DOI: 10.1111/1471-0528.

13582 Epidemiology
www.bjog.org

Motor development in children prenatally

exposed to selective serotonin reuptake
inhibitors: a large population-based pregnancy
cohort study
M Handal,a S Skurtveit,a,b K Furu,a S Hernandez-Diaz,c E Skovlund,a W Nystad,a R Selmera
a
Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway b Norwegian Centre for Addiction Research, University of
Oslo, Oslo, Norway c Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
Correspondence: M Handal, Department of Pharmacoepidemiology, Division of Epidemiology, Norwegian Institute of Public Health. PO
Box 4404 Nydalen, 0403 Oslo, Norway. Email marte.handal@fhi.no

Accepted 27 May 2015. Published Online 15 September 2015.

Objectives To estimate the association between prenatal exposure
to selective serotonin reuptake inhibitors (SSRIs) and motor
development in children considering the effect of maternal
symptoms of anxiety and depression before, during and after
pregnancy.
Design Population-based prospective pregnancy cohort study.
Setting The Norwegian Mother and Child Cohort study (MoBa)
(1999–2008).
Population A total of 51 404 singleton pregnancies.
Methods Self-reported use of SSRIs was collected for the
6 months before pregnancy and prospectively during pregnancy.
We used ordinal logistic regression as the statistical analysis.
Main outcome measures Motor development was assessed by
maternal reports of fine and gross motor development at child age
3 years by items from the Ages and Stages Questionnaire (ASQ).
The maternal ASQ scores were compared with data from a MoBa
sub-study where clinicians assessed motor development with the
Gross and Fine Motor Mullen scales of early learning.
Results In all 381 women (0.7%) reported use of SSRIs during
pregnancy, of these 159 reported on at least two questionnaires
(prolonged use). Prolonged SSRI exposure was associated with a
delay in fine motor development, odds ratio 1.42 (95% CI 1.07–
1.87) compared with no SSRI exposure, after adjusting for
symptoms of anxiety and depression before and during pregnancy.
Severity of maternal depression seemed to explain the association
only partially. Stratifying on depression after pregnancy had no
impact on the estimated effect of SSRIs.
Conclusions Prolonged prenatal exposure to SSRIs was weakly
associated with a delayed motor development at age 3 years, but
not to the extent that the delay was of clinical importance.
Keywords Anxiety, cohort studies, depression, Norwegian Mother
and Child Cohort study (MoBa), pregnancy, psychomotor
disorder, selective serotonin reuptake inhibitors.
Tweetable abstract Long-term prenatal SSRI exposure is weakly
associated with delayed motor development independent of
depression.
Linked article This article is commented on by L Siminerio et al.,
p. 1918 in this issue. To view this mini commentary visit http://
dx.doi.org/10.1111/1471-0528.13581.

Please cite this paper as: Handal M, Skurtveit S, Furu K, Hernandez Diaz S, Skovlund E, Nystad W, Selmer R. Motor development in children prenatally
exposed to selective serotonin reuptake inhibitors: a large population-based pregnancy cohort study. BJOG 2016;123:1908–1917.

associated with increased risk of several adverse pregnancy

Introduction
Untreated maternal depression may be harmful to both the
mother and the fetus,1 but concerns about the safety of
selective serotonin reuptake inhibitor (SSRI) use during
pregnancy have also been raised.2 Use of SSRIs has been
outcomes, including preterm delivery and discontinuation
syndrome in the newborn.2
Data on the association between prenatal SSRI exposure
and long-term neurodevelopment are limited, and the evi-
dence is inconclusive.2,3 Early studies were mostly reassur-

1908 ª 2015 Royal College of Obstetricians and Gynaecologists


ing,2 but some recent studies have indicated that SSRI
exposure during pregnancy might influence children’s
motor development.4–8
The study of prenatal SSRI exposure and neurodevelop-
ment is complicated by the effects of the underlying mood
disorder. The results from a systematic review suggested
that both untreated prepartum and postpartum depression
could have an adverse effect on developmental outcomes in
the offspring.9 Whether prenatal SSRI exposure and mater-
nal depression independently or cumulatively contribute to
the adverse developmental outcomes remains a key area of
concern.
The aim of the present study was to examine if prenatal
SSRI exposure was associated with delay in motor
development in children aged 3 years using a large popula-
tion-based pregnancy cohort considering the mothers’
symptoms of anxiety and depression before, during and
after pregnancy.
Methods
The Norwegian Mother and Child Cohort Study
The Norwegian Mother and Child Cohort Study (MoBa) is
a prospective population-based pregnancy cohort study
conducted by the Norwegian Institute of Public Health and
described in detail elsewhere.10,11 Pregnant women in Nor-
way were recruited through a postal invitation in connec-
tion with the routine ultrasound examination offered to all
pregnant women around pregnancy week 17. Participants
were recruited from all over Norway from 1999 to 2008,
and 38.7% of invited women consented to participate. The
cohort includes 108 000 children, 90 700 mothers and
71 500 fathers. Follow up is conducted by questionnaires at
regular intervals. Some of the information in MoBa is
obtained from the Medical Birth Registry of Norway
(MBRN), which is a nationwide registry that is based on
the compulsory notification of every birth or late abortion
from 12 weeks of gestation onwards in Norway.12
Study population
This study was based on 58 410 pregnancies where the
mother returned the 3-year questionnaire (see Figure S1).
Twin or triplet pregnancies (n = 1748) and pregnancies
resulting in a child with malformation and/or chromoso-
mal abnormalities (n = 1555) were excluded. Pregnancies
where the woman did not answer all three questionnaires
containing questions regarding drug use during pregnancy
(Table 1) were excluded (n = 3069). Pregnancies where the
mother returned the 3-year questionnaire but did not fill
in the motor development measures in the questionnaire
(n = 634) were also excluded. This resulted in a study pop-
ulation of 51 404 mother–child pairs. The MoBa data file
version 7 was used.
ª 2015 Royal College of Obstetricians and Gynaecologists
Motor development after prenatal SSRIs exposure
Table 1. Questionnaires in MoBa with information regarding drug
use during pregnancy
Questionnaire Drug exposure Time period of Time of
(Q) periods drug exposure reporting
Q1 Before pregnancy 6 months before Pregnancy
pregnancy week 17/18
Q1 During pregnancy Pregnancy Pregnancy
week 0–17/18 week 17/18
Q3 During pregnancy Pregnancy Pregnancy
week 19–29 week 30
Q4 During pregnancy Pregnancy 6 months
week 30 to birth after birth
Exposure
The mothers received three questionnaires with questions
regarding drug use before and during pregnancy. Table 1
provides an overview of the time intervals for which the dif-
ferent questionnaires contain information. Complete ques-
tionnaires with phrasings of the questions on use of
medication are available on the Norwegian Institute of Pub-
lic Health’s website (www.fhi.no/moba-en). All SSRIs were
studied as one drug group. A woman was defined as a
nonuser of SSRIs if she did not report any use of SSRI in
any of the time periods above, as a user only before preg-
nancy if she wrote a trade name of an SSRI or only wrote
‘SSRI’ and only ticked the box for use before pregnancy and
none of the boxes indicating the pregnancy weeks, or as a
user of SSRIs during pregnancy if she ticked at least one of
the boxes for use from pregnancy week 0 until birth.
In accordance with previous work11 duration of SSRI
treatment was categorised as use during one period if the
woman reported use only on one questionnaire and as use
during at least two periods (prolonged use) if she reported
use on more than one questionnaire.
In Norway, SSRIs may in some instances be used to treat
anxiety, obsessive-compulsive disorders, bulimia, post-trau-
matic stress syndrome and cataplexy. However, the main
indication for use is depression.
Outcome
Motor skills at the age of 3 years were assessed through
maternal ratings on selected items from the Ages and Stages
Questionnaire (ASQ).13 Each motor area was represented by
two items (see Table S1) and both areas were scored using
the response categories yes, very often (1); yes, sometimes
(2); not yet (3) and don’t know (missing). The fine and
gross motor development scores were calculated as the aver-
age values of the two items respectively to generate average
scores of 1, 1.5, 2, 2.5 and 3 where 1 was the best score. For
gross motor development the score distribution was skewed;
more than 75% of the children got the score 1 and only
1909
 Handal et al.
0.3% got a score of either 2.5 or 3. We therefore collapsed
the three categories with scores ≥2 into one category. The
distribution of the fine motor development scores was less
skewed and was treated as five categories corresponding to
the five different scores. For both fine and gross motor
development the last category (ASQ scores 3 and ≥2, respec-
tively) corresponds to clinically fine or gross motor impair-
ment defined as an ASQ score equal or larger than two
standard deviations above the mean.14
Validity of the outcome measure
Regarding the validity of the ASQ scores, there are data sug-
gesting that most parents can accurately judge whether their
child can or cannot perform observable behaviours, as they
have firsthand experience with their child’s development.14
To further check this in our study sample we used a subsam-
ple of children who underwent an in-depth assessment
shortly after completion of the age 3 years questionnaire as
part of a case–control study of autism spectrum disorders
nested within MoBa (The Autism Birth Cohort).15 Cases
selected to participate in the Autism Birth Cohort study were
potential autism spectrum disorder cases that were positive
on the screening instruments used (Social and Communica-
tion Questionnaire and selected Modified Checklist for Aut-
ism in Toddlers items) in MoBa.15 We compared scores on
the Gross Motor and Fine Motor Mullen scales of early
learning with the maternal ratings on the ASQ items. The
Mullen scales were administered by trained clinicians who
were blind to the maternal reports.
In (Figure S2) the boxplots compare categories of fine
and gross motor ASQ scores from the mother’s report with
scores based on the fine and gross motor Mullen scales of
early learning in a subset of children (n = 637 for fine
motor and n = 449 for gross motor). In the tested subsets,
15% had a fine motor ASQ score of 3 compared with 3.5%
in the whole data set and 14% had a gross motor ASQ
score of ≥2 compared with 3%. Hence, because of the selec-
tion of screen-positive cases to the subset tested with Mul-
len scales, more children had fine and gross motor delay
compared with all children included in the present study.
Regarding fine motor development there was a negative
association between the ASQ score and the Mullen score
with a Spearman correlation of 0.40 (95% CI 0.47 to
0.34). Children with a score of 3 (the worst category)
had a clearly lower Mullen score than the other groups.
The estimated Spearman correlation was 0.25 (95% CI
0.34 to 0.17) for the Gross Motor scales and children
in the worst category (ASQ ≥ 2) had a low Mullen score.
Potential confounding
We considered factors that might be associated with use of
SSRIs in pregnancy and motor development in the child.
1910
Potential confounding variables, their sources and categori-
sations are shown in Table 2.
Depression before pregnancy was assessed in pregnancy
week 17–18 and was defined as ever having experienced
three or more of the following symptoms simultaneously
for a continuous period of 2 weeks or more without any
particular reason (death, divorce etc.): felt depressed or
sad; had problems with appetite or eaten too much; been
bothered by feeling weaker or a lack of energy; really
blamed yourself and felt worthless; had problems with con-
centration or had problems making decisions.
The mother’s symptoms of anxiety and depression were
assessed by the five-items version (SCL-5) of the Hopkins
Symptom Checklist (SCL-25) twice during pregnancy
(week 17–18 and week 30), and three times after delivery
(child age 6 and 18 months and 3 years) as described in
detail elsewhere.11 Short-term and long-term symptoms in
pregnancy were defined as reporting symptoms once or
twice during pregnancy, respectively.
Statistical analysis
The outcome is ordered, with an ASQ score ranging from
1 to 5. Ordinal logistic regression, that is a proportional
odds model, was applied as we hypothesised a shift in the
distribution of response categories in children prenatally
exposed to SSRIs. We used robust standard errors
‘vce(cluster personid)’ in STATA. This option specifies that
the observations are independent across clusters (mothers)
but not necessarily within clusters. The interpretation of
the odds ratio (OR) is the change in the odds of being in a
lower development category of the ASQ score per unit
increase in the independent variable. An odds ratio above
unity means a shift in the distribution towards higher ASQ
scores. We call this shift in distribution ‘motor delay’. The
model assumes proportional odds. We have also performed
multinomial logistic regression, which relaxes the assump-
tions, showing similar results (results not shown).
To distinguish between the effect of SSRI use and symp-
toms of anxiety and depression before and during preg-
nancy we have used two different approaches. First, we
defined six groups combining use of SSRI during preg-
nancy; no use, use in one period only and use in at least
two periods with the absence or presence of symptoms of
anxiety and depression during pregnancy. Women who did
not use SSRIs and did not report symptoms of anxiety and
depression during pregnancy were the reference category.
In this approach we did not distinguish between short-term
and long-term symptoms of anxiety and depression. In the
next approach we included use of SSRI in four categories
and depression before pregnancy as well as short-term and
long-term symptoms of anxiety and depression during
pregnancy as independent variables in the model.
ª 2015 Royal College of Obstetricians and Gynaecologists
 Motor development after prenatal SSRIs exposure

Table 2. Use of SSRI before and during pregnancy by parental characteristics (n = 51 404)

SSRI exposure P*

No Before only One period At least two periods

n % n % n % n %

Maternal age in years** (n = 51 336)

<25 4534 9.0 46 9.6 26 11.7 17 10.7 0.58
25–29 16 891 33.5 154 32.2 72 32.4 47 29.6
30–34 20 060 39.7 200 41.8 78 35.1 62 39.0
≥34 8991 17.8 79 16.5 46 20.7 33 20.8
Paternal age in years** (n = 51 211)
<25 1870 3.7 18 3.8 19 8.6 7 4.4 0.002
25–29 11 277 22.4 103 21.5 47 21.4 36 22.6
30–34 20 057 39.8 196 40.9 64 29.1 58 36.5
≥35 17 149 34.1 162 33.8 90 40.9 58 36.5
Maternal formal education in years*** (n = 50 324)
<12 8309 16.8 85 18.2 51 23.3 40 25.6 0.003
12 7109 14.4 74 15.9 38 17.4 28 17.9
13–16 21 769 44.0 188 40.3 81 37.0 60 38.5
≥17 12 296 24.8 119 25.5 49 22.4 28 17.9
Paternal formal education in years*** (n = 50 324)
<12 16 081 33.8 155 34.6 87 41.4 64 42.7 <0.001
12 6127 12.9 52 11.6 40 19.0 30 20.0
13–16 13 914 29.2 125 27.9 51 24.3 30 20.0
≥17 11 465 24.1 116 25.9 32 15.2 26 17.3
Marital status*** (n = 51 178)
Married or living with partner 49 008 97.4 462 96.5 193 88.9 145 91.2 <0.001
Single 872 1.7 11 2.3 18 8.3 9 5.7
Other 443 0.9 6 1.3 6 2.8 5 3.1
Parity** (n = 51 336)
0 24 114 47.8 224 46.8 131 59.0 89 56.0 0.003
1 17 303 34.3 158 33.0 54 24.3 51 32.1
≥2 9059 17.9 97 20.3 37 16.7 19 11.9
Planned pregnancy*** (n = 50 869)
No 8407 16.8 75 15.8 87 39.5 40 25.6 <0.001
Yes 41 611 83.2 400 84.2 133 60.5 116 74.4
Maternal work situation*** (n = 51 196)
Working 46 567 92.5 443 93.1 173 77.9 129 81.6 <0.001
Not working 2784 5.5 19 4.0 18 8.1 11 7.0
Disability pension 329 0.7 3 0.6 21 9.5 15 9.5
Other 660 1.3 11 2.3 10 4.5 3 1.9
Maternal BMI in kg/m2 **** (n = 50 294)
< 25 34 390 69.5 321 68.3 143 66.2 96 63.2 0.07
25–29 10 659 21.6 96 20.4 44 20.4 37 24.3
30–34 3251 6.6 38 8.1 18 8.3 13 8.6
≥35 1156 2.3 15 3.2 11 5.1 6 3.9
Maternal smoking***** (n = 49 213)
No 44 745 92.5 423 91.6 180 82.9 119 78.8 <0.001
Yes, sometimes 2302 4.8 24 5.2 19 8.8 15 9.9
Yes, daily 1336 2.8 15 3.2 18 8.3 17 11.3
Maternal analgesic opioid use in pregnancy****** (n = 51 404)
No 49 681 98.3 470 98.1 215 96.8 150 94.3 0.001
Yes 863 1.7 9 1.9 7 3.2 9 5.7
Maternal benzodiazepine use in pregnancy****** (n = 51 404)
No 50 199 99.3 475 99.2 201 90.5 133 83.6 <0.001

ª 2015 Royal College of Obstetricians and Gynaecologists 1911

 Handal et al.

Table 2. (Continued)

SSRI exposure P*

No Before only One period At least two periods

n % n % n % n %

Yes 345 0.7 4 0.8 21 9.5 26 16.4

Maternal alcohol intake in pregnancy*** (n = 51 308)
No 25 084 49.7 232 48.7 99 44.6 65 40.9 0.008
Possible or low alcohol intake 23 478 46.5 229 48.1 109 49.1 81 50.9
High alcohol intake 1889 3.7 15 3.2 14 6.3 13 8.2
Maternal depression before pregnancy*** (n = 50 287)
No 46 879 94.8 433 91.9 119 54.8 82 53.9 <0.001
Yes 2568 5.2 38 8.1 98 45.2 70 46.1
Maternal symptoms of anxiety and depression******* during pregnancy (n = 50 184)
No 45 280 91.8 419 90.1 115 52.5 77 49.7 <0.001
Short term 3026 6.1 33 7.1 46 21.0 30 19.4
Long term 1039 2.1 13 2.8 58 26.5 48 31.0
Maternal symptoms of anxiety and depression******* after pregnancy (n = 47 331)
No 42 201 90.7 406 89.8 116 56.6 83 56.5 <0.001
Short term 3297 7.1 37 8.2 50 24.4 33 22.4
Long term 1029 2.2 9 2.0 39 19.0 31 21.1

*Two-sided chi-square test of independency.

**Data retrieved from the Medical Birth Registry of Norway.
***Data retrieved from the first questionnaire of the Norwegian Mother and Child Cohort study at pregnancy week 17–18.
****Body mass index (BMI) at the beginning of pregnancy (calculated as weight in kilograms divided by height in meters squared).
*****Maternal smoking in this pregnancy, data from all questionnaires concerning pregnancy.
******Self-reported use of analgesics (opioids) and anxiolytics/hypnotics (benzodiazepines [benzodiazepines and benzodiazepine-like drugs]) was
retrieved from all the three questionnaires concerning pregnancy.
*******Symptoms of anxiety and depression were assessed by self-report on Hopkins Symptom Checklist (SCL-5) during pregnancy in week 17–
18 and week 30 and after birth when the child was 6 and 18 months old. Cut off was set at an average value >2.

In the multivariate analysis we adjusted for depression
before and during pregnancy. We also included additional
possible confounders, but these did not have any impact
on the risk estimate for the association between SSRI and
motor development and were therefore not included in the
final multivariate analysis.
To study the possible effects of depression after preg-
nancy we performed a stratified analysis on mother’s symp-
toms of anxiety and depression when the child was 6 and/
or 18 months. Because depressed mothers can underesti-
mate or overestimate their child’s motor development we
performed stratified analyses on the mother’s symptoms of
anxiety and depression when the child was 3 years old.
Stratified analyses were also performed on other possible
effect modifiers such as child gender and maternal smok-
ing. To study if the association between maternal SSRI use
and child motor development was based on direct or indi-
rect effects of SSRI exposure we repeated the main analysis
after excluding children with reduced hearing, impaired
vision, hip dysplasia, birth weight <2500 g, Apgar score (at
5 min) <7 and preterm babies (<37 weeks of gestation).
We also confirmed that the difference in prevalence of
prenatal SSRI exposure between those who were excluded
because of missing or incomplete data on the motor devel-
opment measure and those included in the study popula-
tion was minimal (0.8% versus 0.7%).
Statistical analyses were conducted using SPSS for Win-
dows, 17.0.1 (SPSS Inc., Chicago, IL, USA) and STATA 12
(Stata Corp. LP., College Station, TX, USA).
Results
In all, 45 003 women with 51 404 children were included.
A total of 381 women (0.7%) reported use of an SSRI dur-
ing pregnancy, of these 222, 87 and 72 used SSRIs in one,
two or three time periods, respectively; and 479 women
used SSRIs before, but not during pregnancy.
Fine motor development
Parental education, paternal age, parity, maternal smoking,
depression before pregnancy and symptoms of anxiety and
depression after pregnancy were associated with SSRI use

1912 ª 2015 Royal College of Obstetricians and Gynaecologists

 Motor development after prenatal SSRIs exposure

(Table 2) and with the level of fine motor development in
the child at age 3 years (see Table S2).
The proportion of children with the best ASQ score was
lower when the mother had used SSRIs in at least two time
periods during pregnancy compared with nonusers, 35.8%
versus 49.0%, respectively, with difference 13.2% (95% CI
5.7–20.7%) (Table 3). A shift towards delayed motor devel-
opment was observed after SSRI exposure and the shift was
stronger with prolonged SSRI use.
Only 3.5% of the children had an ASQ score of 3 (clini-
cally fine motor impairment) (Table 3). The percentage
was slightly higher in children whose mothers used SSRI
during pregnancy compared with non-exposed children,
difference 2.1% (95% CI 0.2 to 4.4%). The percentage
did not differ significantly by length of use, difference 1.9%
(95% CI 2.6 to 6.4%). Even though the confidence inter-
val of the difference between children exposed and not
exposed to SSRIs included 0, we cannot rule out the possi-
bility of SSRIs having a harmful effect. With a difference of
2.1% one would expect that one more child will fall in the
worst ASQ category if 49 more women use SSRI during
pregnancy (number needed to harm).
Depression before pregnancy was more common among
women receiving SSRI treatment during one period (45.1%)
or at least two periods (46.7%) than among women with
anxiety/depression not treated with SSRIs (17.6%). Among
the SSRI-treated women the proportions reporting depres-
sion before pregnancy were higher among those experiencing
residual symptoms than among those who did not experi-
ence residual symptoms, independent of treatment duration
(52% versus 39% and risk difference 13.3% [95% CI 3.2–
23.5%] for the combined group of SSRI users).
Compared with the group of women who did not report
use of SSRIs or symptoms of anxiety and depression during
pregnancy, prolonged SSRI use increased the odds ratio of
the child being in a lower fine motor development category
(OR 1.47, 95% CI 1.12–1.94) (Table 4). There was no
additional effect of the mother reporting residual symp-
toms of anxiety and depression in pregnancy compared
with those who did not report such symptoms among
pregnant women who received prolonged SSRI treatment
(OR 1. 47, 95% CI 0.94–2.29 versus OR 1.48, 95% CI
1.06–2.07). Symptoms of anxiety and depression reported
by women not treated with SSRI showed no effect on the
child’s motor development (OR 1.01, 95% CI 0.95–1.08).
Including other possible confounders did not affect the
estimates after prolonged SSRI treatment (Table 4).
Depression before, but not during, pregnancy showed an
independent weak association with the child’s fine motor
development (Table 5). Adjusting for depression before
pregnancy slightly reduced the odds ratio of delayed motor
development after prolonged SSRI exposure from 1.57
(95% CI 1.19–2.07) to 1.45 (95% CI 1.10–1.92) (Table 5).
Further adjustment for duration of symptoms of anxiety
and depression during pregnancy did not change the esti-
mate (OR 1.42, 95% CI 1.07–1.87). Nor did including
other confounders (Table 5).
Gross motor development
Similar results on absolute and relative associations
between SSRI use and motor development were obtained
for gross as for fine motor development (see Tables S3–S6).
Stratified and secondary analysis
The main results (Tables 4 and 5 and see Tables S5 and S6)
were stratified by child gender, maternal symptoms of anxi-
ety and depression after pregnancy and by such symptoms at
the time of the maternal evaluation of the child’s motor
development. The results for fine motor development were
also similar in models stratified by the mothers’ smoking

Table 3. Number and frequency of children in the different fine motor development categories according to maternal SSRI use and duration of
such use (n = 51 404)

SSRI use ASQ Score*

1 1.5 2 2.5 3

n % n % n % n % n %

No 24 786 49.0 12 313 24.4 8190 16.2 3511 6.9 1744 3.5
Only before pregnancy 240 50.1 126 26.3 65 13.6 37 7.7 11 2.3
Used in pregnancy 168 44.1 96 25.2 63 16.5 33 8.7 21 5.5
Use in 1 time period 111 50.0 51 23.0 27 12.2 19 8.6 14 6.3
At least two time periods 57 35.8 45 28.3 36 22.6 14 8.8 7 4.4
Total 25 194 49.0 12 535 24.4 8318 16.2 3581 7.0 1776 3.5

*The fine motor development score was calculated as the average value of two items of the Ages and Stages Questionnaires (ASQ) to generate
an average score of 1, 1.5, 2, 2.5 and 3, where 1 was the best score.

ª 2015 Royal College of Obstetricians and Gynaecologists 1913

 Handal et al.

Table 4. Odds ratios from ordinal logistic regression of having delayed fine motor development according to different combinations of SSRI
treatment and symptoms of anxiety and depression during pregnancy (n = 49 428)

SSRI use and/or anxiety/ n Crude OR (95% CI) Adjusted** OR (95% CI)
depression*

No SSRI
No anxiety/depression 44 975 1 (Reference) 1 (Reference)
Anxiety/depression 4088 1.04 (0.98–1.10) 1.01 (0.95–1.08)
SSRI one period 215 1.07 (0.81–1.40) 0.99 (0.75–1.30)
No anxiety/depression 110 0.77 (0.53–1.12) 0.73 (0.50–1.08)
Anxiety/depression 105 1.49 (1.00–2.22) 1.37 (0.92–2.05)
SSRI at least two periods 150 1.59 (1.21–2.09) 1.47 (1.12–1.94)***
No anxiety/depression 74 1.58 (1.13–2.21) 1.48 (1.06–2.07)
Anxiety/depression 76 1.60 (1.03–2.51) 1.47 (0.94–2.29)

*Symptoms of anxiety and depression were assessed in pregnancy weeks 17–18 and 30 by the five-items version of Hopkins Symptom Checklist.
A score >2.0 on at least one of the questionnaires was defined as symptoms of anxiety and depression.
**Adjusted for depression before pregnancy.
***Including additional confounders (parental education, paternal age, parity, maternal smoking, prepregnancy BMI) in addition to depression
before pregnancy did not change the OR (1.51 [95% CI 1.11–2.05] not including and 1.52 [95% CI 1.12–2.07] including the additional
confounders in the reduced data set of 43 147 women).

during pregnancy. The association between exposure to SSRI
and gross motor development was, however, stronger in
smokers than in nonsmokers (P(interaction) = 0.054 in the
models adjusted for symptoms of anxiety and depression
before and during pregnancy).
The results were unchanged after exclusion of children
with reduced hearing, impaired vision, hip dysplasia, low
birthweight and Apgar score and babies born preterm.
Discussion
Main findings
In this large prospective cohort study we found that treat-
ment with SSRIs during longer time periods of pregnancy
was weakly associated with a delay in both fine and gross
motor development in children aged 3 years. However, only
a few children fell into the worst category representing clini-
cal motor impairment and the association between SSRI
exposure and clinical impairment was only borderline statis-
tically significantly different from zero. Severity of maternal
depression seemed to explain the association only partially.
Strengths and limitations
A major strength of this study is that self-reported SSRI
use has been validated against data on dispensed drugs in
the Norwegian Prescription Database showing substantial
agreement between the two data sources.16,17 The mothers
provided data on SSRI exposure during pregnancy for most
of the pregnancy period, and shortly after birth for the last
part of the pregnancy, making recall bias a minor problem.
Data on many health-related and sociodemographic fac-
tors made it possible to study several potential confounding
factors. A particular strength was the opportunity to study
the presence and/or duration of symptoms of anxiety and
depression before and during pregnancy and to study the
effects of these symptoms separately and in combination
with SSRI use.
The participation rate in MoBa is low (38.7%), with a pos-
sible self-selection of the healthiest women in the study. The
selection bias potentially related to participation in MoBa
has been studied, but no evidence of selection bias was
found.18 In addition we have shown that the prevalence of
SSRI use in responders and nonresponders was very similar.
The ASQ instruments used in our study have some limi-
tations. Some underestimation of the effect of SSRI due to
misclassification of motor development is likely.
Even though MoBa is a large birth cohort the number of
SSRI users was too low to perform stratified analysis on
the different SSRIs. We also did not have any dose infor-
mation. Instead we studied the duration of use as an
expression of the amount of SSRI exposure. By including
the information on short-term and long-term symptoms of
anxiety and depression and a history of depression before
pregnancy in the models we attempted to control for con-
founding by indication. However, the challenge of con-
founding by severity still remains.
Fewer than 40 women received tricyclic antidepressants,
the second most prescribed antidepressant drug group.
Hence, we were not able to include an active comparison
group in the analyses.
Symptoms of anxiety and depression were measured by
self-assessment with the SCL-5. In a validity study this ver-
sion of SCL performed as well as a screening instrument
as the full 25-item version, at least when considering

1914 ª 2015 Royal College of Obstetricians and Gynaecologists

 Motor development after prenatal SSRIs exposure

depression, and among them, those with residual symptoms

Table 5. Odds ratios from ordinal logistic regression of having
delayed fine motor development according to use of SSRIs or despite treatment could have the most severe illness.
symptoms of anxiety and depression before and/or during However, adjusting for depression before pregnancy had
pregnancy (n = 49 349) minor impact on the estimated association between SSRI use
and motor development. Further, in spite of the possible
Crude* OR Model 1*,** Model 2***
(95% CI) OR (95% CI) OR (95% CI)
variation in severity of the disease, there was no difference in
the estimate for the groups reporting or not reporting
SSRI treatment
residual symptoms of anxiety and depression among those
No 1 1 1 with prolonged SSRI treatment during pregnancy.
Only before 0.93 (0.79–1.10) 0.92 (0.78–1.09) 0.92 (0.78–1.09) Even though we found an association between prolonged
pregnancy SSRI exposure and delayed motor development only a
One period 1.06 (0.81–1.39) 0.98 (0.75–1.29) 0.96 (0.73–1.27) small proportion of children were in the least developed
At least two 1.57 (1.19–2.07) 1.45 (1.10–1.92) 1.42 (1.07– category, corresponding to clinical motor delay, both with
periods 1.87)******
respect to fine and gross motor development. The calcu-
Depression before pregnancy****
No 1 1 1
lated number needed to harm suggests that the clinical
Yes 1.21 (1.13–1.31) 1.20 (1.12–1.30) 1.19 (1.11–1.29) importance is limited.
Anxiety/Depression in pregnancy***** Some studies support the hypothesis that SSRIs could
No 1 1 affect brain development in early life. Neurotransmitters
Short term 1.02 (0.95–1.09) 1.00 (0.93–1.07) such as serotonin are known to be important for neurogen-
Long term 1.17 (1.05–1.30) 1.10 (0.98–1.23) esis, migration and differentiation in the developing human
*The crude ordinal logistic regression and model 1 were restricted brain.20 Animal data have shown that exposure to SSRI
to the same study sample as in model 2. during early development causes histological and beha-
**SSRI treatment in pregnancy and depression before pregnancy is vioural changes that persist into adulthood.21,22
included in model 1. Most previous studies include small samples.4–7,23–27
***SSRI treatment in pregnancy, depression before pregnancy and
With some exceptions4,25 the studies have examined devel-
symptoms of anxiety and depression in pregnancy (pregnancy week
17–18 and/or 30) are included in model 2. opment at an earlier age than 3 years. The early studies on
****Depression before pregnancy was assessed by questions in fetal exposure to SSRIs on subsequent child motor develop-
pregnancy week 17–18 about earlier major depression. ment mostly concluded that there was no demonstrable
*****During pregnancy symptoms of anxiety and depression were effect.2 However, most of the more recent studies have
assessed by the five-items version of Hopkins Symptom Checklist in
shown an increased risk of delayed motor development
pregnancy week 17–18 and 30. Short-term and long-term
symptoms were defined as reporting symptoms on one or both associated with fetal SSRI exposure.4–8
questionnaires, respectively. In our study we did not examine the timing of SSRI
******Including additional confounders (parental education, exposure. Results from the Danish National Birth Cohort,
paternal age, parity, maternal smoking, prepregnancy BMI) in a large pregnancy cohort similar to MoBa, showed that
addition to depression before pregnancy did not change the OR
children with second-trimester or third-trimester exposure
(1.44, 95% CI 1.06–1.97 not including and 1.44, 95% CI 1.06–
1.96 including the additional confounders in the reduced data set of became able to sit and walk later than children of women
43 087 women). not exposed to antidepressants.8 However, the timing of
exposure was correlated with the duration of use during
pregnancy and the results are therefore not inconsistent
depression.19 A screen positive on SCL-5 is not a clinical with ours. Similar to our results, the children were still
diagnosis and underestimation is probably a greater prob- within the normal range of development.
lem for the ‘softer’ measure of symptoms of anxiety and
depression than for use of SSRI.
Conclusions
Interpretation In summary, in this large prospective pregnancy cohort in
Having had a depression before pregnancy was weakly Norway, prolonged prenatal exposure to SSRIs was weakly
associated with delayed motor development, whereas having associated with a delay in motor development at 3 years of
symptoms of anxiety and depression during pregnancy was age, but not to the extent that the motor delay was of clini-
not associated. Stratifying on depression after pregnancy had cal importance. Taking into consideration the woman’s his-
no impact on the estimated effect of SSRIs on motor devel- tory of depression before pregnancy and symptoms of
opment. Having a history of depression before pregnancy anxiety and depression during and after pregnancy did not
might indicate a more severe disease. Hence, our results may substantially influence the risk estimate. Effective treatment
indicate that the SSRI-treated women had more severe of depression during pregnancy is essential, and the results

ª 2015 Royal College of Obstetricians and Gynaecologists 1915

 Handal et al.
of this study should not lead clinicians to be reluctant to
initiate or continue antidepressant treatment in pregnant
women who are in need of such treatment.
Disclosure of interest
None declared. Completed disclosure of interests form
available to view online as supporting information.
Contribution to authorship
MH, contributed to the conception and design, acquisition
of data, analysis and interpretation of data and drafted the
initial manuscript. SS contributed to conception and
design, acquisition of data, analysis and interpretation of
data and reviewed and revised the manuscript; KF con-
tributed to acquisition of data, analysis and interpretation
of data; SHD and RN contributed to conception and
design, analysis and interpretation of data; ES, contributed
to analysis and interpretation of data; and WN contributed
to acquisition of data. SS, KF, SHD, ES, WN and RN
reviewed and revised the manuscript; all authors approved
the final manuscript as submitted and agree to be account-
able for all the aspects of the work.
Details of ethics approval
Informed consent was obtained from each MoBa partici-
pant upon recruitment. MoBa has obtained a license from
The Norwegian Data Protection Authority.
Funding
This study was funded by the Norwegian Institute of Pub-
lic Health. The Norwegian Mother and Child Cohort
Study is supported by the Norwegian Ministry of Health
and the Ministry of Education and Research, NIH/NIEHS
(Contract no. NO-ES-75558), NIH/NINDS (grant no. 1
UO1 NS 047537-01), and the Norwegian Research Coun-
cil/FUGE (grant no. 151918/S10). The funding sources
had no role in the design and conduct of the study; the
collection, management, analysis and interpretation of the
data; and the preparation, review and approval of the
manuscript; and the decision to submit the manuscript for
publication.
Acknowledgements
We are grateful to all the participating families in Norway
who take part in this ongoing cohort study.
Supporting Information
Additional Supporting Information may be found in the
online version of this article:
Figure S1. Flow chart of the study, The Mother and
Child Cohort Study.
1916
Figure S2. Boxplots comparing categories of maternal
report on fine (A) and (B) gross motor ASQ scores with
scores based on the gross and fine motor Mullen scales of
early learning performed by clinicians in a subset of chil-
dren (N = 637 for fine motor scores and N = 449 for gross
motor scores).
Table S1. Items assessing gross and fine motor skills at
3 years of age.
Table S2. Parental characteristics by fine motor develop-
ment in children (N = 51 404).
Table S3. Gross motor development in children by par-
ental characteristics (N = 51 404).
Table S4. Number and frequency of children in the dif-
ferent gross motor development categories according to
maternal SSRI use and duration of such use (N = 51 404).
Table S5. Odds ratios from ordinal logistic regression of
having delayed gross motor development according to dif-
ferent combinations of SSRI treatment and symptoms of
anxiety and depression during pregnancy (N = 49 428).
Table S6. Odds ratios from ordinal logistic regression of
having delayed gross motor development according to use
of SSRIs or symptoms of anxiety and depression before
and/or during pregnancy (N = 49 349). &
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