ORIGINAL CONTRIBUTION
Selective Serotonin Reuptake Inhibitors
During Pregnancy and Risk of Stillbirth
and Infant Mortality
Olof Stephansson, MD, PhD
Helle Kieler, MD, PhD
Bengt Haglund, PhD
Miia Artama, PhD
Anders Engeland, PhD
Kari Furu, PhD
Mika Gissler, PhD
Mette Nrgaard, MD, PhD
Rikke Beck Nielsen, MSc
Helga Zoega, PhD
Unnur Valdimarsdottir, PhD
D
EPRESSION DURING PREG -
nancy is common with
prevalences ranging be-
tween 7% and 19% in eco-
nomically developed countries.1,2 Ma-
ternal depression is associated with
poorer pregnancy outcomes,3,4 includ-
ing increased risk of preterm delivery,
which in turn may cause neonatal mor-
bidity and mortality.5 However, it is dif-
ficult to disentangle whether such re-
productive hazards are caused by the
underlying depression, the medical
treatment, or possible confounding by
lifestyle factors such as stress, alcohol
use, and smoking status.5
Management of depression during
pregnancy is a clinical challenge. The
Nordic countries generally recom-
mend a careful risk-benefit analysis of
each patient for treatment decisions.
Nonpharmaceutical interventions are
generally recommended for milder con-
ditions while major depression is fre-
quently treated with antidepressant
medication. Selective serotonin reup-
take inhibitors (SSRIs) are now the most
48 JAMA, January 2, 2013Vol 309, No. 1
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Importance Maternal psychiatric disease is associated with adverse pregnancy out-
comes. Use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy has been
associated with congenital anomalies, neonatal withdrawal syndrome, and persistent
pulmonary hypertension of the newborn. However, the risk of stillbirth and infant mor-
tality when accounting for previous maternal psychiatric disease remains unknown.
Objective To study risk of stillbirth and infant mortality associated with use of SSRIs
during pregnancy.
Design, Setting, and Participants Population-based cohort study from all Nordic
countries (Denmark, Finland, Iceland, Norway, and Sweden) at different periods from 1996
through 2007. The study included women with singleton births. We obtained informa-
tion on maternal use of SSRIs from prescription registries. Maternal characteristics, preg-
nancy, and neonatal outcomes were obtained from patient and medical birth registries.
Main Outcome Measures We used logistic regression to estimate relative risks of still-
birth, neonatal death, and postneonatal death associated with SSRI use during pregnancy
taking into account maternal characteristics and previous psychiatric hospitalization.
Results Among 1 633 877 singleton births in the study, 6054 were stillbirths; 3609,
neonatal deaths; and 1578, postneonatal deaths. A total of 29 228 (1.79%) of mothers
had filled a prescription for an SSRI during pregnancy. Women exposed to an SSRI pre-
sented with higher rates of stillbirth (4.62 vs 3.69 per 1000, P=.01) and postneonatal
death (1.38 vs 0.96 per 1000, P=.03) than those who did not. The rate of neonatal
death was similar between groups (2.54 vs 2.21 per 1000, P=.24). Yet in multivariable
models, SSRI use was not associated with stillbirth (adjusted odds ratio [OR], 1.17; 95%
CI, 0.96-1.41; P=.12), neonatal death (adjusted OR, 1.23; 95% CI, 0.96-1.57; P=.11),
or postneonatal death (adjusted OR, 1.34; 95% CI, 0.97-1.86; P=.08). Estimates were
further attenuated when stratified by previous hospitalization for psychiatric disease. The
adjusted OR for stillbirth in women with a previous hospitalization for psychiatric dis-
ease was 0.92 (95% CI, 0.66-1.28; P=.62) and was 1.07 (95% CI, 0.84-1.36; P=.59)
for those who had not been previously hospitalized. The corresponding ORs for neo-
natal death were 0.89 (95% CI, 0.58-1.39; P=.62) for women who were hospitalized
and 1.14 (95% CI, 0.84-1.56; P=.39) for women who were not. For postneonatal death,
the ORs were 1.02 (95% CI, 0.61-1.69; P=.95) for women who were hospitalized and
1.10 (95% CI, 0.71-1.72; P=.66) for women who were not.
Conclusions and Relevance Among women with singleton births in Nordic coun-
tries, no significant association was found between use of SSRIs during pregnancy and
risk of stillbirth, neonatal mortality, or postneonatal mortality. However, decisions about
use of SSRIs during pregnancy must take into account other perinatal outcomes and
the risks associated with maternal mental illness.
JAMA. 2013;309(1):48-54 www.jama.com
Author Affiliations are listed at the end of this article.
commonly prescribed drugs for depres- Corresponding Author: Olof Stephansson, MD, PhD,
Clinical Epidemiology Unit, T2, Karolinska University
sion during pregnancy. 6 Although Hospital Solna, SE-171 76 Stockholm, Sweden (olof
somewhat equivocal, the evidence sug- .stephansson@ki.se).
2013 American Medical Association. All rights reserved.

gests that SSRI use during pregnancy
may be associated with poor birth out-
comes, such as congenital anomalies,7
spontaneous abortion,8 neonatal with-
drawal syndrome,9 and persistent pul-
monary hypertension of the new-
born.10,11 The influence of SSRI use on
risk of stillbirth, neonatal death, and in-
fant death has been less studied.12
Conversely, discontinuing antidepres-
sant treatment has been associated with
increased risk that pregnant women will
experience a relapse of major depres-
sion.13 According to a recent study on
women delivering in Sweden in 2007, 3%
of women filled a prescription for anti-
depressants in the 3-month period be-
fore conception while only 1% filled a
prescription during the third trimes-
ter.14 Maternal mental illness has con-
sistently been associated with risks of in-
fant mortality15 and in particular sudden
infant death syndrome.16
Because the Nordic countries have
similar nationwide registries of births
and dispensed drugs, studies on the ef-
fect of medications on birth outcomes
are possible. By using these data sources
and taking into account previous psy-
chiatric disease and maternal charac-
teristics, we aimed to elucidate whether
SSRI exposure during pregnancy was
associated with increased risks of still-
birth, neonatal death, and postneona-
tal death.
METHODS
We conducted a registry-based cohort
study that included women and their
infants born in the Nordic countries
(Denmark, Finland, Iceland, Norway,
and Sweden) between 1996 and 2007.
Each Nordic country has national reg-
istries, which include prospectively col-
lected health and social information on
all inhabitants. All registries include the
Civil Personal Registration (CPR) num-
bers, a unique number assigned to each
resident at birth or immigration. Re-
porting to the registries is mandatory
and regulated by national laws. The na-
tional parliaments in the Nordic coun-
tries have on behalf of their popula-
tions given informed consent to be
included in the registries.17
2013 American Medical Association. All rights reserved.
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SSRIS DURING PREGNANCY AND INFANT MORTALITY
The start of follow-up was defined
from the initiation of the nationwide
prescription registry in each participat-
ing country and end of follow-up by
availability of registry data. We there-
fore identified all singletons born after
154 gestational days between January
1, 1996, and December 31, 2007, in
Denmark; January 1, 1996, and De-
cember 31, 2006, in Finland; January
1, 2003, and December 31, 2007, in Ice-
land; January 1, 2005, and December
31, 2007, in Norway; and January 1,
2006, and December 31, 2007, in
Sweden.
Ascertainment of Exposure
Exposure was defined as 1 or more filled
prescriptions for an SSRI from 3 months
before the start of pregnancy until birth.
Eligible pregnancies were identified
through the Nordic medical birth reg-
istries along with data on maternal de-
mographics, the pregnancy, delivery,
and neonatal period.18 Determination
of start of pregnancy and gestational age
were based on prenatal ultrasound es-
timation or on last menstrual pe-
riod.10,19 The prescription registries in
the Nordic countries include data on the
dispensed item, substance, brand name,
and formulation together with date of
dispensing for more than 95% of the
total outpatient population. All drugs
are classified according to the World
Health Organization Anatomical Thera-
peutic Chemical (ATC) classification.
The SSRIs used during the study pe-
riod and included in the analyses were
fluoxetine, citalopram, paroxetine, ser-
traline, fluvoxamine, and escitalo-
pram (eTable 1 available at http://www
.jama.com). In general, prescriptions are
filled for a maximum of 3 months.20 We
excluded pregnancies and births
(n = 5396) of mothers who had used
other antidepressants with an effect on
serotonin or norepinephrine activity
(imipramine, amitriptyline, dulox-
etine, dosulepine, melnacipran, trazo-
done, nefazodone, and moklobemide).
Ascertainment of Outcome
We assessed 3 outcomes: stillbirth (in-
trauterine death after 22 weeks of ges-
tation in Finland, Norway, Iceland, and
Denmark from 2004 onward, and af-
ter 28 weeks in Sweden and Denmark
from 1997 through 2003), neonatal
death (death within 0-27 days among
live born infants), and postneonatal
death (death between 28-364 days
among neonatal survivors). Informa-
tion on stillbirth was obtained from the
medical birth registries in each coun-
try and on neonatal and postneonatal
deaths from the Nordic causes of death
registries, which contain information on
the date and causes of death for all in-
dividuals who were residents at the time
of death. All diagnoses and causes of
death are classified according to the na-
tional version of International Statisti-
cal Classification of Diseases, 10th Re-
vision (ICD-10) codes.
Potential Confounders
or Effect-Modifiers
As possible confounders, we included
information from the birth registries on
maternal age, parity, birth year, coun-
try of birth, and maternal smoking sta-
tus (not available in Iceland), and in-
formation on maternal diseases from
birth registries and patient registries
(except for Norway), although only hy-
pertension and diabetes were retained
in the final models. Women with dia-
betes were identified by filled prescrip-
tions of antidiabetic medications from
3 months before pregnancy through de-
livery using prescription registries.
Complications and maternal diseases
are recorded according to the ICD-10
codes.
Because psychiatric disease has been
associated with the outcomes under
study15 and SSRI use, we obtained avail-
able information from each country on
the previous psychiatric hospitaliza-
tions of the mothers. The patient reg-
istries in Denmark, Finland, Iceland,
and Sweden record information on all
hospitalizations (including treatment of
psychiatric disorders), with date of ad-
mission and discharge, and primary and
secondary diagnoses. Additionally, the
Danish Psychiatric Central Register in-
cludes information on psychiatric treat-
ments at specialized psychiatric clin-
JAMA, January 2, 2013Vol 309, No. 1 49
 SSRIS DURING PREGNANCY AND INFANT MORTALITY
ics and emergency care units.21 During
the study period, the Norwegian pa-
tient registry did not contain CPR num-
bers, which are needed for linkages to
other registries. Thus, we included data
on the mothers previous psychiatric
hospitalizations from patient regis-
tries in Denmark, Iceland, Sweden, and
Finland and from the Danish Psychi-
atric Central Register during a 10-year
period before giving birth. For Nor-
way, previous psychiatric treatments
were obtained from the medical birth
registry; information on past medical
history, including treatment for psy-
chiatric disease, is reviewed with the
mother during antenatal care by a gen-
eral practitioner, midwife, or an obste-
trician and then later recorded in the
medical birth registry.
Statistical Analyses
We used logistic regression analysis to
estimate the association of SSRI use dur-
ing pregnancy with 3 outcomes: still-
birth, neonatal death, and postneona-
tal death. Women with missing data on
any of the covariates were excluded
from the multivariable analysis. Be-
cause information on cigarette smok-
ing was missing in 9.5% of exposed and
6.2% of unexposed women, we per-
formed a sensitivity analysis that in-
cluded women whose smoking status
was missing by adding smoking as a
separate category in the multivariable
analysis.
Analyses were performed using crude
and adjusted odds ratios (ORs) with
95% CIs. In stratified analyses, we fur-
ther explored whether history of ma-
ternal psychiatric hospitalization modi-
fied the association between SSRI use
during pregnancy and risk of still-
birth, neonatal death, and postneona-
tal death. We also analyzed ORs for
SSRIs by time of exposure during preg-
nancy divided into (1) only within 3
months before first trimester, (2) only
before and during first trimester, (3) be-
fore and during first and second tri-
mester, and (4) before and during the
entire pregnancy. Because observa-
tions are not independent in women
who delivered more than once during
50 JAMA, January 2, 2013Vol 309, No. 1
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the study period, we calculated esti-
mates using clustered data in the gen-
eralized estimation equation method.
We finally present rates of specific
causes of death for neonatal and post-
neonatal mortality.
All analyses were conducted using
SAS software, version 9.2 (SAS Insti-
tute Inc). We used a significance level
of .05 (2-sided testing). The study was
approved by the Regional Ethical Re-
view Board at Karolinska Institute in
Stockholm, Sweden; the National Board
of Health, Denmark; the Danish Data
Protection Agency; the National Insti-
tute for Health and Welfare of Fin-
land; Statistics Finland; the Data Pro-
tection Authority and the National
Bioethics Committee in Iceland; and the
Norwegian Data Inspectorate.
RESULTS
Descriptive Data
In total 1 633 877 singleton births
occurred during the study periods
and were included in the analysis. Of
these, in 29 228 births (1.79%), the
mother had filled a prescription for an
SSRI during pregnancy. Of those
women, 91.21% used a single SSRI.
Filling of SSRI prescriptions was more
common in the later years of the
study period (TABLE 1). The mothers
who had filled a prescription with an
SSRI were generally older, more often
smokers, previously hospitalized for
psychiatric disease, and more likely to
have diabetes and hypertension than
mothers not using SSRIs. The most
frequently filled SSRI prescription was
for citalopram (6.49 per 1000) fol-
lowed by fluoxetine (4.66 per 1000)
and sertraline (3.93 per 1000). The
distribution of the different SSRI use
is presented in eTable 1 (available at
http://www.jama.com).
The 6054 stillbirths corresponded to
a rate of 3.71 per 1000 births. The 3609
neonatal deaths corresponded to a rate
of 2.22 per 1000 live births, and 1578
postneonatal deaths corresponded to a
rate of 0.97 per 1000 live births. A cause
of death was reported in 96.92% of neo-
natal and 96.96% of postneonatal
deaths. Of the neonatal deaths, 55.77%
2013 American Medical Association. All rights reserved.
were due to perinatal conditions;
28.10%, congenital anomalies; 7.83%,
chromosomal abnormalities; 1.57%,
sudden infant death syndrome; 0.29%,
external causes; and 6.43%, other causes
(eTable 2). Of the postneonatal deaths,
29.54% were due to congenital anoma-
lies; 20.33%, sudden infant death syn-
drome; 11.57%, perinatal conditions;
6.47%, chromosomal abnormalities;
5.10%, external causes; and 26.99%,
other causes (eTable 2).
SSRIs and Risks of Stillbirth,
Neonatal Death,
and Postneonatal Death
In total, 135 stillbirths, 74 neonatal
deaths, and 40 postneonatal deaths
occurred among mothers exposed to
SSRI during pregnancy. Compared
with women who were unexposed,
those who were exposed to SSRIs
presented with higher rates of still-
birth (4.62 vs 3.69 per 1000 births)
with a crude OR of 1.25 (95% CI,
1.06-1.49; P = .01) and postneonatal
death (1.38 vs 0.96 per 1000) with a
crude OR of 1.43 (95% CI, 1.04-1.96;
P = .03; TABLE 2). Selective serotonin
reuptake inhibitor use was not asso-
ciated with increased risk of neonatal
death (2.54 vs 2.21 per 1000) with a
crude OR of 1.15 (95% CI, 0.91-1.45;
P = .24). After adjusting for maternal
characteristics, country, and year of
birth, SSRI exposure was no longer
significantly associated with stillbirth
(adjusted OR, 1.17; 95% CI, 0.96-
1.41; P = .12) or postneonatal death
(adjusted OR, 1.34; 95% CI, 0.97-
1.86; P = .08). The adjusted OR for
neonatal death was 1.23 (95% CI,
0.96-1.57; P = .11). In the sensitivity
analysis including women with miss-
ing data on smoking in early preg-
nancy, the estimates were only mar-
ginally altered.
When we stratified by previous psy-
chiatric hospitalization, estimates for
stillbirth, neonatal death, and postneo-
natal death were attenuated (Table 2).
The adjusted OR for stillbirth in women
who were previously hospitalized for
a psychiatric disease was 0.92 (95% CI,
0.66-1.28; P=.62) and was 1.07 (95%
 SSRIS DURING PREGNANCY AND INFANT MORTALITY

CI, 0.84-1.36; P=.59) for women who COMMENT Data on potential risks of stillbirth
were not. For neonatal death, the ad- The present study of more than 1.6 mil- and infant mortality by SSRI use are
justed ORs were 0.89 (95% CI, 0.58- lion births suggests that SSRI use dur- scarce. Recently the Danish Medi-
1.39; P=.62) for women previously hos- ing pregnancy was not associated with cines Agency reported 2 cases of neo-
pitalized and 1.14 (95% CI, 0.84-1.56; increased risks of stillbirth, neonatal natal death following use of fluox-
P=.39) for women who were not. For death, or postneonatal death. The in- etine in pregnancy.22 To our knowledge,
postneonatal death, the adjusted OR was creased rates of stillbirth and postneo- only 2 studies have specifically ad-
1.02 (95% CI, 0.61-1.69; P = .95) for natal mortality among infants ex- dressed the risk of stillbirth or infant
women who were hospitalized and 1.10 posed to an SSRI during pregnancy were death after prenatal SSRI exposure. Ku-
(95% CI, 0.71-1.72; P=.66) for women explained by the severity of the under- lin et al23 did not find any increased risk
who were not. Because information on lying maternal psychiatric disease and of stillbirth among 267 women ex-
previous hospitalization could not be ob- unfavorable distribution of maternal posed to SSRIs. Colvin et al24 recently
tained from Norway, we performed a characteristics such as cigarette smok- reported no increased risk of stillbirth
sensitivity analysis excluding Norwe- ing and advanced maternal age. but found an increased risk of infant
gian data, which demonstrated only mar-
ginal changes in the point estimates
(eTable 3, available at http://www.jama Table 1. Maternal Characteristics by Exposure to Selective Serotonin Reuptake Inhibitors
.com). When restricting the analysis for From 3 Months Before Pregnancy Until Birth Among Singleton Births
stillbirths to include gestational age 22 No. (%) of Births
weeks or longer, the adjusted OR was Total Unexposed SSRI
1.16 (95% CI, 0.92-1.47; P=.21) and for (N=1 633 877) (n = 1 604 649) (n = 29 228)
28 weeks or longer, 1.07 (95% CI, 0.86- Country
1.34; P=.55). Denmark 687 756 (42.1) 677 349 (42.2) 10 407 (35.6)
TABLE 3 presents associated risks Finland 611 245 (37.4) 600 946 (37.5) 10 299 (35.2)
Iceland 19 567 (1.2) 18 262 (1.1) 1305 (4.5)
with SSRI use by trimester of expo-
Norway 166 783 (10.2) 164 030 (10.2) 2753 (9.4)
sure. Among women exposed from 3
Sweden 148 526 (9.1) 144 062 (9.0) 4464 (15.3)
months before pregnancy and during
Year of birth
the first trimester, there was an in- 1996-1999 417 672 (25.6) 414 521 (25.8) 3151 (10.8)
crease in the OR for stillbirth com- 2000-2003 469 603 (28.7) 462 205 (28.8) 7398 (25.3)
pared with unexposed (adjusted OR, 2004-2007 746 602 (45.7) 727 923 (45.4) 18 679 (63.9)
1.56; CI, 1.06-2.30; P = .03), whereas Maternal age, y
this was not observed when the expo- 24 266 627 (16.3) 261 313 (16.3) 5314 (18.2)
sure window included from 3 months 25-34 1 081 309 (66.2) 1 063 726 (66.3) 17 583 (60.2)
before pregnancy to the first and sec- 35-44 284 063 (17.4) 277 794 (17.3) 6269 (21.4)
ond trimester or entire pregnancy. For 45 1878 (0.1) 1816 (0.1) 62 (0.2)
women exposed to an SSRI from be- Birth order
1 690 209 (42.2) 677 628 (42.2) 12 581 (43.0)
fore pregnancy through the first tri-
2-3 818 471 (50.1) 804 809 (50.2) 13 662 (46.7)
mester, the adjusted OR for stillbirth
4 117 944 (7.2) 115 082 (7.2) 2862 (9.8)
among women hospitalized for a psy-
Missing 7253 (0.4) 7130 (0.4) 123 (0.4)
chiatric disease was 1.04 (95% CI, 0.54-
Smoking in early pregnancy
2.02; P = .90) and was 1.64 (95% CI, No 1 275 808 (78.1) 1 257 358 (78.4) 18 450 (63.1)
1.08-2.50; P=.02) for women who were Yes 255 243 (15.6) 247 229 (15.4) 8014 (27.4)
not hospitalized. For neonatal and post- Missing 102 826 (6.3) 100 062 (6.2) 2764 (9.5)
neonatal deaths, no significant associa- Previous psychiatric hospitalization a
tions were observed by trimester of ex- No 1 570 597 (96.1) 1 549 430 (96.6) 21 167 (72.4)
posure. We then estimated risks of Yes 63 280 (3.9) 55 219 (3.4) 8061 (27.6)
neonatal and postneonatal mortality by Diabetes b
No 1 617 247 (99.0) 1 588 610 (99.0) 28 637 (98.0)
cause of death. However, no signifi- Yes 16 630 (1.0) 16 039 (1.0) 591 (2.0)
cant associations between maternal Hypertension
SSRI and specific causes of death were No 1 624 395 (99.4) 1 595 378 (99.4) 29 017 (99.3)
found (eTable 2). Yes 9482 (0.6) 9271 (0.6) 211 (0.7)
Finally, absolute rates of stillbirth, Abbreviation: SSRI, selective serotonin reuptake inhibitor.
a Maternal hospitalizations for a psychiatric diagnosis during a 10-year period before giving birth recorded in patient reg-
neonatal death, and postneonatal death istries for Denmark, Finland, Iceland, and Sweden, and the Danish Psychiatric Central Register. For Norway defined as
varied by specific SSRI type during preg- psychiatric disease recorded in the birth registry.
b Defined as use of antidiabetes drugs from 90 days before last menstrual period to birth.
nancy (eTable 4).
2013 American Medical Association. All rights reserved. JAMA, January 2, 2013Vol 309, No. 1 51

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 SSRIS DURING PREGNANCY AND INFANT MORTALITY

Table 2. Exposure to Selective Serotonin Reuptake Inhibitors From 3 Months Before Pregnancy Until Birth and Risk of Stillbirth and Infant Mortality
Exposure

SSRI No SSRI
Crude OR P Adjusted a OR P
No. Per 1000 No. Per 1000 (95%CI) Value (95%CI) Value
Stillbirth 135 4.62 5919 3.69 1.25 (1.06-1.49) .01 1.17 (0.96-1.41) .12
No previous psychiatric hospitalization 84 3.97 5542 3.58 1.11 (0.89-1.38) .34 1.07 (0.84-1.36) .59
Previous psychiatric hospitalization b 51 6.33 377 6.83 0.93 (0.69-1.25) .61 0.92 (0.66-1.28) .62
Neonatal death 74 2.54 3535 2.21 1.15 (0.91-1.45) .24 1.23 (0.96-1.57) .11
No previous psychiatric hospitalization 45 2.13 3297 2.14 1.00 (0.74-1.34) .99 1.14 (0.84-1.56) .39
Previous psychiatric hospitalization b 29 3.62 238 4.34 0.83 (0.56-1.24) .37 0.89 (0.58-1.39) .62
Postneonatal death 40 1.38 1538 0.96 1.43 (1.04-1.96) .03 1.34 (0.97-1.86) .08
No previous psychiatric hospitalization 23 1.09 1401 0.91 1.20 (0.80-1.82) .38 1.10 (0.71-1.72) .66
Previous psychiatric hospitalization b 17 2.13 137 2.51 0.85 (0.51-1.41) .52 1.02 (0.61-1.69) .95
Abbreviation: OR, odds ratio; SSRI, serotonin reuptake inhibitor.
a Adjusted for country and year of birth, maternal age, birth order, smoking in early pregnancy, and maternal diabetes and hypertension. Women with no SSRI were the reference.
b Maternal hospitalizations for a psychiatric diagnosis during a 10-year period before giving birth recorded in patient registries for Denmark, Finland, Iceland, Sweden, and the Danish
Psychiatric Central Register. For Norway defined as psychiatric disease recorded in the birth registry.

womenwithpreviouspsychiatricdisease.
Table 3. Exposure to Selective Serotonin Reuptake Inhibitor per Trimester and Risk of Stillbirth In our study, when taking disease sever-
and Infant Mortality
ity and maternal characteristics into con-
No. of
Outcome, Trimester Women Adjusted OR P sideration, women taking SSRIs did not
of SSRI Exposure a Exposed Per 1000 (95% CI) b Value have an increased risk of stillbirth or in-
Stillbirth fant death.
T0 49 4.92 1.19 (0.87-1.65) .28
We were able to study risk of still-
T0-T1 31 6.17 1.56 (1.06-2.30) .03
birth and infant mortality among SSRI
T0-T2 8 4.94 1.11 (0.50-2.48) .80
users by trimester of pregnancy. Al-
T0-T3 14 3.71 0.94 (0.53-1.65) .83
though the risk of stillbirth appeared to
Other 33 3.73 1.01 (0.70-1.46) .94
be increased among women exposed be-
Unexposed 5919 3.69 1 [Reference]
Neonatal death
fore pregnancy through the first trimes-
T0 22 2.22 1.04 (0.66-1.64) .86 ter, these results should be interpreted
T0-T1 12 2.40 1.16 (0.61-2.21) .65 with caution due to the few observa-
T0-T2 4 2.48 1.35 (0.51-3.62) .55 tions for each category of exposure. Yet,
T0-T3 13 3.45 1.56 (0.86-2.83) .14 a possible explanation for this finding
Other 23 2.61 1.31 (0.85-2.02) .22 may be the increased risk of congenital
Unexposed 3535 2.21 1 [Reference] anomalies reported to be associated with
Postneonatal death SSRI use including fluoxetine and ser-
T0 14 1.42 1.28 (0.72-2.26) .40 traline.7 Risk estimates for neonatal death
T0-T1 5 1.00 1.02 (0.42-2.46) .96
appeared not to differ by trimester ex-
T0-T2 3 1.87 2.06 (0.66-6.39) .21
posure. However, the number of ex-
T0-T3 6 1.60 1.76 (0.79-3.93) .17
posed women in this analysis was re-
Other 12 1.36 1.31 (0.72-2.37) .38
stricted and estimates should be
Unexposed 1538 0.96 1 [Reference]
interpreted with caution.
Abbreviations: OR, odds ratio, SSRI, selective serotonin reuptake inhibitor.
a T0 denotes from 3 months before until last menstrual period before pregnancy; T1, first trimester; T2, second trimes-
ter; and T3, third trimester.
b Adjusted for country and year of birth, maternal age, birth order, smoking in early pregnancy, and maternal diabetes
Strengths and Limitations
and hypertension. This cohort study was population
based, using information on almost all
singleton births in the 5 Nordic coun-
mortality among 3703 Australian wom- bySSRIusehavemostlybeensmall(250 tries during the study period. The large
en exposed to SSRIs. Whether the risk of exposedwomen)andsomehavereported size enabled us to study rare preg-
infant mortality was due to prenatal ex- increasedrisks,25 whileothershavenot.23,26 nancy outcomes such as stillbirth, neo-
posure to SSRIs or underlying maternal The small size of the studies along with natal death, and postneonatal death.
psychiatric disease could not be deter- other methodological problems has ham- The minimal clinically detectable dif-
mined from these studies. The few stud- peredsolidconclusions.16 Finally,1study15 ferences for an assumed power of 86%
iesexploringpotentialrisksofmiscarriages found increased infant mortality among (given 1.6 million pregnancies, 2% of
52 JAMA, January 2, 2013Vol 309, No. 1 2013 American Medical Association. All rights reserved.

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mothers exposed to SSRIs, and the an-
ticipated rates of outcomes) were ORs
of 1.3 for stillbirth, 1.4 for neonatal
death, and 1.6 for postneonatal death.
Because these are small, the study is un-
likely to be underpowered.
In addition, information on SSRI
exposure and maternal characteristics
was prospectively collected, excluding
the possibility of recall bias. The study
included information on maternal
smoking, which was more common
among women with SSRI use and has
been associated with stillbirth and
neonatal mortality.27 Furthermore, in
sensitivity analyses, we evaluated
women with missing data on smoking
in early pregnancy. We did not have
information on alcohol intake during
pregnancy or use of illegitimate drugs,
and the use of these could be related
to SSRI use as well as stillbirth and
infant death. However, since we did
not observe any association between
SSRIs and stillbirth or infant death,
the absence of this information may
be of limited concern.
Our study considered previous psy-
chiatric disease. For Denmark, Fin-
land, Iceland, and Sweden, this infor-
mation was obtained from recorded
hospitalizations. In Norway, informa-
tion on previous psychiatric disease was
obtained from the birth registry, which
may be a concern because it differs from
the data from the other countries. How-
ever, excluding Norwegian data did not
alter the results.
Apart from previous psychiatric hos-
pitalization, we did not have detailed
information on the severity of the dis-
ease or any information on mild de-
pression treated in outpatient psychi-
atric clinics or by general practitioners.
Relative risk estimates for adverse out-
comes by SSRI use during pregnancy
were generally higher among women
without previous hospitalization for
psychiatric disease than women with
previous hospitalization. Hence it is
possible that residual confounding
due to unmeasured mild psychiatric
disorders treated in outpatient clinics
or among general practitioners affects
our estimates in the population of
2013 American Medical Association. All rights reserved.
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SSRIS DURING PREGNANCY AND INFANT MORTALITY
women without previous psychiatric
hospitalization.
We also do not know what psychi-
atric disease was responsible for hos-
pitalizations. Although SSRIs are used
for depression, they also may be used
for women with a history of bipolar dis-
order or schizophrenia. Because the out-
come under study is rare, we may have
reduced power in stratified analyses by
previous psychiatric hospitalization and
for specific trimester use during preg-
nancy, as seen by the wide CIs. Con-
sequently, despite being the largest
study investigating this question, the
lack of power in the subanalyses has to
be considered a limitation and these re-
sults should be interpreted with
caution.
In the present study, we did not have
information on spontaneous and in-
duced abortions. It is therefore pos-
sible that we have underestimated an
association between SSRI use and ad-
verse pregnancy outcome if women ex-
posed to SSRIs were more likely to have
a spontaneous or induced abortion be-
cause of a severe congenital abnormal-
ity. Because inclusion of stillbirths by
gestational age differed between coun-
tries for the study period, we pre-
sented estimates for stillbirths from the
gestational age of 22 weeks and longer
and for the gestational age of 28 weeks
and longer. However, choice of gesta-
tional week for defining stillbirth did
not influence the results because we
found no association between SSRI ex-
posure and stillbirth for either gesta-
tional age cutoff.
Information on dispensed drugs is
not the same as intake of drugs. A re-
cent Swedish study showed close to
60% agreement of maternal antidepres-
sant use, when comparing informa-
tion on dispensed drugs and reported
drug intake at the first antenatal care
visit.14 Whether this moderate agree-
ment reflects a lower drug intake com-
pared with dispensing or unwilling-
ness to report intake of antidepressants
at antenatal care is unknown. We also
did not have information on dosage lev-
els. In addition, it is possible that
women lower their dose of antidepres-
sants when planning pregnancy. Con-
sequently, we may have underesti-
mated the proportion of women using
SSRIs during pregnancy. The start of the
study period varied by country be-
cause it was set by the year prescrip-
tion data were available. This should not
introduce bias because we have com-
plete follow-up data for all pregnan-
cies and end points for each country
during the periods they provided data.
Furthermore, we included both coun-
try of origin and calendar year in our
models.
In conclusion, we found that after
taking maternal characteristics and psy-
chiatric disease hospitalizations into ac-
count, there was no significant asso-
ciation between use of SSRIs during
pregnancy and risk of stillbirth, neo-
natal mortality, or postneonatal mor-
tality. However, decisions regarding use
of SSRIs during pregnancy must take
into account other perinatal outcomes
and the risks associated with maternal
mental illness.
Author Affiliations: Centre for Pharmacoepidemiol-
ogy and Clinical Epidemiology Unit, Department of
Medicine Solna, Karolinska Institutet, Stockholm (Drs
Stephansson, Kieler, and Haglund); Department of
Womens and Childrens Health, Karolinska Institu-
tet, Stockholm (Dr Stephansson); and the Nordic School
of Public Health, Gothenburg (Dr Gissler), Sweden;
THL National Institute for Health and Welfare, Hel-
sinki, Finland (Drs Artama and Gissler); Division of Epi-
demiology, Department of Pharmacoepidemiology,
Norwegian Institute of Public Health, Oslo (Drs En-
geland and Furu); Department of Public Health and
Primary Health Care, University of Bergen, Bergen (Dr
Engeland); Department of Pharmacy, University of
Troms, Troms, Norway (Dr Furu); Department of
Clinical Epidemiology, Institute of Clinical Medicine,
Aarhus University Hospital, Aarhus, Denmark (Dr
Nrgaard and Mrs Nielsen); Centre of Public Health
Sciences, School of Health Sciences, University of Ice-
land, Reykjavik, Iceland (Drs Zoega and Valdimars-
dottir); Department of Epidemiology, School of Pub-
lic Health, Harvard University, Boston, Massachusetts
(Dr Valdimarsdottir); and Institute for Translational Epi-
demiology, Mount Sinai School of Medicine, New York,
New York (Dr Zoega).
Author Contributions: Dr Stephansson had full ac-
cess to all of the data in the study and takes respon-
sibility for the integrity of the data and the accuracy
of the data analysis.
Study concept and design: Stephansson, Kieler,
Haglund, Artama, Engeland, Gissler, Nrgaard,
Valdimardottir.
Acquisition of data: Kieler, Haglund, Engeland, Furu,
Gissler, Nrgaard, Nielsen, Zoega, Valdimardottir.
Analysis and interpretation of data: Stephansson,
Kieler, Haglund, Engeland, Nrgaard, Zoega,
Valdimardottir.
Drafting of the manuscript: Stephansson,
Valdimardottir.
Critical revision of the manuscript for important in-
tellectual content: Stephansson, Kieler, Haglund,
JAMA, January 2, 2013Vol 309, No. 1 53
 SSRIS DURING PREGNANCY AND INFANT MORTALITY
Artama, Engeland, Furu, Gissler, Nrgaard, Nielsen,
Zoega, Valdimardottir.
Statistical analysis: Haglund.
Obtained funding: Kieler.
Administrative, technical, or material support: Kieler,
Haglund, Artama, Nrgaard, Zoega.
Study supervision: Kieler, Nrgaard.
Conflict of Interest Disclosures: All authors have com-
pleted and submitted the ICMJE Form for Disclosure
of Potential Conflicts of Interest and none were re-
ported.
Funding/Support: This study was funded by the Swed-
ish Pharmacy Company and by the authors affilia-
tions. Olof Stephansson was supported by a postdoc-
torate scholarship from the Swedish Society of
Medicine.
Disclaimer: The Swedish Pharmacy Company was not
involved in the design and conduct of the study; col-
lection, management, analysis, or interpretation of the
data; and preparation, review, or approval of the manu-
script.
Online-Only Material: The eTables are available at
http://www.jama.com.
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