Original Investigation | Pediatrics

Neurodevelopmental Outcomes Among Offspring Exposed to Corticosteroid
and B2-Adrenergic Agonists In Utero
Abir Nagata, PhD; Toshio Masumoto, PhD; Hidekazu Nishigori, MD, PhD; Takatoshi Nakagawa, PhD; Shinji Otani, MD, PhD; Youichi Kurozawa, PhD;
and the Japan Environment and Children’s Study Group

Abstract

Key Points

IMPORTANCE Corticosteroids and β2-adrenergic agonists are commonly used during pregnancy totreat asthma. However, offspring neurodevelopmental outcomes following in utero exposure tothese medications remain unclear.

Question Is the timing of in utero
corticosteroid and β2-adrenergic
agonist exposure associated with
offspring neurodevelopmental

OBJECTIVE To investigate the association between timing of in utero exposure to corticosteroids

outcomes during the first 3 years of life?

and β2-adrenergic agonists and offspring neurodevelopmental milestones during the first 3 years

Findings In this cohort study of 91 460

of life.

mother-offspring pairs, no associations
were found between corticosteroid and

DESIGN, SETTING, AND PARTICIPANTS This cohort study obtained data from the Japan

β2-adrenergic agonist exposure in early

Environment and Children’s Study, an ongoing birth cohort study conducted in collaboration with 15

pregnancy, mid- to late pregnancy, or

Regional Centers across Japan. Participants were mother-offspring pairs who were recruitedboth stages of pregnancy and the

between January 1, 2011, and March 31, 2014. Data were analyzed between January anddevelopment of communication, grossFebruary 2023.

motor, fine motor, problem-solving, andpersonal-social skills in offspring, when

EXPOSURE Corticosteroids and β2-adrenergic agonists were the exposure of interest. Timing ofcompared with nonexposed offspring,corticosteroid and β2-adrenergic agonist exposure included early pregnancy (weeks 0-12), mid- toduring the first 3 years of life.

late pregnancy (weeks >12), and both stages of pregnancy.

Meaning Findings of this study suggestthat corticosteroids and β2-adrenergic

MAIN OUTCOMES AND MEASURES Offspring neurodevelopmental milestones (communication,
gross motor, fine motor, problem-solving, and personal-social skills) were assessed using theJapanese version of the Ages and Stages Questionnaires, 3rd edition, at 6, 12, 18, 24, 30, andagonists are safe for pregnant
individuals with asthma and theiroffspring’s neurodevelopment.

36 months.
RESULTS In total, 91 460 mother-offspring pairs were analyzed. Among mothers, the mean (SD) age
at delivery was 31.20 (5.05) years. Among offspring, 46 596 (50.9%) were males and 44 864 (49.1%)
were females, of whom 66.4% had a gestational age of 39 to 41 weeks. During early, mid- to late, and+ Supplemental content
Author affiliations and article information arelisted at the end of this article.

both stages of pregnancy, 401 (0.4%), 935 (1.0%), and 568 (0.6%) offspring, respectively, were
exposed to corticosteroids, whereas 170 (0.2%), 394 (0.4%), and 184 (0.2%), respectively, were
exposed to β2-adrenergic agonists. No association of corticosteroid exposure during early, mid- tolate, and both stages of pregnancy with all 5 neurodevelopmental milestones was found. Similarly, no
association between β2-adrenergic agonist use during early pregnancy and all 5 neurodevelopmental
milestones was observed. An association was found between β2-adrenergic agonist exposure during
mid- to late pregnancy and delayed personal-social skills (adjusted odds ratio, 1.48; 95% CI,
1.01-2.32; P = .045).
CONCLUSIONS AND RELEVANCE Results of this study found no association between in utero
corticosteroid and β2-adrenergic agonist exposure and offspring neurodevelopmental outcomes,
regardless of the timing of exposure. Despite the limitations and low power of the study, the findings(continued)
Open Access. This is an open access article distributed under the terms of the CC-BY License.
JAMA Network Open. 2023;6(10):e2339347. doi:10.1001/jamanetworkopen.2023.39347 (Reprinted)

Downloaded From: https://jamanetwork.com/ by a Osaka University- GAIZATSU (HANDAI) User on 10/24/2023

October 24, 2023

1/14

JAMA Network Open | Pediatrics

In Utero Corticosteroids and β2-Adrenergic Agonists and Neurodevelopmental Outcomes

Abstract (continued)

suggest that corticosteroids and β2-adrenergic agonists are safe for pregnant individuals with asthma
and the neurodevelopment of their offspring.
JAMA Network Open. 2023;6(10):e2339347. doi:10.1001/jamanetworkopen.2023.39347

Introduction
Asthma is one of the foremost obstructive pulmonary diseases encountered during pregnancy,
affecting 4% to 13% of females, and may require medicinal intervention to lessen complications.1-4
Complications of asthma exacerbation during pregnancy are associated with an increased risk ofadverse maternal and fetal outcomes, including preterm delivery, low birth weight, congenital
malformation, preeclampsia, and perinatal mortality, which affect the well-being of both the motherand offspring.4-6 Accordingly, optimizing and sustaining adequate asthma control during pregnancy
with appropriate medications are recommended.1,4Several medications are considered to be acceptable for treating asthma during pregnancy;
however, some may have teratogenic potential and, hence, pose a risk to the fetus. During
pregnancy, commonly used therapeutics include corticosteroids for their anti-inflammatory
properties and β2-adrenergic agonists as bronchodilators.7-9 Evidence from animal studies suggeststhat these medications have the capability to permeate both the placenta and blood-brain barrier,leading to concerns regarding their biological potential to pose a risk to fetal neurodevelopment.10-13
However, evidence is lacking on offspring neurodevelopmental outcomes following in utero
exposure to corticosteroids and β2-adrenergic agonists.
Existing information on cognitive and psychomotor developmental outcomes associated withmaternal antiasthmatic medication use during pregnancy is inconsistent. For instance, someobservational studies have found an association between in utero antiasthmatic medication
exposure and subsequent neurophysiological, behavioral, and developmental disorders inoffspring14-16; however, other studies have found that offspring neurodevelopmental outcomes areless likely to be associated with fetal antiasthmatic medication exposure.17,18 Currently, there exists a
gap in the body of literature regarding the safety of asthma medications when used during
pregnancy.19 Moreover, understanding the susceptibility to antiasthmatic medication exposure andits association with early-life offspring neurodevelopment is crucial for guiding clinical decisions.
Thus, we aimed to investigate the association between timing (early, mid- to late, and both stages ofpregnancy) of in utero exposure to corticosteroids and β2-adrenergic agonists and offspringneurodevelopmental milestones (communication, gross motor, fine motor, problem-solving, andpersonal-social skills) compared with nonexposed offspring during the first 3 years of life.

Methods
Data for this cohort study were derived from the Japan Environment and Children’s Study (JECS), an
ongoing prospective birth cohort study in Japan. The Ministry of the Environment’s Institutional
Review Board on Epidemiological Studies and the ethics committees of all participating institutions
reviewed and approved the JECS protocol. The JECS was conducted in accordance with the
Declaration of Helsinki20 and the Ethical Guidelines for Medical and Health Research Involving
Human Subjects, which were established by the Ministry of Education, Culture, Sports, Science andTechnology and the Ministry of Health, Labour, and Welfare of Japan. All JECS participants provided
written informed consent after the study aims and protocol were explained. The JECS approval andparticipants' consent also apply to the current study. We followed the Strengthening the Reporting ofObservational Studies in Epidemiology (STROBE) reporting guideline.

JAMA Network Open. 2023;6(10):e2339347. doi:10.1001/jamanetworkopen.2023.39347 (Reprinted)

Downloaded From: https://jamanetwork.com/ by a Osaka University- GAIZATSU (HANDAI) User on 10/24/2023

October 24, 2023

2/14

JAMA Network Open | Pediatrics

In Utero Corticosteroids and β2-Adrenergic Agonists and Neurodevelopmental Outcomes

Study Design, Data Sources, and Participants
Details of the JECS design have been previously described.21 Briefly, the JECS began in 2011 toevaluate the role of environmental factors in the health and development of children in Japan.21,22
The project was designed to observe offspring prenatally until age 13 years and to operate incollaboration with 15 Regional Centers across Japan; more information on the JECS is provided in theeMethods in Supplement 1. Eligibility criteria were pregnancy and residency within the study area
between January 1, 2011, and March 31, 2014. Among 104 062 fetal records from 103 060
pregnancies, 100 303 live births were included; thereafter, multiple births, preterm and postterm
births, births with missing data on maternal antiasthmatic medication use, and births with missing orindeterminant offspring sex were excluded. The data used in this study were obtained from the JECS
data set that was released in October 2019.

Exposure
Corticosteroids (Anatomical Therapeutic Chemical code R01AD) and β2-adrenergic agonists (codeR03AC or R03CC) were the exposure of interest in this study. Data on exposure variables werecollected using 2 face-to-face prenatal interviews, based on a medication list, conducted by the
research coordinator at each Regional Center. The interview questions included “Did you takemedicine, drugs, or supplements in the past year?” Those participants who responded affirmatively
were then asked about the timing of their medication use and the specific type of medication. In thefirst interview, which was conducted at the time of enrollment (during early to mid-pregnancy),
participants were asked, “Did you take any corticosteroids (whether orally, injected, or inhaled) forthe purpose of preventing asthma and/or β2-adrenergic agonists (orally or inhaled) 1 year prior [to]confirmation of pregnancy, between the confirmation of pregnancy and gestational age of 12 weeks,
and after gestational age of 12 weeks until now?” In the second interview, which took place during
mid- to late pregnancy, similar questions were repeated, with the exception of prepregnancy
exposure. An affirmative response in interview 1 and interview 2 was considered as an exposure
variable.
The timing of exposure to antiasthmatic medications was categorized into early (weeks 0-12),
mid- to late (weeks >12), or both stages of pregnancy. The comparison group comprised offspringwhose mothers did not use antiasthmatic medications during pregnancy. We also stratified thetiming of exposure as follows: during early pregnancy (yes or no) and during mid- to late pregnancy(yes or no). Additionally, we assessed 1-year prepregnancy exposure and incorporated it as a negative
control group, as prepregnancy exposure to antiasthmatic medications presumably is not a direct
factor in offspring development; accordingly, a null result was anticipated.

Developmental Assessment
Offspring neurodevelopmental outcomes between 6 and 36 months of age were assessed using theJapanese version of the Ages and Stages Questionnaires, 3rd edition (J-ASQ-3),23 which was sent by
mail every 6 months post partum. The ASQ-3 is an age-specific screening tool completed by parents
or primary guardians that measures developmental delays in 5 domains or milestones:
communication, gross motor, fine motor, problem-solving, and personal-social skills24 (eMethods in
Supplement 1). Achievement of neurodevelopmental milestones was assessed using 6 questions
with the following answer options: yes (score: 10), sometimes (score: 5), or not yet (score: 0).
Individual item scores were summed for a total score in each domain (range: 0-60). If 1 or 2 out of the
6 questions were left unanswered, the total score was multiplied by 1.2 (with 1 unanswered question)or 1.5 (with 2 unanswered questions), based on a score range of 0 to 60. Within the domain of grossmotor skills assessment for offspring aged 2 years, 1 question was about behaviors that might havebeen exhibited previously but ceased due to acquisition of more advanced skills. When parents or
guardians indicated not yet or sometimes for the simpler item and yes for the more advanced item,
the response for the earlier item was revised to yes.

JAMA Network Open. 2023;6(10):e2339347. doi:10.1001/jamanetworkopen.2023.39347 (Reprinted)

Downloaded From: https://jamanetwork.com/ by a Osaka University- GAIZATSU (HANDAI) User on 10/24/2023

October 24, 2023

3/14

JAMA Network Open | Pediatrics

In Utero Corticosteroids and β2-Adrenergic Agonists and Neurodevelopmental OutcomesChild development was defined as a total score in each domain that was less than 2 SDs
compared with the mean in the reference indicated as typical or potentially delayed (ie, requiringreferral for further assessment of the evaluated domain) and was validated by Mezawa et al.23 The
age-specific cutoff points of the J-ASQ-3 are provided in eTable 1 in Supplement 1. A previous study
demonstrated that this threshold exhibited moderate sensitivity and specificity in identifying delays,
ranging from any delay to severe delay, motor delay, and cognitive delay,25 and the threshold has
been widely adopted in the assessment of Japanese children.26,27 In sensitivity analyses, we also
used the present sample mean of less than 2 SDs as cutoff values for each J-ASQ-3 domain.

Potential Confounders
To delineate assumptions regarding the causal pathway between antiasthmatic medication exposure
and offspring neurodevelopment, we identified potential confounding variables through theliterature14-17,26,27 and conceptualized it using a directed acyclic graph (eFigure 1 in Supplement 1)
that included maternal age at delivery, marital status, educational level, history of prepregnancy
asthma, and alcohol consumption during pregnancy; maternal and paternal smoking during
pregnancy; household annual income; and offspring sex, which was hypothesized to be associatedwith exposure and outcome variables but not on the causal pathway. Additional factors were
included in the sensitivity analysis: maternal prepregnancy body mass index (BMI), infertility
treatment, psychological distress during pregnancy, gestational diabetes, and comedications(antibiotics, iron, and folic acid) and offspring gestational age, birth weight, breastfeeding duration,and nursery attendance. Covariate sources are provided in the eMethods in Supplement 1.

Statistical Analysis
Descriptive statistics were used to outline the general characteristics of participants and offspringneurodevelopmental status. We used generalized estimating equations (GEEs) with robust SEs andan independent working correlation matrix structure to evaluate the association between the timingof corticosteroids and β2-adrenergic agonist exposure and repeatedly measured
neurodevelopmental milestones using J-ASQ-3 (every 6 months, between age 6 and 36 months). We
constructed GEE models with a binominal probability distribution and logit link function. Specifically,
logistic regression analyses were conducted under GEEs, with dichotomized J-ASQ-3 domain scoresas the outcome. These analyses were stratified by the timing of exposure (ie, no exposure during
pregnancy vs early, mid- to late, or both stages of pregnancy), while being adjusted for confounding
factors. Furthermore, we compared neurodevelopmental outcomes after early pregnancy exposurevs no exposure and after mid- to late pregnancy exposure vs no exposure.
Several sensitivity analyses were conducted to ensure the robustness of the main analysis. First,
we created an additional model with further adjustment of maternal prepregnancy BMI, infertility
treatment, psychological distress during pregnancy, gestational diabetes, and comedications(antibiotics, iron, and folic acid) and offspring gestational age, birth weight, breastfeeding duration,and nursery attendance. Second, to account for incomplete data, we imputed missing data using
multiple imputation techniques after considering data that were missing at random. We imputed 10
data sets using fully conditional specification for each variable and combined the estimates in GEEs.
Third, we applied the present sample mean of less than (2 × SD) as cutoff values for each J-ASQ-3
domain. Fourth, we applied linear multivariable GEE models using the continuous J-ASQ-3 domainscore as the outcome.
Subgroup analyses were performed to understand the role of offspring sex and maternal historyof prepregnancy asthma. We assessed the effect modification using the interaction term in the GEE
models. A 2-tailed P < .05 indicated statistical significance. For subgroup analysis, P < .005 wasconsidered to avoid type I error. The statistical analysis was performed between January andFebruary 2023 using IBM SPSS Statistics for Windows/Macintosh, version 25.0 (IBM Corp).

JAMA Network Open. 2023;6(10):e2339347. doi:10.1001/jamanetworkopen.2023.39347 (Reprinted)

Downloaded From: https://jamanetwork.com/ by a Osaka University- GAIZATSU (HANDAI) User on 10/24/2023

October 24, 2023

4/14

JAMA Network Open | Pediatrics

In Utero Corticosteroids and β2-Adrenergic Agonists and Neurodevelopmental Outcomes

Results
Cohort Characteristics
The final sample comprised 91 460 mother-offspring pairs (Figure). Table 1 shows the participants’characteristics. Among 91 460 mothers, the mean (SD) age at delivery was 31.20 (5.05) years.
Additionally, 4.5% of mothers smoked and 2.8% consumed alcohol during pregnancy, while 10.9%
had a history of prepregnancy asthma. Among 91 460 offspring, 46 596 (50.9%) were males and
44 864 (49.1%) were females, of whom 66.4% had a gestational age of 39 to 41 weeks. More than
65% of offspring were breastfed during the first 12 months of life. During early, mid- to late, and bothstages of pregnancy, 0.4%, 1.0%, and 0.6% of offspring, respectively, were exposed tocorticosteroids, whereas 0.2%, 0.4%, and 0.2%, respectively, were exposed to β2-adrenergic
agonists. Table 2 and eFigure 2 in Supplement 1 summarize the neurodevelopmental milestones ofthe offspring and the J-ASQ-3 domain scores according to age.

Association of Timing of In Utero Corticosteroid and β2-Adrenergic Agonist ExposureWith Offspring Neurodevelopment Outcomes
Table 3 reports the association of the timing of in utero corticosteroid and β2-adrenergic agonist
exposure with offspring neurodevelopment as estimated with GEE models. We found no associationof corticosteroid exposure during early, mid- to late, and both stages of pregnancy with all 5
neurodevelopmental milestones. Similarly, no association between β2-adrenergic agonist use during
early pregnancy and all 5 neurodevelopmental milestones was observed. The odds of having delayedcommunication (adjusted odds ratio [AOR], 1.30; 95% CI, 0.79-2.15), gross motor (AOR, 1.27; 95%
CI, 0.90-1.78), fine motor (AOR, 1.21; 95% CI, 0.83-1.75), and problem-solving (AOR, 1.16; 95% CI,
0.83-1.62) skills were higher in offspring with β2-adrenergic agonist exposure during mid- to latepregnancy compared with nonexposed offspring; however, these findings were not statisticallysignificant. We observed an association between β2-adrenergic agonist exposure during mid- to latepregnancy and delayed personal-social skills (AOR, 1.48; 95% CI, 1.01-2.32; P = .045). Nevertheless,no other neurodevelopmental milestones were associated with other timing of β2-adrenergic agonist
exposure (Table 3), including prepregnancy (eTable 2 in Supplement 1). Furthermore, we found noassociation with neurodevelopmental delays when we compared early pregnancy exposure vs no
exposure with mid- to late pregnancy exposure vs no exposure (Table 4).

Figure. Flowchart of Participants
103 060 Pregnancies enrolled and 104 062
fetuses registered3759 Fetuses excluded
2123 Missing data on live births,
miscarriages, and stillbirths
1636 Miscarriages and stillbirths
100 303 Live births
8843 Births excluded
4617 Preterm births (<37 wk)
1891 Multiple births
1403 Missing data on antiasthmatic
medication exposure
at enrollment (interview 1)
696 Missing data on antiasthmatic
medication exposure
during mid-to-late pregnancy
226 Postterm births (>41 wk)
8 Missing data on offspring sex
2 Indeterminant offspring sex
91 460 Mother-offspring pairs included in the analysis

JAMA Network Open. 2023;6(10):e2339347. doi:10.1001/jamanetworkopen.2023.39347 (Reprinted)

Downloaded From: https://jamanetwork.com/ by a Osaka University- GAIZATSU (HANDAI) User on 10/24/2023

October 24, 2023

5/14

JAMA Network Open | Pediatrics

In Utero Corticosteroids and β2-Adrenergic Agonists and Neurodevelopmental Outcomes

Table 1. Distribution of Participant Characteristics by Corticosteroid and/or β2-Adrenergic Agonist Exposure
Participants, No. (%)
Characteristic

Total (n = 91 460)

Unexposed (n = 89 138)

Exposed (n = 2322)<25

7218 (7.9)

7112 (10.1)

106 (6.5)

25-29

19 845 (21.7)

19 446 (27.6)

399 (24.3)

30-34

25 519 (27.9)

24 917 (35.3)

602 (36.7)≥35

19 556 (21.4)

19 023 (27.0)

533 (32.5)

Missing data

19 322 (21.1)

NA

NA

Single3181 (3.5)

3114 (3.5)

67 (2.9)

Married86 849 (95.0)

84 636 (95.7)

2213 (96.1)

Maternal
Age at delivery, yMarital status

Divorced or widowed739 (0.8)717 (0.8)

22 (1.0)

Missing data

691 (0.7)

NA

NA≤High school diploma

32 902 (36.0)

32 115 (36.4)

787 (34.2)

College attendance

38 081 (41.6)

37 049 (42.0)1032 (44.8)≥Bachelor’s degree

19 637 (21.5)

19 153 (21.6)

484 (21.0)

Missing data

840 (0.9)

NA

NA

Educational level

Prepregnancy BMI<18.5

14 917 (16.3)

14 571 (16.8)

346 (15.3)

18.5-24.9

65 680 (71.8)

64 077 (73.6)

1603 (70.8)≥258650 (9.5)

8336 (9.6)

314 (13.9)

Missing data

2213 (2.4)

NA

NA

Smoking during pregnancy
No

86 274 (94.3)

84 092 (95.5)

2182 (95.2)

Yes

4100 (4.5)

3990 (4.5)

110 (4.8)

Missing data

1086 (1.2)

NA

NA

Alcohol consumption during pregnancy
No

87 814 (96.0)

85 594 (97.2)

2220 (97.0)

Yes2562 (2.8)

2494 (2.8)

68 (3.0)

Missing data

1084 (1.2)

NA

NA

Infertility treatment
No

85 376 (93.3)

83 204 (93.7)2172 (93.9)

Yes5712 (6.2)

5571 (6.3)

141 (6.1)

Missing data

372 (0.5)

NANA

Psychological distress during pregnancy, scorea
0-4

61 847 (67.6)

60 360 (68.2)

1487 (64.4)≥5

28 950 (31.7)

28 127 (31.8)

823 (35.6)

Missing data

663 (0.7)

NANA

Gestational diabetes
No

88 808 (97.1)

86 558 (97.4)

2250 (97.2)

Yes

2421 (2.6)

2356 (2.6)

65 (2.8)

Missing data

231 (0.3)

NA

NA

History of prepregnancy asthma
No

81 200 (88.8)

80 006 (90.1)

1194 (51.6)

Yes9959 (10.9)8837 (9.9)

1122 (48.4)

Missing data

301 (0.3)

NA

NA

Comedication: antibiotics
No

71 692 (78.4)

69 990 (78.7)

1 702 (73.5)

Yes

19 537 (21.3)

18 924 (21.3)

613 (26.5)

Missing data

231 (0.3)(continued)

JAMA Network Open. 2023;6(10):e2339347. doi:10.1001/jamanetworkopen.2023.39347 (Reprinted)

Downloaded From: https://jamanetwork.com/ by a Osaka University- GAIZATSU (HANDAI) User on 10/24/2023

October 24, 2023

6/14

JAMA Network Open | Pediatrics

In Utero Corticosteroids and β2-Adrenergic Agonists and Neurodevelopmental Outcomes

Table 1. Distribution of Participant Characteristics by Corticosteroid and/or β2-Adrenergic Agonist Exposure(continued)
Participants, No. (%)
Characteristic

Total (n = 91 460)

Unexposed (n = 89 138)

Exposed (n = 2322)

Iron
No

52 415 (57.3)

50 999 (57.4)

1416 (61.2)

Yes

38 814 (42.4)

37 915 (42.6)

899 (38.8)

Missing data

231 (0.3)

NA

NA

Folic acidNo

89 354 (97.7)

87 089 (97.9)

2 265 (97.8)

Yes1875 (2.0)

1825 (2.1)

50 (2.2)

Missing data

231 (0.3)

NA

NAHouseholdPaternal smoking
No

47 682 (52.1)

46 427 (53.3)

1255 (55.4)

Yes

41 766 (45.7)

40 756 (46.7)

1010 (44.6)

Missing data

2012 (2.2)

NA

NA

<4

34 058 (37.2)

33 182 (40.2)

876 (40.4)

4-8

41 499 (45.4)

40 438 (49.0)

1061 (48.9)≥89109 (10.0)8876 (10.8)233 (10.7)

Missing data

6 794 (7.4)

NANA

Annual income, in millions, ¥b

OffspringSex
Male

46 596 (50.9)

45 403 (50.9)1193 (51.4)

Female44 864 (49.1)

43 735 (49.1)

1129 (48.6)

Missing data

NA

NA

NA

37-38

30 470 (33.3)

29 601 (33.3)

869 (37.5)

39-41

60 759 (66.4)

59 313 (66.7)

1446 (62.5)

Missing data

231 (0.3)

NA

NA

<2500

4953 (5.4)

4821 (5.4)

132 (5.7)

2500-4000

85 415 (93.4)

83 254 (93.7)

2161 (93.4)

Gestational age, wk

Birth weight, g>4000

810 (0.9)790 (0.9)

20 (0.9)

Missing data

282 (0.3)

NA

NA

No

5544 (6.1)

5403 (6.4)

141 (6.4)

Yes

80 497 (88.0)

78 450 (93.6)

2047 (93.6)

Missing data

5419 (5.9)

NA

NA

No

21 398 (23.4)

20 781 (25.6)

617 (28.5)

Yes

61 946 (67.7)

60 398 (74.4)

1548 (71.5)

Missing data

8116 (8.9)

NA

NA

No

60 637 (66.3)

59 097 (73.1)

1540 (71.6)

Yes

22 350 (24.4)

21 738 (26.9)

Missing data

8473 (9.3)

NA

Breastfeeding duration
1-6 mo7-12 moNursery attendancec

Abbreviations: BMI, body mass index (calculated asweight in kilograms divided by height in meterssquared); K6, Kessler Psychological Distress Scale(range: 0 to ⱖ5, with the highest score indicating poor
mental health); NA, not applicable.
aMaternal psychological distress during pregnancy
was measured by the K6 scale.

612 (28.4)b

To convert yen to US dollars, multiply by 0.00677.

NAc

Going to nursery school at 1 year of age.

Sensitivity and Subgroup Analyses
Results of the sensitivity analyses on adjusted models were consistent with findings of the main
analyses (eTable 3 in Supplement 1). In models with missing value imputation, models with a sample
mean of less than (2 × SD) as a cutoff on the J-ASQ-3, and linear multivariate models, we found no

JAMA Network Open. 2023;6(10):e2339347. doi:10.1001/jamanetworkopen.2023.39347 (Reprinted)

Downloaded From: https://jamanetwork.com/ by a Osaka University- GAIZATSU (HANDAI) User on 10/24/2023

October 24, 2023

7/14

JAMA Network Open | Pediatrics

In Utero Corticosteroids and β2-Adrenergic Agonists and Neurodevelopmental Outcomes

association with any timing of corticosteroid and β2-adrenergic agonist exposure during pregnancy
with any of the 5 neurodevelopmental milestones (eTables 4, 5, and 6 in Supplement 1). In thesubgroup analysis, we observed an increased risk of delayed problem-solving skills (AOR, 1.65; 95%
CI, 1.11-2.45; P for interaction =.006) in males compared with females following β2-adrenergic agonist
use during mid- to late pregnancy; however, this finding was not statistically significant (eTable 7 in
Supplement 1). Furthermore, no effect modification was observed between corticosteroid andβ2-adrenergic agonist exposure and offspring neurodevelopment with maternal history of
prepregnancy asthma (eTable 8 in Supplement 1).

Discussion
In this cohort study, we found no association between any timing of corticosteroid exposure during
pregnancy and communication, gross motor, fine motor, problem-solving, and personal-social skills.
However, we observed an association between β2-adrenergic agonist exposure during mid- to latepregnancy and delayed personal-social skills. In contrast, no other factor affecting

Table 2. Offspring Neurodevelopmental Milestones (n = 91 460)a
J-ASQ-3 domains, No. (%)
Offspring age, mo

Developmental status

Communication skills

Gross motor skills

Fine motor skills

Problem-solving skills

Personal-social skills

6

Typical

79 219 (99.3)

71 504 (89.7)

75 487 (94.9)

71 118 (89.2)

76 676 (96.3)

Delayed522 (0.7)8226 (10.3)

4025 (5.1)

8616 (10.8)

2951 (3.7)

Typical

75 662 (99.9)

71 412 (94.3)

71 288 (94.1)

71 668 (94.7)

74 594 (98.8)

Delayed100 (0.1)4354 (5.7)

4439 (5.9)

3990 (5.3)

938 (1.2)

Typical

69 795 (97.8)

68 055 (95.3)

68 211 (95.6)

68 060 (95.9)

71 905 (98.5)

Delayed1598 (2.2)

3357 (4.7)

3160 (4.4)

2909 (4.1)

1110 (1.5)

Typical

70 274 (96.1)

68 906 (94.2)

71 461 (97.8)

69 858 (95.8)

70 955 (97.2)

Delayed2847 (3.9)

4216 (5.8)

1594 (2.2)

3062 (4.2)

2060 (2.8)

Typical

67 922 (95.2)

68 315 (95.7)

66 938 (94.2)

67169 (94.3)

68 897 (96.7)

Delayed3443 (4.8)

3078 (4.3)

4109 (5.8)

4042 (5.7)

2371 (3.3)

Typical

70 195 (96.1)

69 939 (95.6)

67 452 (92.6)

67 212 (92.8)

70 615 (96.8)

Delayed2837 (3.9)

3193 (4.4)

5403 (7.4)

5238 (7.2)

2345 (3.2)

12

18

24

30

36

Abbreviation: J-ASQ-3, Japanese version of the Ages and Stages Questionnaires, 3rd edition.
aChild development was a total score in each domain that was less than 2 SDs compared with the mean in the reference indicated as typical or potentially delayed developmental
status. The cutoff values of J-ASQ-3 are provided in eTable 1 in Supplement 1.

Table 3. Association of Corticosteroids and β2-Adrenergic Agonists Exposure In Utero With Offspring Neurodevelopmental Milestones
J-ASQ-3 domains, AOR (95% CI)a
Offspring, No. (%)

Communication skills

Gross motor skills

Fine motor skills

Problem-solving skills

Personal-social skills

Unexposed, during pregnancy

87 677 (98.0)

1 [Reference]

1 [Reference]

1 [Reference]

1 [Reference]

1 [Reference]

Exposed, early pregnancy

401 (0.4)

1.00 (0.59-1.67)

0.83 (0.59-1.16)

0.89 (0.66-1.22)

0.96 (0.71-1.29)

0.93 (0.57-1.52)

Exposed, mid- to late pregnancy

935 (1.0)

1.09 (0.78-1.52)

0.97 (0.78-1.20)

0.93 (0.75-1.16)

0.95 (0.77-1.18)

0.99 (0.72-1.37)

Exposed, both early and midto late pregnancy

568 (0.6)

1.19 (0.80-1.77)

1.08 (0.82-1.42)

1.18 (0.92-1.50)

1.15 (0.91-1.46)

0.89 (0.56-1.41)

Unexposed, during pregnancy

90 278 (99.2)

1 [Reference]

1 [Reference]

1 [Reference]

1 [Reference]

1 [Reference]

Exposed, early pregnancy

170 (0.2)

0.71 (0.23-2.21)

0.99 (0.56-1.74)

0.67 (0.38-1.17)

0.81 (0.49-1.35)

0.68 (0.24-1.95)

Exposed, mid- to late pregnancy

394 (0.4)

1.30 (0.79-2.15)

1.27 (0.90-1.78)

1.21 (0.83-1.75)

1.16 (0.83-1.62)

1.48 (1.01-2.32)b

Exposed, both early and mid184 (0.2)
1.33 (0.68-2.62)
0.79 (0.51-1.21)
0.81 (0.51-1.28)
to late pregnancy
Abbreviations: AOR, adjusted odds ratio; J-ASQ-3, Japanese version of the Ages and Stages Questionnaires, 3rd edition.

1.05 (0.69-1.60)

0.52 (0.25-1.07)

Corticosteroids

β2-adrenergic agonistsaAdjusted for maternal age at delivery, marital status, educational level, history of prepregnancy asthma, and alcohol consumption during pregnancy; maternal and paternal smoking
during pregnancy; household annual income; and offspring sex.

b

P < .05.
JAMA Network Open. 2023;6(10):e2339347. doi:10.1001/jamanetworkopen.2023.39347 (Reprinted)

Downloaded From: https://jamanetwork.com/ by a Osaka University- GAIZATSU (HANDAI) User on 10/24/2023

October 24, 2023

8/14

JAMA Network Open | Pediatrics

In Utero Corticosteroids and β2-Adrenergic Agonists and Neurodevelopmental Outcomesneurodevelopmental milestones was associated with β2-adrenergic agonist during the exposure
window of interest compared with unexposed offspring, collectively suggesting that no reasonableneurodevelopmental outcomes were associated with in utero corticosteroid and β2-adrenergic
agonist exposure.
The findings were consistent with those of recent studies17,28 that investigated susceptible
antiasthmatic medication exposure windows of neurocognitive development. A case-control study
showed no evidence of an association between β2-adrenergic agonists and autism spectrum
disorder risk.17 In a population-based and family-based case-control study, no association was foundbetween inhaled corticosteroids and β2-adrenergic agonist use during pregnancy and offspring
autism spectrum disorder.18 Similarly, a cohort study of 961 202 children reported no increased riskof attention-deficit/hyperactivity disorder following in utero exposure to antiasthmatic
medication.28 Liang et al29 suggested an increased risk of attention-deficit/hyperactivity disorder
following in utero β2-adrenergic agonist exposure; however, they also acknowledged that theassociation may be confounded by indication. Still, these observations may not be comparable witheach other or with the present study’s findings due to variations in study designs, sample sizes, andassessment tools for medication exposure and offspring developmental outcomes.
Generally, most females of reproductive age with asthma were concerned about the
implications of pharmacotherapy for fetal delivery and development, exhibiting reluctance to use
medication during pregnancy.3,30 Current asthma management primarily relies on inhalation
therapy; in Japan, inhaled corticosteroids and inhaled β2-adrenergic agonists are recommended as
the first-choice treatment for asthma during pregnancy.30 Drug intake by inhalation may be
associated with lower systemic exposure and, accordingly, may be less likely to reach the fetus,
resulting in a decreased risk of adverse effects.
Animal experiments demonstrate that administering antiasthmatic medications during prenatal
or early postnatal periods disrupts brain development, leading to biochemical and architecturalabnormalities and changes in neurotransmitter pathways in the immature brain.31,32 However,caution must be exercised when comparing animal and human studies, as β2-adrenergic agonists aremainly administered subcutaneously in animals, not by inhalation.
We noticed an association between β2-adrenergic agonist exposure during mid- to latepregnancy and personal-social skills; however, it can be argued that medication exposure during theTable 4. Association of Corticosteroids and β2-Adrenergic Agonist Exposure During Early and Mid- to Late Pregnancy With Offspring
Neurodevelopmental Milestones
J-ASQ-3 domains, AOR (95% CI)a
Offspring, No. (%)

Communication skills

Gross motor skills

Fine motor skills

Problem-solving skills

Personal-social skills

No

90 491 (98.9)

1 [Reference]

1 [Reference]

1 [Reference]

1 [Reference]

1 [Reference]Yes

969 (1.1)

1.00 (0.72-1.38)

0.93 (0.75-1.16)

0.99 (0.81-1.20)

0.99 (0.82-1.21)

0.82 (0.58-1.16)

No

89 957 (98.4)

1 [Reference]

1 [Reference]

1 [Reference]

1 [Reference]

1 [Reference]

Yes

1503 (1.6)

1.05 (0.81-1.38)

0.97 (0.81-1.15)

0.99 (0.84-1.18)

0.99 (0.84-1.16)

0.85 (0.64-1.12)

No

91 106 (99.6)

1 [Reference]

1 [Reference]

1 [Reference]

1 [Reference]

1 [Reference]Yes

354 (0.4)

0.96 (0.52-1.78)

0.92 (0.64-1.31)

0.74 (0.52-1.06)

0.93 (0.67-1.29)

0.61 (0.31-1.18)

No

90 882 (99.4)

1 [Reference]

1 [Reference]

1 [Reference]

1 [Reference]

1 [Reference]Yes

578 (0.6)

1.37 (0.91-2.06)

1.13 (0.85-1.51)

1.11 (0.82-1.52)

1.14 (0.87-1.50)

1.21 (0.80-1.83)

Corticosteroids
Exposed, early pregnancy

Exposed, mid- to late pregnancy

β2-adrenergic agonists
Exposed, early pregnancy

Exposed, mid- to late pregnancy

Abbreviations: AOR, adjusted odds ratio; J-ASQ-3, Japanese version of the Ages and Stages Questionnaires, 3rd edition.
aAdjusted for maternal age at delivery, marital status, educational level, history of prepregnancy asthma, and alcohol consumption during pregnancy; maternal and paternal smoking
during pregnancy; household annual income; and offspring sex.
JAMA Network Open. 2023;6(10):e2339347. doi:10.1001/jamanetworkopen.2023.39347 (Reprinted)

Downloaded From: https://jamanetwork.com/ by a Osaka University- GAIZATSU (HANDAI) User on 10/24/2023

October 24, 2023

9/13

JAMA Network Open | Pediatrics

In Utero Corticosteroids and β2-Adrenergic Agonists and Neurodevelopmental Outcomes

second and third trimesters is less likely to be associated with teratogenesis. These associations
could be due to underlying disorders, pathological conditions, or environmental factors. Conversely,
the observation may be probable when reflecting on the dynamic neurodevelopmental process thatencompasses the fetal period to early childhood, as neuroplasticity is a complex process that occurs
during time-sensitive periods of prenatal and postnatal brain development during which the brain ismost amenable to change.33,34
A potential confounder of the association between maternal antiasthmatic medication use andsubsequent offspring development is the maternal history of asthma during pregnancy.18,28 We
found no evidence of confounding by a maternal history of prepregnancy asthma, consistent withthose of several studies.35-37 Furthermore, we examined the effect modification by sex; the results
suggested no sex differences regarding the association between in utero antiasthmatic medication
exposure and offspring development. Yet, further replication in high-powered studies across diverse
contexts and long-term neurodevelopmental outcomes is warranted. Nevertheless, this study’s
findings provide new insights for clinicians and pregnant individuals in asthma treatment during
pregnancy. Moreover, to our knowledge, the current study is the largest in Japan to examine
offspring neurodevelopmental outcomes after in utero corticosteroid and β2-adrenergic agonist
exposure using a large birth cohort data set of populations from both rural and urban areas.22,38
Moreover, we included a wide range of confounding factors and longitudinal outcome data that few
previous studies have considered.

Limitations
This study has limitations. First, although the JECS has a substantial sample size and demographic
similarities to the Japanese population, generalization to other populations should be performed
with caution because the JECS does not adhere strictly to a population-based approach.39 Second,
the JECS was not primarily designed to evaluate the association of antiasthmatic medications with
offspring development. Therefore, there is a lack of information regarding maternal asthma severity
during pregnancy, medication dose, duration, and route of administration as well as participants’capacity to accurately report their medication use, including both medication types and timing,
which may have confounded the true association. Third, a recall bias or exposure misclassification
may have occurred, although we collected antiasthmatic medication exposure information by faceto-face interviews. Fourth, we had a limited number of exposed cases, specifically with β2-adrenergic
agonists; thus, there was a low study power in some of the analyses. Fifth, observer bias may haveaffected child neurodevelopment data, despite using the J-ASQ-3. Sixth, although the analyses were
adjusted for several confounders, it is likely that residual confounding through unmeasured
covariates may have remained.

Conclusions
In this cohort study, we observed no association between the timing of in utero corticosteroid andβ2-adrenergic agonist exposure and offspring neurodevelopment milestones during the first 3 yearsof life. Despite the study’s limitations and its low power, these findings suggest that corticosteroids
and β2-adrenergic agonists could be considered safe for use by pregnant individuals with asthma andsafe for the neurodevelopment of their offspring. Additionally, the findings may inform choices
regarding the management of maternal asthma during pregnancy.

ARTICLE INFORMATION
Accepted for Publication: September 12, 2023.
Published: October 24, 2023. doi:10.1001/jamanetworkopen.2023.39347

JAMA Network Open. 2023;6(10):e2339347. doi:10.1001/jamanetworkopen.2023.39347 (Reprinted)

Downloaded From: https://jamanetwork.com/ by a Osaka University- GAIZATSU (HANDAI) User on 10/24/2023

October 24, 2023

10/13

JAMA Network Open | Pediatrics

In Utero Corticosteroids and β2-Adrenergic Agonists and Neurodevelopmental OutcomesOpen Access: This is an open access article distributed under the terms of the CC-BY License. © 2023 Nagata A
et al. JAMA Network Open.
Corresponding Authors: Abir Nagata, PhD, Department of Regenerative Dermatology, Graduate School of
Medicine, Osaka University, 2-2, Yamadaoka, Suita-shi, Osaka 565-0871, Japan (abir.med@osaka-u.ac.jp); Toshio
Masumoto, PhD, Division of Health Administration and Promotion, Faculty of Medicine, Tottori University, 86
Nishi-cho, Yonago-shi, Tottori, 683-8503, Japan (tmasumoto@tottori-u.ac.jp).
Author Affiliations: Department of Regenerative Dermatology, Graduate School of Medicine, Osaka University,
Osaka, Japan (Nagata, Nakagawa); Graduate School of Public Health, St Luke’s International University, Tokyo,
Japan (Nagata); Division of Health Administration and Promotion, Faculty of Medicine, Tottori University, Tottori,
Japan (Masumoto, Kurozawa); Department of Development and Environmental Medicine, Fukushima Medical
Center for Children and Women, Fukushima Medical University Graduate School of Medicine, Fukushima, Japan(Nishigori); International Platform for Dryland Research and Education, Tottori University, Tottori, Japan (Otani).
Author Contributions: Drs Nagata and Masumoto had full access to all of the data in the study and takeresponsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Nagata, Masumoto, Nishigori, Kurozawa.
Acquisition, analysis, or interpretation of data: Nagata, Masumoto, Nakagawa, Otani.
Drafting of the manuscript: Nagata, Masumoto, Kurozawa.
Critical review of the manuscript for important intellectual content: Nagata, Masumoto, Nishigori, Nakagawa, Otani.
Statistical analysis: Nagata, Masumoto.
Obtained funding: Kurozawa.
Administrative, technical, or material support: Masumoto, Nishigori, Otani, Kurozawa.
Supervision: Masumoto, Nishigori, Nakagawa, Otani, Kurozawa.
Conflict of Interest Disclosures: None reported.
Funding/Support: This study was funded by the Ministry of Environment, Japan.
Role of the Funder/Sponsor: The funder 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; anddecision to submit the manuscript for publication.
Group Information: The Japan Environment and Children’s Study Group members are listed in Supplement 2.
Disclaimer: The findings and conclusions of this article are solely the responsibility of the authors and do not
represent the official views of the Japanese government.
Data Sharing Statement: See Supplement 3.
Additional Contributions: We thank all of the participants in this study and the cooperating health carepractitioners for their contribution to the Japan Environment and Children’s Study.
REFERENCES
1. National Heart, Lung, and Blood Institute; National Asthma Education and Prevention Program Asthma andPregnancy Working Group. NAEPP expert panel report. Managing asthma during pregnancy: recommendations forpharmacologic treatment-2004 update. J Allergy Clin Immunol. 2005;115(1):34-46. doi:10.1016/j.jaci.
2004.10.023
2. Bonham CA, Patterson KC, Strek ME. Asthma outcomes and management during pregnancy. Chest. 2018;153(2):515-527. doi:10.1016/j.chest.2017.08.029
3. Grosso A, Locatelli F, Gini E, et al. The course of asthma during pregnancy in a recent, multicase-control study
on respiratory health. Allergy Asthma Clin Immunol. 2018;14:16. doi:10.1186/s13223-018-0242-0
4. Ibrahim WH, Rasul F, Ahmad M, et al. Asthma knowledge, care, and outcome during pregnancy: the QAKCOP
study. Chron Respir Dis. 2019;16:1479972318767719. doi:10.1177/1479972318767719
5. Clifton VL. Managing asthma in pregnancy: effects on future child health. Lancet Respir Med. 2019;7(6):485-486. doi:10.1016/S2213-2600(19)30149-3
6. Abdullah K, Zhu J, Gershon A, Dell S, To T. Effect of asthma exacerbation during pregnancy in women withasthma: a population-based cohort study. Eur Respir J. 2020;55(2):1901335. doi:10.1183/13993003.01335-2019
7. Papi A, Blasi F, Canonica GW, Morandi L, Richeldi L, Rossi A. Treatment strategies for asthma: reshaping theconcept of asthma management. Allergy Asthma Clin Immunol. 2020;16(1):75. doi:10.1186/s13223-020-00472-8
8. Murphy VE, Powell H, Gibson P. Exacerbations following step down and step up inhaled corticosteroid therapy
in the Managing Asthma in Pregnancy (MAP) study. Respirology. 2015;20:54-54.

JAMA Network Open. 2023;6(10):e2339347. doi:10.1001/jamanetworkopen.2023.39347 (Reprinted)

Downloaded From: https://jamanetwork.com/ by a Osaka University- GAIZATSU (HANDAI) User on 10/24/2023

October 24, 2023

11/13

JAMA Network Open | Pediatrics

In Utero Corticosteroids and β2-Adrenergic Agonists and Neurodevelopmental Outcomes

9. Murphy VE, Jensen ME, Gibson PG. Exacerbations of asthma following step-up and step-down inhaledcorticosteroid and long acting beta agonist therapy in the managing asthma in pregnancy study. J Asthma. 2022;
59(2):362-369. doi:10.1080/02770903.2020.1847934
10. Witter FR, Zimmerman AW, Reichmann JP, Connors SL. In utero beta 2 adrenergic agonist exposure andadverse neurophysiologic and behavioral outcomes. Am J Obstet Gynecol. 2009;201(6):553-559. doi:10.1016/j.
ajog.2009.07.010
11. Räikkönen K, Gissler M, Kajantie E. Associations between maternal antenatal corticosteroid treatment andmental and behavioral disorders in children. JAMA. 2020;323(19):1924-1933. doi:10.1001/jama.2020.3937
12. Seckl JR, Meaney MJ. Glucocorticoid programming. Ann N Y Acad Sci. 2004;1032:63-84. doi:10.1196/annals.
1314.006
13. Huang LT. The link between perinatal glucocorticoids exposure and psychiatric disorders. Pediatr Res.
2011;69(5 Pt 2):19R-25R. doi:10.1203/PDR.0b013e318212c29b
14. Gidaya NB, Lee BK, Burstyn I, Michael Y, Newschaffer CJ, Mortensen EL. In utero exposure to β-2-adrenergic
receptor agonist drugs and risk for autism spectrum disorders. Pediatrics. 2016;137(2):e20151316. doi:10.1542/
peds.2015-1316
15. Su X, Yuan W, Chen J, et al. Prenatal exposure to β2-adrenoreceptor agonists and the risk of autism spectrum
disorders in offspring. Pharmacoepidemiol Drug Saf. 2017;26(7):812-818. doi:10.1002/pds.4214
16. Tao S, Du J, Chi X, et al; China National Birth Cohort (CNBC Study Group). Associations between antenatal
corticosteroid exposure and neurodevelopment in infants. Am J Obstet Gynecol. 2022;227(5):759.e1-759.e15. doi:
10.1016/j.ajog.2022.05.060
17. Croen LA, Connors SL, Matevia M, Qian Y, Newschaffer C, Zimmerman AW. Prenatal exposure to β2-adrenergic
receptor agonists and risk of autism spectrum disorders. J Neurodev Disord. 2011;3(4):307-315. doi:10.1007/
s11689-011-9093-4
18. Gong T, Lundholm C, Rejnö G, et al. Parental asthma and risk of autism spectrum disorder in offspring:a population and family-based case-control study. Clin Exp Allergy. 2019;49(6):883-891. doi:10.1111/cea.13353
19. Chambers CD, Krishnan JA, Alba L, et al. The safety of asthma medications during pregnancy and lactation:clinical management and research priorities. J Allergy Clin Immunol. 2021;147(6):2009-2020. doi:10.1016/j.jaci.
2021.02.037
20. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical
research involving human subjects. JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053
21. Kawamoto T, Nitta H, Murata K, et al; Working Group of the Epidemiological Research for Children’s
Environmental Health. Rationale and study design of the Japan Environment and Children’s Study (JECS). BMC
Public Health. 2014;14:25. doi:10.1186/1471-2458-14-25
22. Michikawa T, Nitta H, Nakayama SF, et al; Japan Environment and Children’s Study Group. Baseline profile ofparticipants in the Japan Environment and Children’s Study (JECS). J Epidemiol. 2018;28(2):99-104. doi:10.2188/
jea.JE20170018
23. Mezawa H, Aoki S, Nakayama SF, et al. Psychometric profile of the Ages and Stages Questionnaires, Japanesetranslation. Pediatr Int. 2019;61(11):1086-1095. doi:10.1111/ped.13990
24. Squires J, Twombly E, Bricker DD, Potter L. ASQ-3 User’s Guide. Brookes Publishing; 2009.
25. Muthusamy S, Wagh D, Tan J, Bulsara M, Rao S. Utility of the Ages and Stages Questionnaire to identify
developmental delay in children aged 12 to 60 months: a systematic review and meta-analysis. JAMA Pediatr.
2022;176(10):980-989. doi:10.1001/jamapediatrics.2022.3079
26. Miyake T, Yamamoto M, Sakurai K, Eguchi A, Yoshida M, Mori C; Japan Environment and Children’s Study(JECS) Group. Neurological development in 36-month-old children conceived via assisted reproductive
technology: the Japan Environment and Children’s Study. Reprod Med Biol. 2022;21(1):e12457. doi:10.1002/
rmb2.12457
27. Takahashi I, Obara T, Ishikuro M, et al. Screen time at age 1 year and communication and problem-solving
developmental delay at 2 and 4 years. JAMA Pediatr. 2023;177(10):1039-1046. doi:10.1001/jamapediatrics.
2023.3057
28. Liu X, Dalsgaard S, Munk-Olsen T, Li J, Wright RJ, Momen NC. Parental asthma occurrence, exacerbations andrisk of attention-deficit/hyperactivity disorder. Brain Behav Immun. 2019;82:302-308. doi:10.1016/j.bbi.2019.
08.19829. Liang H, Chen J, Miao M, et al. In utero exposure to β-2-adrenergic receptor agonist and attention-deficit/
hyperactivity disorder in children. Eur Child Adolesc Psychiatry. 2017;26(7):847-856. doi:10.1007/s00787-0170956-4
JAMA Network Open. 2023;6(10):e2339347. doi:10.1001/jamanetworkopen.2023.39347 (Reprinted)

Downloaded From: https://jamanetwork.com/ by a Osaka University- GAIZATSU (HANDAI) User on 10/24/2023

October 24, 2023

12/13

JAMA Network Open | Pediatrics

In Utero Corticosteroids and β2-Adrenergic Agonists and Neurodevelopmental Outcomes

30. Nakamura Y, Tamaoki J, Nagase H, et al; Japanese Society of Allergology. Japanese guidelines for adult asthma
2020. Allergol Int. 2020;69(4):519-548. doi:10.1016/j.alit.2020.08.001
31. Rhodes MC, Seidler FJ, Abdel-Rahman A, et al. Terbutaline is a developmental neurotoxicant: effects onneuroproteins and morphology in cerebellum, hippocampus, and somatosensory cortex. J Pharmacol Exp Ther.
2004;308(2):529-537. doi:10.1124/jpet.103.060095
32. Zerrate MC, Pletnikov M, Connors SL, et al. Neuroinflammation and behavioral abnormalities after neonatal
terbutaline treatment in rats: implications for autism. J Pharmacol Exp Ther. 2007;322(1):16-22. doi:10.1124/jpet.
107.121483
33. Ismail FY, Fatemi A, Johnston MV. Cerebral plasticity: windows of opportunity in the developing brain. Eur J
Paediatr Neurol. 2017;21(1):23-48. doi:10.1016/j.ejpn.2016.07.007
34. Meredith RM. Sensitive and critical periods during neurotypical and aberrant neurodevelopment: a frameworkfor neurodevelopmental disorders. Neurosci Biobehav Rev. 2015;50:180-188. doi:10.1016/j.neubiorev.2014.12.001
35. Schatz M, Harden K, Kagnoff M, Zeiger RS, Chilingar L. Developmental follow-up in 15-month-old infants ofasthmatic vs. control mothers. Pediatr Allergy Immunol. 2001;12(3):149-153. doi:10.1034/j.1399-3038.2001.
012003149.x
36. Mallise CA, Murphy VE, Campbell LE, et al. Early sensory and temperament features in infants born to motherswith asthma: a cross-sectional study. Front Psychol. 2021;12:713804. doi:10.3389/fpsyg.2021.713804
37. Whalen OM, Karayanidis F, Murphy VE, Lane AE, Mallise CA, Campbell LE. The effects of maternal asthma
during pregnancy on child cognitive and behavioral development: a systematic review. J Asthma. 2019;56(2):130-141. doi:10.1080/02770903.2018.1437174
38. Michikawa T, Nitta H, Nakayama SF, et al; Japan Environment and Children’s Study Group. The Japan
Environment and Children’s Study (JECS): a preliminary report on selected characteristics of approximately
10 000 pregnant women recruited during the first year of the study. J Epidemiol. 2015;25(6):452-458. doi:10.
2188/jea.JE20140186
39. Yang L, Sato M, Saito-Abe M, et al; on behalf of the Japan Environment and Children’s Study JECS Group.
Allergic disorders and risk of anemia in Japanese children: findings from the Japan Environment and Children’s
Study. Nutrients. 2022;14(20):4335. doi:10.3390/nu14204335
SUPPLEMENT 1.
eMethods. Supplementary Methods
eTable 1. Validated Japanese Version of the Ages and Stages Questionnaires, Third Edition (J-ASQ-3), Cutoff Values
eTable 2. Association of Pre-Pregnancy Exposure to Corticosteroids and β2-Adrenergic Agonists (β2AAs) With
Offspring Neurodevelopmental Milestones
eTable 3. Sensitivity Analysis on the Association of Timing of In-Utero Exposure to Corticosteroids and β2AAs With
Offspring Neurodevelopmental Milestones in Additionally Adjusted Generalized Estimating Equation (GEE)ModelseTable 4. Sensitivity Analysis on the Association of Timing of In-Utero Exposure to Corticosteroids and β2AAs With
Offspring Neurodevelopmental Milestones in GEE Models With Multiple Imputations of Missing Values
eTable 5. Sensitivity Analysis on the Association of Timing of In-Utero Exposure to Corticosteroids and β2AAs With
Offspring Neurodevelopmental Milestones in GEE Models With Sample Mean Less Than (2× Standard Deviation[SD]) as Cutoff Values for Each J-ASQ-3 Domain
eTable 6. Sensitivity Analysis on the Association of Timing of In-Utero Exposure to Corticosteroids and β2AAs With
Offspring Neurodevelopmental Milestones in Linear Multivariable GEE Models
eTable 7. Subgroup Analysis of the Association of Timing of In-Utero Exposure to Corticosteroids and β2AAs With
Offspring Neurodevelopmental Milestones According to the Child’s Sex
eTable 8. Subgroup Analysis of the Association of Timing of In-Utero Exposure to Corticosteroids and β2AAs With
Offspring Neurodevelopmental Milestones According to the Maternal History of Pre-Pregnancy Asthma
eFigure 1. Directed Acyclic Graph for the Association Between In-Utero Corticosteroids and β2AA Exposure andOffspring Neurodevelopment
eFigure 2. Scores of J-ASQ-3 According to Age
eReference
SUPPLEMENT 2.
Nonauthor Collaborators
SUPPLEMENT 3.
Data Sharing Statement

JAMA Network Open. 2023;6(10):e2339347. doi:10.1001/jamanetworkopen.2023.39347 (Reprinted)

Downloaded From: https://jamanetwork.com/ by a Osaka University- GAIZATSU (HANDAI) User on 10/24/2023

October 24, 2023

13/13