 SDs for GA.

no longer significant. Stratification of unspecified eating disorder into ongoing vs previous disease
did not reveal any significant differences in estimates (Figure 2A).
The Offspring ASD Risk

The risk of ASD was increased among children born to mothers with anorexia nervosa (crude HR,
2.04 [95% CI, 1.58-2.63]) and remained similarly increased after adjusting for parental educational
level and psychiatric comorbidities (fully adjusted HR, 1.96 [95% CI, 1.46-2.64]) during a mean (SD)
follow-up of 10.8 (5.6) years. Children of mothers with ongoing anorexia nervosa had a 4-fold
increased risk of ASD (crude HR, 3.98 [95% CI, 2.49-6.37]; fully adjusted HR, 2.67 [95% CI,
1.40-5.09]) compared with an 80% increased risk for children of mothers with previous anorexia
nervosa (crude HR, 1.81 [95% CI, 1.38-2.38]; fully adjusted HR, 1.84 [95% CI, 1.34-2.52]). The crude
HRs for ASD among children of mothers with bulimia nervosa (HR, 2.70 [95% CI, 1.68-4.32]) and an
unspecified eating disorder (HR, 1.95 [95% CI, 1.49-2.54]) were similar to those of children born to
mothers with anorexia nervosa, but estimates of the stratified fully adjusted model did not remain
significantly increased (Figure 2B).
Table 2. Parental Sociodemographic Factors and Psychiatric Comorbidities of Exposed Children of Mothers With Eating Disorders and Their Matched Comparators
Children’s groupa
Maternal anorexia nervosa Maternal bulimia nervosa Maternal unspecified eating disorder
Unexposed Unexposed Unexposed
Characteristics Exposed comparator Exposed comparator Exposed comparator
Maternal
Educational level, y
<9 312/4047 (7.7) 1799/20 235 (8.9) 94/1185 (7.9) 518/5925 (8.7) 396/3581 (11.1) 1702/17 905 (9.5)
9-12 1468/4047 (36.3) 8202/20 235 (40.5) 449/1185 (37.9) 2210/5925 (37.3) 1468/3581 (41.0) 7190/17 905 (40.2)
>12 2176/4047 (53.8) 9681/20 235 (47.8) 631/1185 (53.2) 3052/5925 (51.5) 1642/3581 (45.9) 8490/17 905 (47.4)
Missing 91/4047 (2.2) 553/20 235 (2.7) 11/1185 (0.9) 145/5925 (2.5) 75/3581 (2.1) 523/17 905 (2.9)
b
Psychiatric comorbidities
Depressive disorder 856/4047 (21.2) 534/20 235 (2.6) 357/1185 (30.1) 179/5925 (3.0) 1392/3581 (38.9) 492/17 905 (2.7)
Anxiety disorder 592/4047 (14.6) 420/20 235 (2.1) 554/1185 (46.8) 194/5925 (3.3) 996/3581 (27.8) 474/17 905 (2.6)
ADHD 63/4047 (1.6) 65/20 235 (0.3) 33/1185 (2.8) 19/5925 (0.3) 109/3581 (3.0) 50/17 905 (0.3)
ASD 27/4047 (0.7) 8/20 235 (0.04) 6/1185 (0.5) 7/5925 (0.1) 36/3581 (1.0) 12/17 905 (0.1)
Substance abuse 223/4047 (5.5) 105/20 235 (0.5) 126/1185 (10.6) 37/5925 (0.6) 344/3581 (9.6) 102/17 905 (0.6)
Paternalc
Age, mean (SD), y 32.8 (6.2) 32.6 (6.3) 32.8 (6.2) 33.3 (6.1) 32.2 (6.4) 32.6 (6.3)
Educational level, y
<9 358/4000 (9.0) 2416/20 014 (12.1) 121/1166 (10.4) 612/5865 (10.4) 355/3511 (10.1) 2133/17 700 (12.1)
9-12 1947/4000 (48.7) 9595/20 014 (47.9) 590/1166 (50.6) 2818/5865 (48.0) 1811/3511 (51.6) 8623/17 700 (48.7)
>12 1579/4000 (39.5) 7275/20 014 (36.3) 430/1166 (36.9) 2257/5865 (38.5) 1231/3511 (35.1) 6326/17 700 (35.7)
Missing 116/4000 (2.9) 728/20 014 (3.6) 25/1166 (2.1) 178/5865 (3.0) 114/3511 (3.2) 618/17 700 (3.5)
Psychiatric comorbiditiesb
Depressive disorder 96/4000 (2.4) 260/20 014 (1.3) 57/1166 (4.9) 106/5865 (1.8) 152/3511 (4.3) 230/17 700 (1.3)
Anxiety disorder 90/4000 (2.3) 223/20 014 (1.1) 36/1166 (3.1) 85/5865 (1.4) 116/3511 (3.3) 240/17 700 (1.4)
ADHD 30/4000 (0.8) 51/20 014 (0.3) 12/1166 (1.0) 24/5865 (0.4) 44/3511 (1.3) 86/17 700 (0.5)
ASD 3/4000 (0.1) 6/20 014 (0.03) 3/1166 (0.3) 1/5865 (0.02) 4/3511 (0.1) 4/17 700 (0.02)
Substance abuse 65/4000 (1.6) 120/20 014 (0.6) 27/1166 (2.3) 46/5865 (0.8) 82/3511 (2.3) 130/17 700 (0.7)
b
Abbreviations: ADHD, attention-deficit/hyperactivity disorder; ASD autism spectrum Registered diagnosis in the patient register before delivery date.
disorder. c
Includes number/total number (%) of fathers with valid information from the personal
a
Unless otherwise indicated, data are expressed as number/total number (%) of identification number.
children.

Figure 2. Forest Plot of the Hazard Ratios (HRs) of Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD)
A Attention-deficit/hyperactivity disorder HR, crude

Rate per 1000 person-years (95% CI) HR, adjusted 1
HR, adjusted 2
Maternal HR (95% CI)
Maternal eating non–eating
disorder disorder Crudea Adjusted 1b Adjusted 2c No ADHD ADHD
Anorexia nervosa
All 6.6 (4.1-9.3) 4.7 (3.8-5.7) 1.42 (1.23-1.63) 1.27 (1.09-1.50) 1.26 (1.06-1.50)
Ongoing 13.0 (2.0-23.9) 4.7 (3.8-5.7) 2.52 (1.86-3.42) 1.72 (1.17-2.52) 1.59 (1.08-2.33)
Previous 5.9 (3.4-8.4) 4.7 (3.8-5.7) 1.26 (1.06-1.48) 1.16 (0.96-1.39) 1.15 (0.95-1.40)
Bulimia nervosa
All 9.4 (3.8-14.9) 5.0 (3.2-6.8) 1.91 (1.43-2.54) 1.45 (1.04-2.15) 1.51 (1.04-2.17)
Ongoing 11.6 (0.0-23.1) 5.0 (3.2-6.8) 2.12 (1.42-3.18) 1.38 (0.84-2.29) 1.42 (0.86-2.39)
Previous 8.3 (2.2-14.5) 5.0 (3.2-6.8) 1.78 (1.27-2.50) 1.46 (0.95-2.24) 1.56 (1.02-2.38)
Unspecified eating disorder

All 9.0 (5.9-12.1) 4.5 (3.6-5.5) 2.00 (1.72-2.32) 1.65 (1.35-2.02) 1.51 (1.23-1.85)
Ongoing 10.4 (3.3-17.5) 4.5 (3.6-5.5) 2.24 (1.74-2.88) 1.51 (1.02-2.23) 1.55 (1.05-2.29)
Previous 8.6 (5.1-12.0) 4.5 (3.6-5.5) 1.93 (1.63-2.30) 1.56 (1.25-1.95) 1.56 (1.24-1.95)
0.5 1 4
HR (95% CI)
B Autism spectrum disorder
Rate per 1000 person-years (95% CI)
Maternal HR (95% CI)
Maternal eating non–eating
disorder disorder Crudea Adjusted 1b Adjusted 2c No ASD ASD
Anorexia nervosa
All 2.2 (0.7 to 3.6) 1.1 (0.6-1.5) 2.04 (1.58-2.63) 1.93 (1.44-2.63) 1.96 (1.46-2.64)
Ongoing 4.3 (–2.0 to 10.5) 1.1 (0.6-1.5) 3.98 (2.49-6.37) 2.88 (1.59-5.22) 2.67 (1.40-5.09)
Previous 1.9 (0.5 to 3.4) 1.1 (0.6-1.5) 1.81(1.38-2.38) 1.76 (1.29-2.41) 1.84 (1.34-2.52)
Bulimia nervosa
All 3.0 (–0.1 to 6.2) 1.1 (0.3-2.0) 2.70 (1.68-4.32) 1.60 (0.78-3.27) 1.61 (0.76-3.42)
Ongoing 4.1 (–2.7 to 11.0) 1.1 (0.3-2.0) 3.46 (1.86-6.44) 2.11 (0.68-6.59) 1.96 (0.62-6.25)
Previous 2.5 (–0.9 to 5.9) 1.1 (0.3-2.0) 2.26 (1.31-3.90) 1.14 (0.53-2.47) 1.20 (0.55-2.64)
Unspecified eating disorder

All 2.3 (0.7 to 3.9) 1.2 (0.7-1.7) 1.95 (1.49-2.54) 1.42 (0.98-2.07) 1.42 (0.97-2.07)
Ongoing 2.7 (–0.9 to 6.3) 1.2 (0.7-1.7) 2.37 (1.50-3.75) 1.04 (0.48-2.25) 1.17 (0.53-2.60)
Previous 2.2 (0.4 to 1.7) 1.2 (0.7-1.7) 1.84 (1.40-2.49) 1.35 (0.90-2.02) 1.34 (0.89-2.04)
0.4 1 8
HR (95% CI)
b
Comparisons are between children of mothers with eating disorders vs mothers without Adjusted for maternal smoking status, parity, maternal educational level, maternal
eating disorders. Circles indicate all children; squares, children with ongoing disease; psychiatric comorbidities, and maternal alcohol or substance use disorder in addition
diamonds, children with previous disease. Parent psychiatric comorbidities adjusted for to factors adjusted for in crude model.
included anxiety disorder, depressive disorder, ADHD, and ASD. c
Adjusted for paternal educational level, psychiatric comorbidities, and alcohol or
a
Adjusted for maternal age at birth, sex, and birth year. substance use disorder in addition to factors adjusted for in the first adjusted model.

Within-Family and Sensitivity Analyses

Complete baseline characteristics of the exposed children, by maternal eating disorder subtype, and
their full maternal cousins are presented in eTables 3 and 4 in the Supplement. The results based on
the within-family analysis (Table 3) were similar to those of the main analysis for the maternal
anorexia nervosa cohort (fully adjusted HR for ADHD, 1.85 [95% CI, 1.06-3.22]; fully adjusted HR for
ASD, 1.90 [95% CI, 0.47-7.65]), whereas estimates for the maternal unspecified eating disorder
cohort diminished and were no longer significant (fully adjusted HR for ADHD, 1.17 [95% CI,
0.72-1.91]; fully adjusted HR for ASD, 0.79 [95% CI, 0.21-2.95]). For the maternal bulimia nervosa
cohort, the risk of ADHD was more pronounced compared with the main analysis (fully adjusted HR,
30.92 [95% CI, 2.56-373.19]), and the analysis for ASD could not be performed owing to the small
sample size.
Analysis of unspecified eating disorder exposure without overlapping specific eating disorder
subtypes was similar to the main analysis (eTable 5 in the Supplement). There were no distinct
patterns or significant differences in analysis stratified by child sex (eTable 6 in the Supplement) or
birth cohort period (eTable 7 in the Supplement).
Discussion
In this population-based prospective cohort study, we observed an increased risk of ADHD and ASD
among children of mothers with eating disorders, regardless of subtype, compared with children of
mothers free of eating disorder diagnoses. Furthermore, we observed a tendency to a higher risk
among children of mothers with ongoing eating disorders that was most prominent among children
to mothers with anorexia nervosa.
Previous studies14,15 have observed poorer neurobehavioral, language, and motor development
(which could be indicative of neuropsychiatric disorders) in children of mothers with self-reported
eating disorders, whereas we could associate maternal eating disorder exposure with
neuropsychiatric diseases in an unselected study population. In contrast to previous studies, we
could also provide information on and adjust for many potential confounders, as well as adjust for
familial confounding. In general, the observed association could not be fully explained by parental
psychiatric comorbidity status.
Stratification into previous vs ongoing eating disorder revealed a tendency toward a higher risk
among children of mothers with ongoing eating disorders that, to the best of our knowledge, is a
novel finding. Although our results do not provide information on causality, some assumptions can
be generated. The risk of ADHD and ASD was twice as high (2.5-fold and 4.0-fold, respectively)
among children of mothers with ongoing anorexia nervosa compared with children of mothers with
Table 3. Within-Family Analysis (Full Maternal Cousin Clusters) of the Relative Risk of Neuropsychiatric Diseases Among Children of Mothers With Eating Disorders
ADHD ASD
HR (95% CI) HR (95% CI)
Maternal diagnosis No of casesa Crudeb Partially adjustedc Fully adjustedd No of casesa Crudeb Partially adjustedc Fully adjustedd
Anorexia nervosa 1400 1.59 2.06 1.85 1410 2.25 3.28 1.90
(1.03-2.45) (1.22-3.48) (1.06-3.22) (1.08-4.69) (1.12-9.65) (0.47-7.65)
Bulimia nervosa 351 7.32 33.33 30.92 354 3.16 NA NA
(2.27-23.57) (2.86-389.07) (2.56-373.19) (0.18-52.21)
Unspecified eating 1110 1.11 1.17 1.17 1125 1.11 0.82 0.79
disorder (0.72-1.70) (0.73-1.87) (0.72-1.91) (0.39-3.13) (0.22-2.98) (0.21-2.95)
c
Abbreviations: ADHD, attention-deficit hyperactivity disorder; ASD, autism spectrum Adjusted for maternal psychiatric comorbidities (anxiety disorder, depressive disorder,
disorder; HR, hazard ratio; NA, not applicable. ADHD, and ASD) and alcohol or substance use disorder in addition to factors adjusted
a
Indicates the number of families with full maternal cousins discordant for both for in crude model.
d
maternal eating disorder exposure and respective neuropsychiatric disease outcome Adjusted for paternal psychiatric comorbidities (anxiety disorder, depressive disorder,
(contributing to estimate by design, but all exposure-discordant families included in ADHD, and ASD) and alcohol or substance use disorder in addition to factors adjusted
analysis). for in the partially adjusted model.
b
Adjusted for maternal age at delivery, sex, and birth year.

previous anorexia nervosa. Hypothetically, these results are suggestive of an actual effect of disease-
specific factors mediating the association between a maternal eating disorder and childhood
neuropsychiatric disorder. For example, ongoing anorexia nervosa is associated with several
abnormal metabolic17,18 and endocrine biomarkers.17 Epigenetic changes have repeatedly been
suggested a potential mediator between maternal exposures and childhood outcomes,19 and specific
nutritional deficiencies have been linked to DNA hypomethylation.20 In fact, 1 study21 found lower
levels of cord blood DNA methylation, specifically in genes relevant for neuronal development, in
offspring of mothers with active eating disorder.
Interestingly, the risk of ADHD and ASD was also increased in children of mothers with previous
eating disorder. Whether mothers with previous eating disorder were in complete disease remission
during pregnancy is not known. Given the substantial number of women with eating disorders for
whom the disease course is chronic4,22 and there is potential risk of relapse during pregnancy,5,6
there might be women with disease relapse and/or residual eating disorder symptoms during
pregnancy within the group who would be defined as having a previous eating disorder. Moreover,
eating disorders are associated with an increased co-occurrence of other psychiatric conditions,23
which also was observed in the present study. Several positive genetic correlations between eating
disorders and other psychiatric diseases, including ADHD and eating disorders other than anorexia
nervosa,18 have been described. Hence, intergenerational transmission of a genetic risk of specific
psychiatric phenotypes is another potential rationale for the association between maternal eating
disorders and childhood neuropsychiatric diseases. To control for genetic factors, we adjusted for
parental psychiatric comorbidities, which attenuated the estimates of the main analysis slightly, but
most remained significantly increased. Interestingly, maternal anorexia nervosa exposure estimates
were generally attenuated to a lesser extent compared with estimates of other eating disorder
exposures. Hypothetically, this difference indicates that genetic transmission is associated with the
risk of ADHD and ASD in children of mothers with anorexia nervosa to a lesser extent compared with
children of mothers with bulimia nervosa or an unspecified eating disorder. In addition, we
performed an analysis based on exposed children compared with their full maternal cousins
accounting for 12.5% of their genetic risk, in which the estimates of children of mothers with anorexia
nervosa did not change significantly compared with the main analysis. The results from the family
analysis supports the hypothesis of a low genetic transmission effect on the association between
maternal anorexia nervosa exposure and offspring neuropsychiatric risk. Estimates of children of
mothers with bulimia nervosa remained significantly increased for ADHD, but with poor precision
owing to limited number of participants and outcomes. Clearly, we could only adjust for a minor part
of the genetic risk and can therefore not conclude that the observed association is not mediated via
familial confounding, but presumably the association would have been attenuated if this was
the case.
Strengths and Limitations

Our study has several major strengths, including the population-based approach and use of
nationwide registers with prospectively collected data, precluding recall bias, and an established high
validity of most diagnoses.19 However, our results should be interpreted within the context of the
study’s limitations. Although the positive predictive values of most diagnoses are high in data sources
from which exposure status was derived,24 the validity of eating disorders has not been assessed.
Moreover, eating disorders are still stigmatized diseases, meaning that there might still be
unrecorded cases and a risk of selecting cases with more severe disease. Furthermore, the outpatient
part of the patient register was initiated in 2001, which is why there may be a difference in the clinical
phenotype (ie, severity) of eating disorders before vs after this time. We attempted to address this
(and the increasing trend of both eating disorders and neuropsychiatric diagnoses) by matching on
birth year. The more frequent contact with health care in combination with a potential tendency to
increased awareness of developmental deviations in children among patients with ongoing diseases
such as eating disorders might result in a differential risk of disease detection compared with healthy

individuals (surveillance bias). In addition, although we adjusted for a large number of predefined
confounders, there might still be residual confounding, and likewise we could only adjust for a small
part of unmeasured familial confounding. Finally, despite being one of the largest studies to date (to
our knowledge), we acknowledge that numbers and precision were sometimes poor in stratified and
adjusted analyses. The relatively short median follow-up time of 9 to 13 years of age does not
introduce a bias per se but may impose difficulties generalizing the results to older groups.
Conclusions
In this prospective nationwide cohort study, we found an association between maternal eating
disorders and neuropsychiatric diseases in children that could not entirely be explained by parental
comorbidities or familial confounding. The risk of neuropsychiatric diseases was highest among
children of mothers with ongoing eating disorders during pregnancy. In addition to stressing the need
of future research addressing factors mediating this association, our results also implicate the
importance of clinical awareness and intensified support to women with eating disorders and their
children.
ARTICLE INFORMATION
Accepted for Publication: November 22, 2021.
Published: January 18, 2022. doi:10.1001/jamanetworkopen.2021.43947
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Mantel N
et al. JAMA Network Open.
Corresponding Author: Ängla Mantel, MD, PhD, Division of Clinical Epidemiology, Department of Medicine Solna,
Karolinska Institutet, Karolinska University Hospital, Eugeniahemmet T2, SE-171 76 Stockholm, Sweden (angla.
mantel@ki.se).
Author Affiliations: Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet,
Karolinska University Hospital, Stockholm, Sweden (Mantel, Örtqvist, Stephansson); Theme Women’s Health,
Department of Obstetrics, Karolinska University Hospital, Stockholm, Sweden (Mantel, Stephansson);
Department of Obstetrics and Gynecology, Visby County Hospital, Visby, Sweden (Örtqvist); Division of
Neonatology, Obstetrics and Gynecology, Department of Women’s and Children’s Health, Karolinska Institutet,
Stockholm, Sweden (Hirschberg); Department of Gynecology and Reproductive Medicine, Karolinska University
Hospital, Stockholm, Sweden (Hirschberg).
Author Contributions: Dr Mantel had full access to all the data in the study and takes responsibility for the
integrity of the data and the accuracy of the data analysis.
Concept and design: Mantel, Örtqvist, Hirschberg.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Mantel, Örtqvist.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Mantel.
Obtained funding: Mantel.
Administrative, technical, or material support: Mantel.
Supervision: Hirschberg, Stephansson.
Conflict of Interest Disclosures: None reported.
Funding/Support: This study was supported by Region Stockholm and award 2017-02051 from the Swedish
Research Council.
Role of the Funder/Sponsor: The sponsor had no role in the design and conduct of the study; collection,
management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and
decision to submit the manuscript for publication.

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SUPPLEMENT.
eMethods. Study Setting and Data Linkage
eFigure 1. Overview of Study Data Linkage and Covariates Obtained From Respective Data Source
eFigure 2. Illustration of Overlap Between Exposed Cohorts
eFigure 3. Hypothesized Directed Acyclic Graph of Maternal Eating Disorder and Neurodevelopmental Disorder in
Children
eFigure 4. Cumulative Incidence of Neuropsychiatric Outcomes Among Children of Mothers With Eating Disorder
and Their Controls
eTable 1. Definition of Pregnancy, Delivery, and Neonatal Characteristics Obtained From the Medical Birth Registry
eTable 2. International Classification of Disease Codes Used to Identify Parental Comorbidities
eTable 3. Maternal Pregnancy, Delivery, and Neonatal Characteristics of Exposed Children of Mothers With Eating
Disorder and Their Full Maternal Cousins
eTable 4. Parental Sociodemographic Factors and Psychiatric Comorbidities of Exposed Children of Mothers With
Eating Disorder and Their Full Maternal Cousins
eTable 5. Relative Risk of Neurodevelopmental Disorders Among Children of Mothers With Unspecified Eating
Disorder Without Overlapping Diagnoses
eTable 6. Relative Risk of Neurodevelopmental Disorders Among Children of Mothers With Eating Disorder
Stratified by Sex
eTable 7. Relative Risk of Neurodevelopmental Disorders Among Children of Mothers With Eating Disorder
Stratified by Birth Cohort
eReferences

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Original Investigation | Psychiatry

Analysis of Neurodevelopmental Disorders in Offspring of Mothers

Abstract Key Points

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JAMA Network Open. 2022;5(1):e2143947. doi:10.1001/jamanetworkopen.2021.43947

Study Setting, Data Sources, and Study Base

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which stores information on diseases or cause of death according to International Classification of

Exposed Cohorts and Matched Comparators

Figure 1. Flowchart of Study Population Generation

67 363 Multiple births excluded (2.9%)

2 296 104 Remaining births

10 277 Women with any prior eating

1412 Children with ≥1 full 4047 Children born to

3581 Children born to mothers

PIN indicates personal identification number.

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Outcomes and Follow-up

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Parental Educational Level and Psychiatric Comorbidity Status

The Offspring Risk of ADHD

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The Offspring ASD Risk

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A Attention-deficit/hyperactivity disorder HR, crude

Unspecified eating disorder

Unspecified eating disorder

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Within-Family and Sensitivity Analyses

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Strengths and Limitations

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