Research

JAMA Psychiatry | Original Investigation

Long-term Follow-up of Psychiatric Disorders in Children and Adolescents

Conceived by Assisted Reproductive Techniques in Sweden
Chen Wang, MPH; Anna L. V. Johansson, PhD; Kenny A. Rodriguez-Wallberg, MD, PhD; Mikael Landén, MD, PhD;
Catarina Almqvist, MD, PhD; Sonia Hernández-Díaz, MD, PhD; Anna S. Oberg, MD, PhD

Supplemental content
IMPORTANCE Individuals conceived with assisted reproductive techniques (ARTs) could be at
elevated risk of psychiatric disorders owing to potential adverse effects of the procedures
themselves, or because such traits or their risk factors may be more common in couples with
infertility.

OBJECTIVE To investigate the risk of psychiatric disorders in adolescents and young adults
conceived with ARTs and to evaluate the role of treatment-related parental characteristics.

DESIGN, SETTING, AND PARTICIPANTS This prospective follow-up of a nationwide birth cohort
used linkage of Swedish population registers with coverage through 2018. All children born in
Sweden from January 1, 1994, to December 31, 2006, were included in the analysis.
Follow-up was completed on December 31, 2018, when participants were 12 to 25 years of
age, and data was analyzed from March 17, 2020, to September 10, 2021.

EXPOSURES In vitro fertilization with or without intracytoplasmic sperm injection and transfer
of fresh or frozen-thawed embryos.

MAIN OUTCOMES AND MEASURES Clinical diagnoses of mood disorder, including major
depression, anxiety, obsessive-compulsive disorder (OCD), or suicidal behavior, were
identified from hospital records and outpatient specialist care. Suicide was additionally
identified from death certificates. Antidepressant use was identified from dispensations of
prescribed medications.

RESULTS A total of 1 221 812 children (48.6% female, 51.4% male) born between 1994 and
2006 were followed up to a median age of 18 (IQR, 15-21) years. Among these participants,
31 565 (2.6%) were conceived with ART. Compared with all others, adolescents conceived
with ART had an elevated risk of OCD (hazard ratio [HR], 1.35 [95% CI, 1.20-1.51]), but the
association was attenuated and no longer statistically significant after adjustment for parental
characteristics (adjusted HR [aHR], 1.10 [95% CI, 0.98-1.24]) and was no longer present when
restricted to individuals born to couples with known infertility (aHR, 1.02 [95% CI, 0.89-1.17]).
Adolescents conceived with ARTs were not at elevated risk of depression or suicidal behavior
compared with other adolescents (irrespective of parental infertility). Type of fertilization
(standard in vitro fertilization or intracytoplasmic sperm injection) had no association with
outcomes. Compared with non–ART-conceived children of couples with infertility, fresh, but
not frozen, embryo transfer was associated with a lower risk of mood disorders (aHR, 0.90
[95% CI, 0.83-0.97]), making frozen embryo transfer appear less advantageous when
directly contrasted with fresh embryo transfer.

CONCLUSIONS AND RELEVANCE These findings suggest that adolescents conceived with ARTs
around the millennium are not at risk of poor psychiatric health compared with the general
population, except for an elevated risk of OCD that may be explained by differences in
parental characteristics.

Author Affiliations: Author

affiliations are listed at the end of this
article.
Corresponding Author: Chen Wang,
MPH, Department of Medical
Epidemiology and Biostatistics,
Karolinska Institutet, Nobels väg 12A
JAMA Psychiatry. 2022;79(2):133-142. doi:10.1001/jamapsychiatry.2021.3647 17177 Stockholm, Sweden
Published online December 15, 2021. (chen.wang@ki.se).

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 Research Original Investigation Psychiatric Disorders in Children and Adolescents Conceived by Assisted Reproductive Techniques
T
hroughout 40 years of continuous development,
assisted reproductive techniques (ARTs) have helped
couples overcome infertility through in vitro fertiliza-
tion (IVF), resulting in more than 9 million ART births
worldwide by 2019.1 The practice is not without complica-
tions, in part owing to the high occurrence of multiple
gestations and their inherent complications. 2 However,
previous studies indicate that singletons conceived with
ARTs are also more likely to be born preterm, 3 with low
birth weight, 4,5 and with birth defects 6 compared with
spontaneously conceived children. These perinatal compli-
cations have been linked to neurocognitive development
impairment7,8 and mental health problems later in life.9,10
Greater occurrence of rare imprinting disorders such as
Angelman and Beckwith-Wiedemann syndromes after ART
has also raised concerns that the techniques could disrupt
the epigenetic control of chromatin during early embryonic
development.11
Depression and anxiety are common psychiatric disor-
ders that can lead to considerable problems, and at worst to
suicide, which in 2015 was the second leading cause of
death among young people globally.12 Both conditions can
debut in childhood and early adolescence.13 Major depres-
sion and anxiety tend to cluster within families, seemingly
driven by strong genetic components but also by shared
family environment.14-16 Because some researchers argue
that emotional stress can contribute to infertility,17 depres-
sion and anxiety could be more common among children
born to couples with infertility, 18 with ART use further
f a c i l it at i ng t h e t r a n s m i s s i o n o f s u c h t r a it s t o t h e
next generation. However, the psychiatric health of children
a n d a d o l e s c e nt s c o n c e i ve d b y A RTs h a s n o t b e e n
studied extensively, 1 9 and previous studies relied on
self-reports20,21 as well as inappropriate model adjustments,
including mediators such as preterm birth.22
Because observed elevated risks among children con-
ceived with ARTs could be due to factors associated with
the parental underlying infertility rather than the interven-
tion per se, it is vital to disentangle the influence of ARTs
from parental characteristics, including infertility and psy-
chiatric health. Furthermore, there is an urgent need to
understand the long-term consequences of specific ART
procedures, because technical advances such as intracyto-
plasmic sperm injection (ICSI), prolonged culture of
embryos in the laboratory, and freezing and thawing of
embryos are now commonly and widely implemented in
clinical practice.23 With growing numbers of children con-
ceived with ART reaching adolescence and young adult-
hood, this study was undertaken to advance our under-
standing of the mental health of this group. In this
nationwide, register-based cohort study, we aimed to (1)
quantify the occurrence of psychiatric disorders, use of anti-
depressants, and suicidal behavior among children and ado-
lescents conceived by ARTs and (2) assess whether the asso-
ciation of ARTs with these outcomes spanning across
preteen years, adolescence, and early adulthood is driven
by parental characteristics associated with the indication for
ART use rather than the use per se.
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Key Points
Question Are children conceived with assisted reproductive
techniques at risk of poor psychiatric health owing to adverse
effects of the treatment or parental background factors?
Findings In this long-term follow-up of a Swedish birth cohort of
1 221 812 children, those conceived with assisted reproductive
techniques had an elevated risk of obsessive-compulsive disorder
(OCD) but not of any other types of anxiety, depression, or suicide
compared with all other children. The risk of OCD was no longer
present in comparison with children born to couples with
infertility.
Meaning These findings suggest that adolescents conceived with
ART are not at risk of poor psychiatric health compared with the
general population, except for an elevated risk of OCD that may be
explained by differences in parental characteristics.
Methods
Study Population
This cohort study is based on a linkage of Swedish national reg-
isters, enabled by the personal identification number as-
signed to each individual that allows researchers to track in-
dividuals across multiple registers.24 The Swedish Medical
Birth Register (MBR) was established in 1973 and holds infor-
mation from standardized forms used to record antenatal and
delivery care.25 Using this register, we identified a cohort of
all children born in Sweden between January 1, 1994, and De-
cember 31, 2006 (Figure 1) and followed them up from birth
until December 31, 2018, allowing follow-up to a minimum age
of 12 years and a maximum age of 25 years. Information on emi-
gration or death was retrieved from the Cause of Death Reg-
ister and the Register of the Total Population, and fathers were
identified using the Swedish Multi-generation Register.26 An
overview of the information retrieved from the different reg-
ister sources is given in eTable 1 in the Supplement. The Re-
gional Ethics Committee in Stockholm approved the study and
waived the need for individual informed consent, as is cus-
tomary for register-based studies in Sweden. This study fol-
lowed the Strengthening the Reporting of Observational Stud-
ies in Epidemiology (STROBE) reporting guideline.
Ascertainment of Parental Fertility Status and ART Use
Since 1982, women included in the MBR have been asked about
infertility (defined as taking >1 year of active attempts to
achieve pregnancy) in the standard interview at the first an-
tenatal visit. At the same time, the MBR also started collect-
ing information from all IVF clinics in the country to record
details on the births conceived with ARTs (use of standard IVF
or ICSI or fresh or frozen embryos). From 1995, the enroll-
ment interview also included a follow-up question regarding
potential use and type of fertility assistance. The Swedish Na-
tional Patient Register records diagnoses and procedures from
all hospitalizations since 1987 and from specialist outpatient
care since 2001.27 In both the MBR and National Patient Reg-
ister, medical conditions are recorded using codes from the In-
ternational Classification of Diseases versions in use.28 To op-
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 Psychiatric Disorders in Children and Adolescents Conceived by Assisted Reproductive Techniques Original Investigation Research

timize exposure ascertainment, we identified parental

Figure 1. Flowchart of the Study Population
infertility and potential use of ARTs by combining the infor-
mation from IVF clinics, diagnostic or procedure coding in the
1 238 153 Includes all births in Sweden
National Patient Register, and maternal self-report in the MBR
(eTable 2 in the Supplement). Use of ARTs was grouped into
Noneligible births
standard IVF and ICSI. Based on the IVF clinic reports, proce- 4201 Stillbirths
dures were further grouped according to use of fresh or fro- 5544 Missing ID, child
6596 Missing ID, paternal
zen embryos.

Follow-up of Offspring Psychiatric Health 1 221 812 Study population

Children in the cohort were followed up for the occurrence of

psychiatric disorders, suicide behavior, and antidepressant use 255 398 Missing covariates
(20.9%)
(eTable 2 in the Supplement). Psychiatric disorders were iden-
tified by International Statistical Classification of Diseases and
Related Health Problems, Tenth Revision, diagnostic codes. Imputation of covariates with major missing
Herein, we focused on mood (affective) (F30-F39) and anxi- data (maternal smoking status, civil status,
maternal BMI, and region of residence)
ety (F40-F42 and F93) disorders. We further studied major de-
pression (F32 and F33) specifically and separated the anxiety
Multiple imputation 966 414 Children with
group into obsessive-compulsive disorders (OCD; F42) and all 1 208 554 Each imputationa complete informationa
other anxiety disorders (non-OCD; F40, F41, and F93). We con-
sidered both suicide attempts and completed suicide with de-
126 324 Children born to couples 107 178 Children born to couples
termined intent (X60-X84) from patient records and death cer- with infertilityb with infertilityb
tificates. Use of antidepressants (Anatomical Therapeutic
Chemical Classification code N06A) was identified using the 31 428 Children conceived 25 691 Children conceived
Swedish Prescribed Drug Register,29 which was established in by ARTsc by ARTsc

June 2005 and records all dispensed medications outside the

hospital, using the Anatomical Therapeutic Chemical Classi-
fication System codes. The medications were further catego-
rized as selective serotonin reuptake inhibitor (SSRI) or non-
SSRI antidepressants (eTable 2 in the Supplement).30 Finally,
we also defined severe depression as the combination of a de-
pression diagnosis and dispensation of an antidepressant.
Parental Background Characteristics
In addition to parental infertility, we considered a wide vari-
ety of potential confounding factors that could be determi-
nants of infertility (common causes 0 [CC0] in the eFigure in
the Supplement) and/or ART use (common causes 1 [CC1] in the
eFigure in the Supplement), while also influencing the psy-
chiatric health of the offspring. The characteristics included
in the study were: (1) parental demographics (maternal and pa-
ternal age at delivery, highest level of attained education, and
country of origin) obtained from Statistics Sweden; (2) mater-
nal characteristics at the start of pregnancy (parity, region of
residence, cohabitation status, smoking, and overweight or
obesity); (3) maternal health history (polycystic ovary syn-
drome and endometriosis); and (4) a summary indicator of pa-
rental psychiatric history if either parent had a diagnostic rec-
ord of a mood disorder or a nonaffective psychosis (mainly
relying on hospitalizations, thus capturing more severe con-
ditions). Because this study focused on the overall conse-
quences of ART use, we did not include possible mediating fac-
tors such as multiple gestation,2 preterm birth,4 or low birth
weight.4
Statistical Analysis
Data were analyzed from March 17, 2020, to September 10,
2021. First, parental background characteristics were summa-
Contrasting specific Contrasting specific
ART procedures ART procedures
11 467 ICSI vs 19 961 IVF 9433 ICSI vs 16 258 IVF
3622 Frozen ET vs 3011 Frozen ET vs
22 539 fresh ET 18 274 fresh ET
ART indicates assisted reproductive technique; BMI, body mass index
(calculated as weight in kilograms divided by height in meters squared); ET,
embryo transfer; ICSI, intracytoplasmic sperm injection; ID, identification
number; and IVF, in vitro fertilization.
a
Indicates analysis phase 1: participants conceived using ARTs vs the general
population.
b
Indicates analysis phase 2: participants conceived using ARTs vs non-ARTs
with infertility.
c
Indicates analysis phase 3: contrasting specific ART procedures.
rized according to parental infertility status and use of ARTs,
for which the 3 main and mutually exclusive groups were (1)
all children conceived with ARTs; (2) children of couples with
infertility who did not use ARTs; and (3) children of couples
with no history of infertility (ie, all other children). For the ARTs
group, we further considered standard IVF and ICSI sepa-
rately, and for the subsample with information available, the
use of frozen vs fresh embryos. In a similar fashion, we also
explored the overall association of parental characteristics with
the outcomes of interest.
For each outcome of interest, children were followed up
from birth until the first documented occurrence of that out-
come, death, emigration, or the end of the study period. For
each of the 3 main groups defined by parental infertility and
ART use, we first plotted the cumulative incidence of each out-
come up to 25 years of age using Kaplan-Meier estimates.
Of all children, 20.9% had missing information in at least
1 covariate of interest. Under the missing random assump-

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 Research Original Investigation Psychiatric Disorders in Children and Adolescents Conceived by Assisted Reproductive Techniques
tion, we conducted multiple imputation with fully condi-
tional specification method.31 Given the large sample size, we
opted to exclude the few children with missing information
on parental educational attainment (<1%) or country of origin
(<1%) before imputing all variables with more than 1% miss-
ing. The imputed covariates and their corresponding fre-
quency of missing were mother’s region of residence (2.8%),
smoking (5.7%), civil status (5.8%), and body mass index
(14.8%). In each of the 10 imputation sets, we performed strati-
fied Cox proportional hazards regression with age as under-
lying time scale and allowing the baseline hazard to vary with
birth year. The final estimates were obtained by pooling the
results from the imputed data sets using Rubin’s rules.32 To ex-
plore the association between ARTs and psychiatric out-
comes, we first compared children conceived with ARTs with
all other children (irrespective of parental infertility status) and
then with children whose parents had infertility. After sepa-
rately comparing either type of fertilization (standard IVF or
ICSI) and embryo transfer (fresh or frozen) with the non-
treated children born to couples with infertility, we also com-
pared these specific procedures among the treated children
only. For all comparisons, we estimated unadjusted associa-
tions (crude) and associations with full adjustment, includ-
ing parental demographics, maternal health conditions, and
parental psychiatric history. Schoenfeld residual plots were
used to evaluate the proportional hazards assumption for all
models. The only noted violation was owing to very few cases
of suicidal behavior in young children (younger than 7 years),
and, owing to the uncertainty in these reports, we chose to pri-
marily consider suicidal behavior from 12 years or older. In a
supplemental analysis, we refitted all models in the sample of
children with complete information on covariates (complete-
case analysis). We also evaluated specific types of antidepres-
sants used (SSRIs and non-SSRIs) in both multiple imputa-
tion and complete-case samples. All analyses were conducted
using SAS, version 9.4.4 (SAS Institute Inc) and Stata, version
15.1 (StataCorp LLC).
Results
Of the 1 221 812 children followed up to a median age of 18 (IQR,
15-21) years, 127 123 (10.4%) were born to couples with infer-
tility and 31 565 (2.6%) were conceived with ARTs (Table 1).
Compared with couples with no infertility, mothers in couples
experiencing infertility were on average older (eg, ≥40 years,
6345 [5.0%] vs 25 917 [2.4%]) and were more likely to be pri-
miparous (70 531 [55.5%] vs 445 257 [40.7%]), have over-
weight or obesity (38 405 [30.2%] vs 289 366 [26.4%]), and
have been diagnosed with polycystic ovary syndrome (1993
[1.6%] vs 1218 [0.1%]) or endometriosis (2341 [1.8%] vs 2942
[0.3%]). Among couples with infertility, those who received
ARTs (IVF or ICSI) were more educated (eg, mothers with post-
secondary education, 16 965 [53.7%] vs 44 502 [46.6%]), and
the mothers were less likely to smoke (1914 [6.1%] vs 10 827
[11.3%]). Women using ARTs were also more likely to have been
diagnosed with polycystic ovary syndrome (715 [2.3%] vs 1278
[1.3%]) or endometriosis (1275 [3.7%] vs 1066 [1.1%]), espe-
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cially in the group that underwent standard IVF (528 [2.6%]
and 976 [4.9%], respectively). Similar to ICSI, the use of fro-
zen embryos became more common over time, but no sub-
stantial differences in parental characteristics were noted be-
tween those conceived through frozen vs fresh embryos. A
complementary exposé of the overall association between pa-
rental characteristics and the outcomes under study is pro-
vided in eTable 3 in the Supplement.
Among children born to couples without infertility, the es-
timated cumulative incidence at the end of puberty (18 years
of age) was 5.6% for anxiety, 0.9% for complete or attempted
suicide, and 7.0% for antidepressant use (Figure 2). The cu-
mulative incidence of mood disorders was 4.4%, with depres-
sion accounting for the vast majority (4.2%; specific plot avail-
able at request). Among children conceived with ARTs, the
corresponding cumulative incidences were overall compa-
rable or lower across all ages. Children of couples with infer-
tility who were not conceived with ARTs were noted to be at
slightly elevated overall risk of anxiety (6.2% [95% CI, 6.0%-
6.4%]) and mood disorders (4.7% [95% CI, 4.5%-4.9%])
(Figure 2).
In a regression comparison with all other children (irre-
spective of parental infertility), children conceived with ARTs
were not at any disadvantage with respect to the studied out-
comes (Table 2), except for a slightly elevated rate of anxiety
(hazard ratio [HR], 1.07 [95% CI, 1.02-1.12]), primarily driven
by OCD (HR, 1.35 [95% CI, 1.20-1.51]). Although adjustment for
parental characteristics attenuated observed inverse associa-
tions with mood disorder and suicide behavior, as well as a sub-
stantial part of the association with OCD (adjusted HR [aHR],
1.10 [95% CI, 0.98-1.24]), it had no influence on the small dif-
ference in anxiety overall (aHR, 1.08 [95% CI, 1.03-1.13]). This
was furthermore matched by a slightly elevated rate of anti-
depressant use (aHR, 1.05 [95% CI, 1.01-1.09]). When the com-
parison was restricted to children of couples with known in-
fertility, however, no differences were seen for OCD (aHR, 1.02
[95% CI, 0.89-1.17]) or any of the other outcomes in adjusted
models (Table 2). In further evaluation of specific ART proce-
dures, children conceived with ICSI were no different from chil-
dren of couples with infertility conceived without ARTs, or by
standard IVF (Table 3). Children conceived with fresh, but not
frozen, embryo transfer had a lower risk of mood disorders
compared with children of couples with infertility conceived
without ARTs (aHR, 0.90 [95% CI, 0.83-0.97]). In the direct con-
trast of the 2 procedures, frozen embryo transfer appeared as-
sociated with elevated risk of mood disorders (aHR, 1.25 [95%
CI, 1.03-1.52]) and antidepressant use (aHR, 1.16 [95% CI, 1.01-
1.33]). Finally, the complete cases analysis revealed similar but
somewhat attenuated estimates with wider CIs (eTables 4 and
5 in the Supplement), and the evaluation of SSRI and non-
SSRI use showed similar results (eTables 6 and 7 in the
Supplement).
Discussion
Overall, we found that adolescents conceived with ARTs had
a slightly higher risk of anxiety and antidepressant use but a
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 Psychiatric Disorders in Children and Adolescents Conceived by Assisted Reproductive Techniques Original Investigation Research

Table 1. Parental Characteristics Among the Study Cohort

Participant group, No. (%)a

Children of couples with known infertility
Conceived with ARTs
Children of couples
with no known Conceived Type of ART Type of embryo transferb
infertility without ARTs IVF ICSI Fresh Frozen
Characteristic (n = 1 094 689) (n = 95 558) (n = 20 067) (n = 11 498) (n = 22 603) (n = 3636)
Year of child’s birth
1994-1996 278 775 (25.5) 19 353 (20.3) 3702 (18.4) 838 (7.3) 3617 (16.0) 414 (11.4)
1997-1999 229 477 (21.0) 19 687 (20.6) 3936 (19.6) 2854 (24.8) 4952 (21.9) 557 (15.3)
2000-2002 237 583 (21.7) 23 655 (24.8) 4569 (22.8) 2854 (24.8) 5401 (23.9) 581 (16.0)
2003-2006 348 854 (31.9) 32 863 (34.4) 7860 (39.2) 4952 (43.1) 8633 (38.2) 2084 (57.3)
Paternal characteristics
Age at birth, y
<25 70 306 (6.4) 2789 (2.9) 70 (0.3) 43 (0.4) 49 (0.2) 3 (0.1)
25-29 262 185 (24.0) 17 776 (18.6) 1385 (6.9) 906 (7.9) 1636 (7.2) 180 (5.0)
30-34 386 434 (35.3) 34 292 (35.9) 6432 (32.1) 3557 (30.9) 7217 (31.9) 1087 (29.9)
35-39 239 978 (21.9) 24 749 (25.9) 7132 (35.5) 4013 (34.9) 8108 (35.9) 1311 (36.1)
≥40 135 786 (12.4) 15 952 (16.7) 5048 (25.2) 2979 (25.9) 5593 (24.7) 1055 (29.0)
Highest attained educational level
Secondary
Lower 134 244 (12.3) 11 041 (11.6) 1867 (9.3) 1047 (9.1) 2075 (9.2) 321 (8.8)
Upper 563 742 (51.5) 49 976 (52.3) 9113 (45.4) 5483 (47.7) 10 458 (46.3) 1652 (45.4)
Postsecondary 390 908 (35.7) 34 168 (35.8) 9022 (45.0) 4951 (43.1) 10 033 (44.4) 1655 (45.5)
Missing 5795 (0.5) 373 (0.4) 65 (0.3) 17 (0.1) 37 (0.2) 8 (0.2)
Country of birth
Nordic 913 443 (83.4) 83 488 (87.4) 18 073 (90.1) 10 201 (88.7) 20 355 (90.1) 3303 (90.8)
Other European 68 008 (6.2) 5050 (5.3) 948 (4.7) 636 (5.5) 1130 (5.0) 172 (4.7)
Non-European 112 997 (10.3) 7002 (7.3) 1044 (5.2) 659 (5.7) 1116 (4.9) 161 (4.4)
Unknown 241 (0.02) 18 (0.02) 2 (0.01) 2 (0.02) 2 (0.01) 0
Maternal characteristics
Age at birth, y
<25 187 449 (17.1) 9389 (9.8) 265 (1.3) 282 (2.5) 302 (1.3) 33 (0.9)
25-29 375 821 (34.3) 29 160 (30.5) 2941 (14.7) 2244 (19.5) 3692 (16.3) 471 (13.0)
30-34 359 377 (32.8) 34 564 (36.2) 8345 (41.6) 4876 (42.4) 9711 (43.0) 1472 (40.5)
35-39 146 125 (13.3) 18 125 (19.0) 7054 (35.2) 3533 (30.7) 7694 (34.0) 1392 (38.3)
≥40 25 917 (2.4) 4320 (4.5) 1462 (7.3) 563 (4.9) 1204 (5.3) 268 (7.4)
Highest educational level attained
Secondary
Lower 92 321 (8.4) 6576 (6.9) 955 (4.8) 498 (4.3) 1059 (4.7) 131 (3.6)
Upper 488 940 (44.7) 44 212 (46.3) 8209 (40.9) 4873 (42.4) 9429 (41.7) 1453 (40.0)
Postsecondary 508 071 (46.4) 44 502 (46.6) 10 852 (54.1) 6113 (53.2) 12 087 (53.5) 2047 (56.3)
Missing 5357 (0.5) 268 (0.3) 51 (0.3) 14 (0.1) 28 (0.1) 5 (0.1)
Country of birth
Nordic 922 685 (84.3) 83 551 (87.4) 17 879 (89.1) 10 113 (88.0) 20 166 (89.2) 3259 (89.6)
Other European 49 048 (4.5) 3972 (4.2) 805 (4.0) 534 (4.6) 966 (4.3) 136 (3.7)
Non-European 119 854 (10.9) 7905 (8.3) 1367 (6.8) 849 (7.4) 1463 (6.5) 239 (6.6)
Unknown 3102 (0.3) 130 (0.1) 16 (0.1) 2 (0.02) 8 (0.04) 2 (0.1)
Region of residence in Sweden
East 346 953 (31.7) 30 460 (31.9) 7725 (38.5) 3450 (30.0) 7834 (34.7) 1137 (31.3)
Central 246 278 (22.5) 19 925 (20.9) 4017 (20.0) 2204 (19.2) 4580 (20.3) 706 (19.4)
North 85 346 (7.8) 6868 (7.2) 1194 (6.0) 871 (7.6) 1435 (6.3) 192 (5.3)
South 163 551 (14.9) 17 866 (18.7) 3151 (15.7) 2144 (18.6) 4044 (17.9) 453 (12.5)
West 214 837 (19.6) 18 907 (19.8) 3849 (19.2) 2749 (23.9) 4604 (20.4) 1136 (31.2)

(continued)

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 Research Original Investigation Psychiatric Disorders in Children and Adolescents Conceived by Assisted Reproductive Techniques

Table 1. Parental Characteristics Among the Study Cohort (continued)

Participant group, No. (%)a

Children of couples with known infertility
Conceived with ARTs
Children of couples
with no known Conceived Type of ART Type of embryo transferb
infertility without ARTs IVF ICSI Fresh Frozen
Characteristic (n = 1 094 689) (n = 95 558) (n = 20 067) (n = 11 498) (n = 22 603) (n = 3636)
Missing 37 724 (3.4) 1532 (1.6) 131 (0.7) 80 (0.7) 106 (0.5) 12 (0.3)
Parity
1 445 257 (40.7) 51 122 (53.5) 12 220 (60.9) 7189 (62.5) 14 500 (64.2) 1900 (52.3)
2 407 524 (37.2) 31 160 (32.6) 6081 (30.3) 3428 (29.8) 6429 (28.4) 1327 (36.5)
3 165 230 (15.1) 9851 (10.3) 1384 (6.9) 720 (6.3) 1325 (5.9) 327 (9.0)
≥4 76 678 (7.0) 3425 (3.6) 382 (1.9) 161 (1.4) 349 (1.5) 82 (2.3)
Smoking
Yes 128 043 (11.7) 10 827 (11.3) 1325 (6.6) 589 (5.1) 1352 (6.0) 181 (5.0)
Missing 65 988 (6.0) 2452 (2.6) 1382 (6.9) 823 (7.2) 1689 (7.5) 254 (7.0)
Overweight or obese
Yes 289 366 (26.4) 29 194 (30.6) 5580 (27.8) 3631 (31.6) 6593 (29.2) 1023 (28.1)
Missing 164 958 (15.1) 9977 (10.4) 2989 (14.9) 1594 (13.9) 3428 (15.2) 510 (14.0)
Civil status
Cohabitating 974 335 (89.0) 91 099 (95.3) 18 595 (92.7) 10 691 (93.0) 20 904 (92.5) 3369 (92.7)
Living alone 53 053 (4.8) 2383 (2.5) 144 (0.7) 82 (0.7) 104 (0.5) 30 (0.8)
Missing 67 301 (6.1) 2076 (2.2) 1328 (6.6) 725 (6.3) 1595 (7.1) 237 (6.5)
Maternal medical conditions
PCOS 1218 (0.1) 1278 (1.3) 528 (2.6) 187 (1.6) 495 (2.2) 89 (2.4)
Endometriosis 2942 (0.3) 1066 (1.1) 976 (4.9) 299 (2.6) 963 (4.3) 158 (4.3)
Parental psychiatric historyc
Mood disorders 26 949 (2.5) 2458 (2.6) 549 (2.7) 265 (2.3) 580 (2.6) 82 (2.3)
Psychosis 3561 (0.3) 294 (0.3) 42 (0.2) 32 (0.3) 44 (0.2) 8 (0.2)
b
Abbreviations: ARTs, assisted reproductive techniques; ICSI, intracytoplasmic Concerns a subset (n = 26 239) of participants for whom type of embryo
sperm injection; IVF, in vitro fertilization; PCOS, polycystic ovary syndrome. transfer was recorded.
a c
Percentages have been rounded and may not total 100. Summary indicator of either parent having a diagnosis.

lower risk of mood disorder and suicidal behavior compared
with all other children. Importantly, the observed differences
in risk were explained by differences in parental characteris-
tics, including the underlying infertility, rather than the ART
intervention itself. Type of fertilization (standard IVF or ICSI)
had no association with outcomes. Fresh but not frozen em-
bryo transfer was associated with a lower risk of mood disor-
ders when compared with children from couples with infer-
tility who conceived without ARTs, making frozen embryo
transfer appear less advantageous in direct comparison with
fresh embryo transfer.
This nationwide register-based cohort study enabled in-
vestigation of psychiatric health outcomes based on clinical
diagnosis and medication use, with follow-up into adoles-
cence and early adulthood. Children conceived with ART were
found to be at a slightly elevated risk of anxiety compared with
all other children, largely driven by an excessive risk of OCD.
After adjustment for parental characteristics, children con-
ceived with ART were also slightly more likely to be pre-
scribed antidepressants. At present, SSRIs are still the most
commonly prescribed class of antidepressants for both de-
pression and anxiety,33 whereas prescription of non-SSRI an-
tidepressants might reflect a more severe depressive disorder.30
However, the slightly elevated risks were no longer seen when
the comparison was made only among individuals whose par-
ents experienced infertility. For mood disorders and suicidal
behavior, adolescents conceived with ART were if anything at
lower risk compared with all other adolescents, and this ap-
peared to be explained by differences in parental background
characteristics. Depression, which accounted for most mood
disorders in children and adolescents, consequentially fol-
lowed the same pattern. Before our study, the research on psy-
chiatric disorders in children conceived with ART was scarce
and findings were conflicting. An early study that relied on self-
reported outcomes20 raised concerns for depression and anxi-
ety levels among children conceived with ART, but the find-
ings could not be reproduced in a follow-up study.21 Scanning
any mental disorders (ICD-10 codes F00-F99), a recent study
in Finland22 followed up 17 610 singletons conceived using ART
and found a higher risk of any psychiatric diagnosis com-
pared with the general population. However, the results for de-
pression as well as anxiety were underpowered, and interpre-
tation was complicated by the control for prematurity, which
could be a mediator of a potential effect of ART. Last but most
important, none of previous studies disentangled the poten-
tial influence of the fertility treatment from the underlying in-

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 Psychiatric Disorders in Children and Adolescents Conceived by Assisted Reproductive Techniques Original Investigation Research

Figure 2. Estimated Cumulative Incidence of Indices of Psychiatric Health to 25 Years of Age,

According to Parental Infertility and Use of Assisted Reproductive Techniques (ARTs)

A Anxiety B Mood disorder

0.15 0.12
ART, infertility
No ART, infertility 0.10
0.12
No ART, no infertility

Cumulative incidence, %
Cumulative incidence, %

0.08
0.09
0.06
0.06
0.04

0.03
0.02

0 0
0 5 10 15 20 25 0 5 10 15 20 25
Attained age, y Attained age, y

C Antidepressant use D Suicide

0.25 0.025

0.20 0.020
Cumulative incidence, %

Cumulative incidence, %

0.15 0.015

0.10 0.010

0.05
0.005

0 0
0 5 10 15 20 25 0 5 10 15 20 25
Attained age, y Attained age, y

Shaded areas indicate 95% CIs.

fertility, which has been shown to be associated with poorer
mental health outcomes.18
This long- and wide-spanning birth cohort also enabled
exploration of the association of outcomes with different
ARTs. When compared with spontaneously conceived chil-
dren of couples with infertility, we found no substantial dif-
ferences in the studied outcomes for children conceived by
ICSI, standard IVF, or frozen embryo transfer, but observed
a lower risk of mood disorder for children conceived by
fresh embryo transfer. In the direct comparison of types of
embryo transfer, the group conceived with frozen embryo
thus appeared at elevated risk of depression and use of anti-
depressants. Whether the findings could be due to a benefi-
cial causal effect or perhaps more plausibly unmeasured
confounding, we note that they raise no concerns for the
procedures’ potential influence on psychiatric health. In
previous contrasts, frozen embryo transfer has appeared
more favorable with respect to preterm birth and low birth
weight,34 whereas a recent Swedish study3 found it associ-
ated with higher mortality in the first year of life. We note
that as the technology has improved over time, with vitrifi-
cation replacing slow freezing, so have the indications for
use, with elective freeze-all for later transfer being advo-
cated in specific clinical situations. It will thus be necessary
to continue to monitor the outcomes of children born from
frozen embryo transfer.
Prospectively gathered data in national registers allowed
thorough consideration of parental background characteris-
tics and comprehensive identification of ART use from spe-
cific IVF-clinic reports, general medical records (diagnostic or
procedure codes), and maternal self-report. Because the de-
gree of coverage from either source varies, but each is ex-
pected to contain few false-positive findings, we combined all
sources to boost sensitivity without compromising specific-
ity. Although infertility was primarily based on mothers’ re-
sponse to questions about involuntary childlessness and time
to pregnancy at enrollment in antenatal care, this informa-
tion was further complemented with potential clinical diag-
nosis of infertility.
Limitations
Our study also has some limitations. Anxiety and mood dis-
orders are not typically childhood-onset disorders, and our
study with follow-up mostly focusing on adolescence is

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 Research Original Investigation Psychiatric Disorders in Children and Adolescents Conceived by Assisted Reproductive Techniques

Table 2. Association Between Assisted Reproductive Techniques and Indices of Psychiatric Health

No. of events by group HR (95% CI)

Indices of psychiatric health Exposed Nonexposed Crudea Adjustedb
ARTs-conceived children compared with all other children
Anxiety 1725 71 887 1.07 (1.02-1.12) 1.08 (1.03-1.13)
OCD 307 9782 1.35 (1.20-1.51) 1.10 (0.98-1.24)
Non-OCD 1557 67 104 1.05 (1.00-1.10) 1.07 (1.02-1.13)
Mood disorder 1142 55 555 0.93 (0.88-0.99) 0.99 (0.93-1.05)
Depression 1075 51 997 0.94 (0.88-1.00) 0.98 (0.92-1.04)
Abbreviations: ARTs, assisted
Severe depressionc 933 44 727 0.93 (0.87-0.99) 0.98 (0.92-1.05)
reproductive techniques; HR, hazard
Suicide 196 11 733 0.77 (0.66-0.89) 1.03 (0.89-1.19) ratio; OCD, obsessive-compulsive
Antidepressant use 2383 109 360 1.03 (0.99-1.07) 1.05 (1.01-1.09) disorder.
a
The Cox proportional hazards
ARTs-conceived children compared with non–ARTs-conceived children with parental infertility
regression model was stratified by
Anxiety 1725 5931 0.98 (0.93-1.03) 1.02 (0.96-1.08) birth year.
b
OCD 307 890 1.14 (1.00-1.30) 1.02 (0.89-1.17) The model was adjusted for parents’
age at delivery, country of origin,
Non-OCD 1557 5499 0.96 (0.91-1.02) 1.01 (0.95-1.07)
highest educational attainment,
Mood disorder 1142 4386 0.89 (0.83-0.95) 0.95 (0.89-1.02) parity, civil status, region of
residence, maternal smoking status,
Depression 1075 4114 0.89 (0.83-0.95) 0.95 (0.89-1.02)
maternal overweight and obesity,
Severe depressionc 933 3566 0.88 (0.82-0.95) 0.94 (0.87-1.01) maternal medical conditions, and
Suicide 196 879 0.77 (0.66-0.90) 0.92 (0.78-1.08) parental psychiatric history.
c
Diagnosis of depression combined
Antidepressant use 2383 8620 0.95 (0.91-0.99) 1.00 (0.95-1.05)
with antidepressant use.

Table 3. Association Between Specific Assisted Reproductive Techniques and Indices of Psychiatric Health

Adjusted HR (95% CI)a

Type of fertilization Type of embryo transfer
Psychiatric diagnosis IVF ICSI Fresh Frozen
ARTs compared with non-ARTs with parental infertility
Anxiety 1.00 (0.94-1.07) 1.05 (0.96-1.15) 0.98 (0.92-1.04) 1.08 (0.92-1.26)
OCD 0.97 (0.83-1.14) 1.11 (0.91-1.35) 1.02 (0.88-1.19) 1.14 (0.80-1.61)
Non-OCD 1.00 (0.93-1.07) 1.04 (0.95-1.14) 0.97 (0.91-1.04) 1.02 (0.86-1.21)
Mood disorder 0.95 (0.88-1.03) 0.94 (0.84-1.05) 0.90 (0.83-0.97) 1.07 (0.89-1.29)
Depression 0.95 (0.87-1.03) 0.94 (0.84-1.05) 0.90 (0.83-0.98) 1.09 (0.90-1.32)
Severe depression 0.95 (0.87-1.04) 0.91 (0.81-1.03) 0.90 (0.83-0.98) 1.04 (0.84-1.28)
Suicide 0.95 (0.79-1.14) 0.87 (0.67-1.14) 0.91 (0.76-1.09) 0.92 (0.56-1.51)
Abbreviations: ART, assisted
Antidepressant drug use 0.97 (0.92-1.03) 1.05 (0.97-1.13) 0.97 (0.92-1.02) 1.09 (0.96-1.24) reproductive technique; HR, hazard
ART procedures directly compared ratio; ICSI, intracytoplasmic sperm
injection; IVF, in vitro fertilization;
Anxiety 1 [Reference] 1.02 (0.92-1.13) 1 [Reference] 1.12 (0.95-1.32)
OCD, obsessive-compulsive disorder.
OCD 1 [Reference] 1.08 (0.86-1.36) 1 [Reference] 1.13 (0.79-1.62) a
The model was adjusted for birth
Non-OCD 1 [Reference] 1.02 (0.92-1.14) 1 [Reference] 1.08 (0.91-1.29) year, parents’ age at delivery,
Mood disorder 1 [Reference] 1.01 (0.89-1.15) 1 [Reference] 1.25 (1.03-1.52) country of origin, highest
educational attainment, parity, civil
Depression 1 [Reference] 1.01 (0.89-1.15) 1 [Reference] 1.28 (1.05-1.57)
status, region of residence,
Severe depression 1 [Reference] 0.97 (0.84-1.12) 1 [Reference] 1.24 (1.00-1.54) maternal smoking status, maternal
Suicide 1 [Reference] 0.91 (0.65-1.25) 1 [Reference] 1.06 (0.63-1.80) overweight and obesity, maternal
medical conditions, and parental
Antidepressant drug use 1 [Reference] 1.06 (0.97-1.16) 1 [Reference] 1.16 (1.01-1.33)
psychiatric history.

uninformative as to whether depression and anxiety might
be more common among offspring in adulthood. Second,
the degree of missing information was moderate, and it con-
cerned several of the relevant covariates in the cohort.
Under the assumption of missing at random, we performed
multiple imputations to maximize the power in the main
analysis. Our findings reflect ART practices in Sweden
around the millennium, and the generalizability to other
settings and time periods should consider differences in
clinical practice. In Sweden, the occurrence of multiple ges-
tations decreased substantially after the implementation of
the single-embryo transfer policy in the early 2000s. 35
Aside from increased reliance on ICSI without male factor
infertility, the use of frozen embryos has increased dramati-
cally in recent decades thanks to improvements related to
vitrification compared with slow freezing.

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 Psychiatric Disorders in Children and Adolescents Conceived by Assisted Reproductive Techniques
Conclusions
In this follow-up of a Swedish national birth cohort study,
the findings were reassuring with respect to the psychiatric
ARTICLE INFORMATION
Accepted for Publication: October 22, 2021.
Published Online: December 15, 2021.
doi:10.1001/jamapsychiatry.2021.3647
Open Access: This is an open access article
distributed under the terms of the CC-BY License.
© 2021 Wang C et al. JAMA Psychiatry.
Author Affiliations: Department of Medical
Epidemiology and Biostatistics, Karolinska
Institutet, Stockholm, Sweden (Wang, Johansson,
Landén, Almqvist, Oberg); Department of
Oncology-Pathology, Karolinska Institutet,
Stockholm, Sweden (Rodriguez-Wallberg);
Department of Reproductive Medicine, Division of
Gynecology and Reproduction, Karolinska
University Hospital, Stockholm, Sweden
(Rodriguez-Wallberg); Department of Psychiatry
and Neurochemistry, University of Gothenburg,
Gothenburg, Sweden (Landén); Astrid Lindgren
Children’s Hospital, Karolinska University Hospital,
Stockholm, Sweden (Almqvist); Department of
Epidemiology, Harvard T. H. Chan School of Public
Health, Boston, Massachusetts
(Hernández-Díaz, Oberg).
Author Contributions: Mr Wang and Dr Oberg had
full access to all the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: Wang, Johansson, Landén,
Almqvist, Oberg.
Acquisition, analysis, or interpretation of data:
Wang, Johansson, Rodriguez-Wallberg, Almqvist,
Hernandez-Diaz, Oberg.
Drafting of the manuscript: Wang, Oberg.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Wang, Johansson.
Obtained funding: Almqvist,
Hernandez-Diaz, Oberg.
Administrative, technical, or material support:
Almqvist, Oberg.
Supervision: Johansson, Landén, Almqvist, Oberg.
Other (knowledge and expertise in clinical
reproductive medicine): Rodriguez-Wallberg.
Conflict of Interest Disclosures: Dr Landén
reported receiving personal fees from H Lundbeck
A/S outside the submitted work. Dr Almqvist
reported receiving grants from the Swedish
Research Council outside the submitted work.
Dr Oberg reported receiving personal fees from
Abbott outside the submitted work. No other
disclosures were reported.
Funding/Support: This study was supported by
grant 2016-01202 from Forte and grant
R01HD088393 from the National Institutes
of Health.
Role of the Funder/Sponsor: The sponsors 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.
jamapsychiatry.com
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health of adolescents conceived with ARTs. An elevated risk
of OCD in the overall comparison with all other adolescents
may be explained by differences in parental characteristics,
and parental use of ARTs could be a candidate in potential
screening of this disorder.
REFERENCES
1. ESHRE. ART fact sheet 2020. Updated March 6,
2020. Accessed November 9, 2021. https://www.
eshre.eu/-/media/sitecore-files/Press-room/ART-
fact-sheet-2020-data-2016.pdf?la=en&hash=AB
68A67B4FEA7723F2125B02BCB93FB837139CD4
2. Biggers JD. In vitro fertilization and embryo
transfer in human beings. N Engl J Med. 1981;304
(6):336-342. doi:10.1056/NEJM198102053040607
3. Rodriguez-Wallberg KA, Lundberg FE, Ekberg S,
et al. Mortality from infancy to adolescence in
singleton children conceived from assisted
reproductive techniques versus naturally conceived
singletons in Sweden. Fertil Steril. 2020;113(3):524-
532. doi:10.1016/j.fertnstert.2019.10.018
4. Jackson RA, Gibson KA, Wu YW, Croughan MS.
Perinatal outcomes in singletons following in vitro
fertilization: a meta-analysis. Obstet Gynecol. 2004;
103(3):551-563. doi:10.1097/01.AOG.0000114989.
84822.51
5. Helmerhorst FM, Perquin DAM, Donker D, Keirse
MJNC. Perinatal outcome of singletons and twins
after assisted conception: a systematic review of
controlled studies. BMJ. 2004;328(7434):261.
doi:10.1136/bmj.37957.560278.EE
6. Hansen M, Kurinczuk JJ, Milne E, de Klerk N,
Bower C. Assisted reproductive technology and
birth defects: a systematic review and
meta-analysis. Hum Reprod Update. 2013;19(4):
330-353. doi:10.1093/humupd/dmt006
7. Aarnoudse-Moens CS, Weisglas-Kuperus N, van
Goudoever JB, Oosterlaan J. Meta-analysis of
neurobehavioral outcomes in very preterm and/or
very low birth weight children. Pediatrics. 2009;124
(2):717-728. doi:10.1542/peds.2008-2816
8. Breeman LD, Jaekel J, Baumann N, Bartmann P,
Wolke D. Preterm cognitive function into
adulthood. Pediatrics. 2015;136(3):415-423. doi:10.
1542/peds.2015-0608
9. Pyhälä R, Wolford E, Kautiainen H, et al.
Self-reported mental health problems among adults
born preterm: a meta-analysis. Pediatrics. 2017;139
(4):e20162690. doi:10.1542/peds.2016-2690
10. Nosarti C, Reichenberg A, Murray RM, et al.
Preterm birth and psychiatric disorders in young
adult life. Arch Gen Psychiatry. 2012;69(6):E1-E8.
doi:10.1001/archgenpsychiatry.2011.1374
11. Hattori H, Hiura H, Kitamura A, et al. Association
of four imprinting disorders and ART. Clin Epigenetics.
2019;11(1):21. doi:10.1186/s13148-019-0623-3
12. World Health Organization. Depression and
other common mental disorders: global health
estimates. January 3, 2017. Accessed November 9,
2021. https://apps.who.int/iris/bitstream/handle/
10665/254610/WHO-MSD-MER-2017.2-eng.pdf?
sequence=1&isAllowed=y
13. Kessler RC, Amminger GP, Aguilar-Gaxiola S,
Alonso J, Lee S, Ustün TB. Age of onset of mental
disorders: a review of recent literature. Curr Opin
Psychiatry. 2007;20(4):359-364. doi:10.1097/YCO.
0b013e32816ebc8c
(Reprinted) JAMA Psychiatry February 2022 Volume 79, Number 2
Original Investigation Research
14. Fernandez-Pujals AM, Adams MJ, Thomson P,
et al. Epidemiology and heritability of major
depressive disorder, stratified by age of onset, sex,
and illness course in Generation Scotland: Scottish
Family Health Study (GS:SFHS). PLoS One. 2015;
10(11):e0142197. doi:10.1371/journal.pone.0142197
15. Guffanti G, Gameroff MJ, Warner V, et al.
Heritability of major depressive and comorbid
anxiety disorders in multi-generational families at
high risk for depression. Am J Med Genet B
Neuropsychiatr Genet. 2016;171(8):1072-1079.
doi:10.1002/ajmg.b.32477
16. López-Solà C, Fontenelle LF, Alonso P, et al.
Prevalence and heritability of obsessive-compulsive
spectrum and anxiety disorder symptoms: a survey
of the Australian Twin Registry. Am J Med Genet B
Neuropsychiatr Genet. 2014;165B(4):314-325.
doi:10.1002/ajmg.b.32233
17. Rooney KL, Domar AD. The relationship
between stress and infertility. Dialogues Clin Neurosci.
2018;20(1):41-47. doi:10.31887/DCNS.2018.20.1/
klrooney
18. Svahn MF, Hargreave M, Nielsen TSS, et al.
Mental disorders in childhood and young adulthood
among children born to women with fertility
problems. Hum Reprod. 2015;30(9):2129-2137.
doi:10.1093/humrep/dev172
19. Hart R, Norman RJ. The longer-term health
outcomes for children born as a result of IVF
treatment, part II: mental health and development
outcomes. Hum Reprod Update. 2013;19(3):244-250.
doi:10.1093/humupd/dmt002
20. Wagenaar K, van Weissenbruch MM, Knol DL,
Cohen-Kettenis PT, Delemarre-van de Waal HA,
Huisman J. Behavior and socioemotional
functioning in 9-18-year-old children born after in
vitro fertilization. Fertil Steril. 2009;92(6):1907-1914.
doi:10.1016/j.fertnstert.2008.09.026
21. Wagenaar K, van Weissenbruch MM, van
Leeuwen FE, et al. Self-reported behavioral and
socioemotional functioning of 11- to 18-year-old
adolescents conceived by in vitro fertilization. Fertil
Steril. 2011;95(2):611-616. doi:10.1016/j.fertnstert.
2010.04.076
22. Rissanen E, Gissler M, Lehti V, Tiitinen A. The
risk of psychiatric disorders among Finnish ART and
spontaneously conceived children: Finnish
population-based register study. Eur Child Adolesc
Psychiatry. 2020;29(8):1155-1164. doi:10.1007/
s00787-019-01433-2
23. Rodriguez-Wallberg KA, Waterstone M,
Anastácio A. Ice age: cryopreservation in assisted
reproduction—an update. Reprod Biol. 2019;19(2):
119-126. doi:10.1016/j.repbio.2019.04.002
24. Ludvigsson JF, Otterblad-Olausson P,
Pettersson BU, Ekbom A. The Swedish personal
identity number: possibilities and pitfalls in
healthcare and medical research. Eur J Epidemiol.
2009;24(11):659-667. doi:10.1007/s10654-009-
9350-y
25. Socialstyrelsen. The Swedish Medical Birth
Register—a summary of content and quality.
141
 Research Original Investigation
National Board of Health and Welfare; 2003.
Accessed November 9, 2021. https://www.
socialstyrelsen.se/globalassets/sharepoint-
dokument/artikelkatalog/ovrigt/2003-112-3_
20031123.pdf
26. Ekbom A. The Swedish Multi-generation
Register. Methods Mol Biol. 2011;675:215-220.
doi:10.1007/978-1-59745-423-0_10
27. Socialstyrelsen. Kvalitet och innehåll i
patientregistret. Utskrivningar från slutenvården
1964-2007 och besök i specialiserad öppenvård
(exklusive primärvårdsbesök) 1997-2007 [in
Swedish only]. National Board of Health and
Welfare; 2009. https://www.socialstyrelsen.se/
globalassets/sharepoint-dokument/artikelkatalog/
statistik/2009-125-15_200912515_rev2.pdf
28. World Health Organization. International
Statistical Classification of Diseases and Related
Problems. Accessed November 9, 2021. https://
www.who.int/standards/classifications/
classification-of-diseases
142 JAMA Psychiatry February 2022 Volume 79, Number 2 (Reprinted)
Downloaded From: https://jamanetwork.com/ on 02/09/2022
Psychiatric Disorders in Children and Adolescents Conceived by Assisted Reproductive Techniques
29. Wettermark B, Hammar N, Fored CM, et al. The
new Swedish Prescribed Drug Register—
opportunities for pharmacoepidemiological
research and experience from the first six months.
Pharmacoepidemiol Drug Saf. 2007;16(7):726-735.
Published correction appears in Pharmacoepidemiol
Drug Saf. 2008;17(5):533. doi:10.1002/pds.1294
30. Cesta CE, Viktorin A, Olsson H, et al.
Depression, anxiety, and antidepressant treatment
in women: association with in vitro fertilization
outcome. Fertil Steril. 2016;105(6):1594-1602.e3.
doi:10.1016/j.fertnstert.2016.01.036
31. Raghunathan T, Lepkowski J, Van Hoewyk J,
Solenberger P. A multivariate technique for multiply
imputing missing values using a sequence of
regression models. Survey Methodol. 2001;27(1):
85-96. Accessed November 9, 2021. https://www150.
statcan.gc.ca/n1/pub/12-001-x/2001001/article/
5857-eng.pdf
32. Rubin DB. Multiple Imputation for Nonresponse
in Surveys. John Wiley & Sons; 2004.
33. Meijer WE, Heerdink ER, Leufkens HG, Herings
RM, Egberts AC, Nolen WA. Incidence and
determinants of long-term use of antidepressants.
Eur J Clin Pharmacol. 2004;60(1):57-61. doi:10.
1007/s00228-004-0726-3
34. Maheshwari A, Pandey S, Amalraj Raja E,
Shetty A, Hamilton M, Bhattacharya S. Is frozen
embryo transfer better for mothers and babies?
Can cumulative meta-analysis provide a definitive
answer? Hum Reprod Update. 2018;24(1):35-58.
doi:10.1093/humupd/dmx031
35. Prevention of twin pregnancies after IVF/ICSI
by single embryo transfer: ESHRE Campus Course
Report. Hum Reprod. 2001;16(4):790-800. doi:10.
1093/humrep/16.4.790
jamapsychiatry.com