Pregnancy Complications Following Prenatal Exposure to SSRIs or Maternal Psychiatric Disorders: Results From Population-Based National Register Data

Abstract

Using national register data, the authors examined the relationship between prenatal selective serotonin reuptake inhibitor (SSRI) treatment and pregnancy complications, accounting for psychiatric diagnoses related to SSRI use.
This was a population-based prospective birth cohort study using national register data. The sampling frame included 845,345 offspring, representing all singleton live births in Finland between 1996 and 2010. Pregnancies were classified as exposed to SSRIs (N=15,729), unexposed to SSRIs but with psychiatric diagnoses (N=9,652), and unexposed to medications and psychiatric diagnoses (N=31,394). Pregnancy outcomes in SSRI users were compared with those in the unexposed groups.
Offspring of mothers who received SSRI prescriptions during pregnancy had a lower risk for late preterm birth (odds ratio=0.84, 95% CI=0.74-0.96), for very preterm birth (odds ratio=0.52, 95% CI=0.37-0.74), and for cesarean section (odds ratio=0.70, 95% CI=0.66-0.75) compared with offspring of mothers unexposed to medications but with psychiatric disorders. In contrast, in SSRI-treated mothers, the risk was higher for offspring neonatal complications, including low Apgar score (odds ratio=1.68, 95% CI=1.34-2.12) and monitoring in a neonatal care unit (odds ratio=1.24, 95% CI=1.14-1.35). Compared with offspring of unexposed mothers, offspring of SSRI-treated mothers and mothers unexposed to medications but with psychiatric disorders were both at increased risk of many adverse pregnancy outcomes, including cesarean section and need for monitoring in a neonatal care unit.
In a large national birth cohort, treatment of maternal psychiatric disorders with SSRIs during pregnancy was related to a lower risk of preterm birth and cesarean section but a higher risk of neonatal maladaptation. The findings provide novel evidence for a protective role of SSRIs on some deleterious reproductive outcomes, possibly by reducing maternal depressive symptoms. The divergent findings suggest that clinical decisions on SSRI use during pregnancy should be individualized, taking into account the mother's psychiatric and reproductive history.

Full text

Pregnancy Complications Following Prenatal Exposure
to SSRIs or Maternal Psychiatric Disorders: Results From
Population-Based National Register Data
Heli Malm, M.D., Ph.D., Andre Sourander, M.D., Ph.D., Mika Gissler, Ph.D., David Gyllenberg, M.D., Ph.D.,
Susanna Hinkka-Yli-Salomäki, Ph.Lic., Ian W. McKeague, Ph.D., Miia Artama, Ph.D., Alan S. Brown, M.D., M.P.H.
Objective: Using national register data, the authors examined
the relationship between prenatal selective serotonin reup-
take inhibitor (SSRI) treatment and pregnancy complications,
accounting for psychiatric diagnoses related to SSRI use.
Method: This was a population-based prospective birth
cohort study using national register data. The sampling frame
included 845,345 offspring, representing all singleton live
births in Finland between 1996 and 2010. Pregnancies were
classified as exposed to SSRIs (N=15,729), unexposed to SSRIs
but with psychiatric diagnoses (N=9,652), and unexposed to
medications and psychiatric diagnoses (N=31,394). Preg-
nancy outcomes in SSRI users were compared with those in
the unexposed groups.
Results: Offspring of mothers who received SSRI pre-
scriptions during pregnancy had a lower risk for late preterm
birth (odds ratio=0.84, 95% CI=0.74–0.96), for very preterm
birth (odds ratio=0.52, 95% CI=0.37–0.74), and for cesarean
section (odds ratio=0.70, 95% CI=0.6620.75) compared
with offspring of mothers unexposed to medications but
with psychiatric disorders. In contrast, in SSRI-treated mothers,
the risk was higher for offspring neonatal complications, in-
cluding low Apgar score (odds ratio=1.68, 95% CI=1.34–2.12)
and monitoring in a neonatal care unit (odds ratio=1.24,
95% CI=1.14–1.35). Compared with offspring of unexposed
mothers, offspring of SSRI-treated mothers and mothers
unexposed to medications but with psychiatric disorders
were both at increased risk of many adverse pregnancy out-
comes, including cesarean section and need for monitoring in
a neonatal care unit.
Conclusions: In a large national birth cohort, treatment of
maternal psychiatric disorders with SSRIs during pregnancy
was related to a lower risk of preterm birth and cesarean
section but a higher risk of neonatal maladaptation. The
findings provide novel evidence for a protective role of SSRIs
on some deleterious reproductive outcomes, possibly by
reducing maternal depressive symptoms. The divergent
findings suggest that clinical decisions on SSRI use during
pregnancy should be individualized, taking into account the
mother’s psychiatric and reproductive history.
AJP in Advance (doi: 10.1176/appi.ajp.2015.14121575)
The selective serotonin reuptake inhibitors (SSRIs) are the most
commonly used antidepressants during pregnancy, with 4%2
10% of pregnant women in Finland (1) and in the United States
(2) receiving prescriptions for SSRIs. While considered rela-
tively safe, SSRI use during pregnancy has been associated with
an increased risk for several pregnancy co mplications, including
preterm birth (3–8), small-for-gestational-age offspring (9), and
postpartum hemorrhage (10). Other reported adverse outcomes
include poor neonatal adaptation (5, 6, 11–13) and persistent
pulmonary hypertension of the newborn (14–16). The most
common indications for SSRIs are depressive and anxiety
disorders (17). Depressive disorders occur in 10% of pregnant
women (18), and depression itself has been associated with
adverse pregnancy outcomes (19). Underlying maternal de-
pression is therefore a crucial potential confounder in assessing
the risks related to SSRI use during pregnancy. The few studies
that have adjusted for underlying maternal psychiatric illness
have used small samples and have reported inconsistent results
(5,6,8,20,21).WhetherthereportedoutcomesareduetoSSRI
use or to the underlying psychopathology is of major clinical
importance in the treatment of pregnant women with de-
pressive and anxiety disorders. To address this question, we
conducted a study based on a national birth cohort to examine
pregnancy complications in mothers exposed to SSRIs and in
mothers with a psychiatric diagnosis related to SSRI use but
without antidepressant treatment.
METHOD
This was a population-based prospective birth cohort study
using national register data. The sampling frame was 845,345
offspring, consisting of all singleton live births in Finland
ajp in Advance ajp.psychiatryonline.org 1
ARTICLES

between Jan. 1, 1996, and Dec. 31, 2010, identified from the
national Medical Birth Register maintained by the National
Institute for Health and Welfare. A detailed description of the
data sources and the study design has been published pre-
viously (1), and a summary is provided here. The registers
were linked using personal identity codes assigned to each
Finnish citizen at birth or immigration. Data for this study
were drawn from several registers.
The Drug Reimbursement Register, which has collected
data on prescription drug purchases since 1995, was used to
identify the study groups. Drug purchases are recorded
concomitantly with the purchase at pharmacies using the
Anatomic Therapeutic Chemical (ATC) classification, and
drugs are supplied for a maximum of 3 months at a time. The
register covers 99% of all reimbursed prescription drug
purchases in Finland (22). The Special Reimbursement
Register, maintained since 1964, contains data on certain
chronic illnesses requiring continuous drug treatment. Over-
the-counter drugs and medications administered to in-
stitutionalized persons are not included.
The Hospital Discharge Register was used to identify
mothers’psychiatric history. The register includes inpatient
person-level diagnoses recorded in all somatic and psychi-
atric hospitals in Finland since 1969, and outpatient diagnoses
in public specialized care since 1998. Diagnoses for patients
treated in public primary care or in private outpatient units
are not included. The diagnoses are coded using ICD (ICD-8
for 1969–1986, ICD-9 for 1987–1995, and ICD-10 since 1996).
The Medical Birth Register has collected data since 1987
on maternal demographic characteristics, reproductive and
medical history, health-related behaviors, diagnoses during
pregnancy and delivery, and neonatal outcome using ICD
codes. Data in the register are collected in a standard form
from all maternity hospitals and are virtually complete after
data linkages to other governmental register resources (23).
The Register of Congenital Malformations, established in
1963, collects data from several sources, including hospitals,
health care professionals, and other national registers. The
register uses the ICD-9 coding and collects primarily data
on major congenital malformations, using the European
Surveillance of Congenital Anomalies (EUROCAT) criteria
for exclusion (http://www.eurocat-network.eu/content/
EUROCAT-Guide-1.4-Section-3.2.pdf ).
The utilization of sensitive health register data for sci-
entific research and the data linkages were approved by the
register administrators and the data protection authority. The
study protocol was approved by the Institutional Ethical
Review Board at the National Institute for Health and
Welfare and by the Institutional Review Board of the
New York State Psychiatric Institute.
Definition of Groups
The study examined three groups (Figure 1): women who
used SSRIs during pregnancy (the SSRI group), women who
had a psychiatric diagnosis related to SSRIs but did not use
any SSRIs (the psychiatric diagnosis/no medication group),
and women who had no psychiatric diagnosis and no ex-
posure to SSRIs (the unexposed group).
The SSRI group (N=15,729). All women who purchased
SSRIs (ATC code N06AB, including fluoxetine, citalopram,
paroxetine, sertraline, fluvoxamine, and escitalopram) dur-
ing the period from 30 days before the beginning of gestation
until the end of pregnancy were considered exposed, the
date of purchase marking the beginning of each exposure
(see Figure 1). The beginning of gestation corresponding to
the last menstrual period was calculated from the best
clinical estimate of gestational age at birth, primarily based
on ultrasound and registration in the Medical Birth Register.
Pregnancy trimesters were defined as follows: the first
trimester lasted until day 84 of gestation, the second covered
days 85–182,andthethirdfromday183untilbirth.In-
formation on psychiatric diagnosis in the Hospital Dis-
charge Register was available only for those womenwho had
been treated in a hospital or in public specialized care, and
diagnosis was not available for those women in this group
who had been treated solely in public primary care or in
private medical care.
The psychiatric diagnosis/no medication group (N=9,652). This
group included all mothers who had a diagnosis of a psy-
chiatric disorder related to SSRI use from 1 year before the
beginning of gestation until discharge (#3weeks)from
hospital after delivery but who had no purchases of anti-
depressants (ATC codes N06A, N06CA) or antipsychotics
(N05A) from 3 months before the beginning of gestation
until delivery (see Figure 1). The diagnoses included non-
affective and undefined psychoses (ICD-10 codes F20–F29;
ICD-9 codes 295, 297, 298); bipolar disorder (ICD-10 codes
F30–F31; ICD-9 codes 2962, 2963, 2964, 2967A); depression
or undefined affective disorders (ICD-10 codes F32–F39;
ICD-9 codes 2961, 2968A, 3004A), and anxiety and other
emotional disorders (ICD 10 codes F40–F48; ICD-9 codes
300.x, excluding 3004A). This group was derived exclu-
sively from specialized services.
The unexposed group (N=31,394). This group included
mothers who had made no purchases of antidepressants or
antipsychotics and had no psychiatric diagnoses related to
SSRI use at any time prior to or during pregnancy. The un-
exposed group served as a background control group. Two
unexposed subjects per one SSRI-exposed subject were se-
lected randomly from a cohort matched for offspring date of
birth within a period of 66 months (see Figure 1). We
compared pregnancy outcomes in the SSRI group to out-
comes in the psychiatric diagnosis/no medication group to
control for maternal underlying illness, and to the unexposed
group. Because fluoxetine and paroxetine are the SSRIs most
commonly associated with the neonatal behavioral syndrome
(13), we also compared outcomes after fluoxetine or parox-
etine exposure during the second or third trimester to out-
comes after exposure to other SSRIs.
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Maternal Characteristics and Covariates
Data on covariates were derived from the registers described
above. Covariates included maternal demographic, social,
and medical characteristics.
Outcome Variables
The outcomes of interest were selected based on clinical
importance, for which divergent results have been published
(3–13): 1) diagnoses related to pregnancy and delivery, in-
cluding hypertension of pregnancy/preeclampsia, mode of
delivery (vaginal delivery or cesarean section), and bleeding
during or after delivery; and 2) neonatal outcomes, including
categorically defined late preterm (32–36 gestational weeks)
and very preterm birth (,32 weeks), small for gestational age
(birth weight more than two standard deviations below na-
tional standards for sex and length of gestation) (24), and
neonatal problems, including a 5-minute Apgar score ,7,
neonatal breathing problems, monitoring in a neonatal (in-
tensive) care unit, and hospital stay at 7 days of age. We also
assessed the risk for persistent pulmonary hypertension of
the newborn, a rare outcome, and major congenital anomalies
in an analysis of first-trimester SSRI exposure.
Statistical Analysis
We used logistic regression models within the generalized
linear modeling framework to examine relationships of
pregnancy complications to SSRI use and to maternal psy-
chiatric disorders related to SSRI use but not treated with
antidepressants. Using generalized estimating equation
models,wewereabletospecifyacovariancestructureto
take into account correlations between siblings to control
for nonindependent observations. The crude model included
adjustment for sex and the birth periods1996–2000, 2001–2005,
and 2006–2010. For the adjusted analyses, clinically relevant
and plausible covariates were first tested for association with the
three-class exposure status. When associated with exposure at
asignificance threshold of 0.1, the covariate was tested sepa-
rately for association with each outcome. Rather than including
aspecific set of covariates for each of the 13 outcomes, we in-
cluded as potential confounders in the logistic regression model
those covariates that were associated with exposure and several
of the outcomes at p,0.1 (see Table S1 in the data supplement
that accompanies the online edition of this article). The
“unknown”category for socioeconomic status (18%) was in-
cluded because we anticipated the missing observations to occur
completely at random. Because maternal height and prepreg-
nancy weight were only available from 2004 (missing data
prevalence, 35%), body mass index was not included in
the analyses. All analyses were performed in SAS, version 9.4
(SAS Institute, Cary, N.C.).
RESULTS
A total of 12,817 women purchased SSRIs during the first
trimester or 30 days before the beginning of gestation, and
9,322 (59.3%) made two or more purchases. Use of the in-
dividual SSRIs during the study years is summarized in
Figure S1 in the online data supplement. The maternal
characteristics of the three groups are presented in Table 1.
Information on psychiatric diagnosis was available for
4,811 (30.6%) of mothers in the SSRI group; mothers in the
psychiatric diagnosis/no medication group were all identified
FIGURE 1. Flow Chart of the Register-Based Information and the Time Window Criteria for Definition of Exposure Groups in a Study of
Prenatal Exposure to SSRIs or Maternal Psychiatric Disorders
a
Anytime
before
pregnancy
1 year
before
pregnancy
1 month
before
pregnancy
Delivery
All mothers with SSRI purchases
SSRI group (N=15,729)
All mothers with
singleton live births
in Finland, 1996–2010
(N=845,345)
No purchases of antidepressants or antipsychotics and
no psychiatric diagnoses related to SSRI use
Unexposed group (two matched per one SSRI exposed) (N=31,394)
All mothers with a psychiatric diagnosis related to SSRI use,
and no purchases of antidepressants or antipsychotics
during 3 months before pregnancy until delivery
Psychiatric diagnosis/no medication group (N=9,652)
a
SSRI=selective serotonin reuptake inhibitor. The SSRI group included all mothers with one or more SSRI purchases 1 month prior to or during pregnancy.
The psychiatric diagnosis/no medication group included all mothers who had a psychiatric diagnosis related to SSRI use during pregnancy or within
1 year before pregnancy but who had no purchases of antidepressants or antipsychotics 3 months before or during pregnancy. The unexposed group
included mothers with neither a history of psychiatric diagnoses related to SSRI use (in the Hospital Discharge Register) nor any purchases of anti-
depressants or antipsychotics.
ajp in Advance ajp.psychiatryonline.org 3
MALM ET AL.

from the Hospital Discharge Register, and therefore all had
a diagnosis. Among mothers in the SSRI group who had
a diagnosis, 4,713 (98.0%) had a diagnosis related to affective
disorders (depression, anxiety, bipolar disorder), compared
with 9,407 (97.5%) in the psychiatric diagnosis/no medica-
tion group. A total of 265 (5.5%) mothers in the SSRI group
and 424 (4.4%) in the psychiatric diagnosis/no medication
group had a diagnosis of non-affective or undefined psychosis
(see Table S2 in the data supplement).
Pregnancy and delivery diagnoses by exposure status are
presented in Table 2. Comparedwith the psychiatric diagnosis/
no medication group and after adjustment for confounders,
women in the SSRI group had a lower risk of cesarean section,
emergency or urgent cesarean section, and bleeding; the risk
of hypertension of pregnancy did not differ between the two
groups. Compared with the unexposed group, the SSRI group
had a higher risk of cesarean section, and the psychiatric
diagnosis/no medication group had a higher risk of cesarean
section, emergency or urgent cesarean section, and bleeding
during or after delivery.
Neonatal outcomes are presented in Table 3. Compared
with the psychiatric diagnosis/no medication group, the SSRI
group had a 16% lower risk of late preterm birth and a 48%
lower risk of very preterm birth, but the risk of offspring being
born small for gestational age did not differ between the two
groups. The SSRI group had a higher risk of all neonatal
TABLE 1. Maternal Characteristics Tested as Covariates in a Study of Prenatal Exposure to SSRIs or Maternal Psychiatric Disorders
a
Covariate Associated
With Exposure
SSRI Group
(N=15,729)
Psychiatric Diagnosis/
No Medication Group
(N=9,652)
Unexposed Group
(N=31,394)
Characteristic p N % N % N %
Age (years) ,0.001
#19 524 3.3 954 9.9 775 2.5
20–24 2,747 17.5 2,117 21.9 5,162 16.4
25–29 4,679 29.8 2,414 25.0 10,361 33.0
30–34 4,459 28.4 2,378 24.6 9,518 30.3
35–39 2,564 16.3 1,390 14.4 4,441 14.2
#40 756 4.8 399 4.1 1,137 3.6
Place of residence 0.01
Urban 10,687 67.9 6,707 69.5 21,233 67.6
Semiurban 2,552 16.2 1,512 15.7 5,050 16.1
Rural 2,489 15.8 1,427 14.8 5,054 16.1
Marital status ,0.001
Married, in relationship, divorced,
or widowed
13,364 89.6 7,919 88.1 28,832 95.5
Unmarried 1,546 10.4 1,074 11.9 1,347 4.5
Parity ,0.001
One or more previous births 9,189 58.4 5,194 53.8 18,569 59.2
No previous births 6,534 41.6 4,455 46.2 12,817 40.8
Smoking during pregnancy ,0.001 4,575 29.9 2,737 29.1 3,947 12.9
Socioeconomic status ,0.001
Upper white collar worker 1,857 11.8 1,219 12.6 5,360 17.1
Lower white collar worker 4,954 31.5 2,825 29.3 10,479 33.4
Blue collar worker 2,493 15.9 1,435 14.9 4,271 13.6
Other
b
3,669 23.3 2,365 24.5 5,728 18.3
Unknown 2,756 17.5 1,802 18.7 5,556 17.7
Purchases of other psychiatric drugs
c
,0.001 3,223 20.5 553 5.7 278 0.9
Prepregnancy diabetes ,0.001 108 0.7 88 0.9 154 0.5
Other chronic diseases
d
,0.001 1,325 8.4 756 7.8 1,666 5.3
Artificial reproduction 0.4 335 2.1 227 2.4 716 2.3
Body mass index ,0.001
,18.5 422 4.0 311 5.8 789 3.8
18.5–24.9 (reference) 5,982 56.4 3,266 60.8 13,465 64.1
25–29.9 2,462 23.2 1,139 21.2 4,466 21.3
$30 1,734 16.4 653 12.2 2,282 10.9
a
SSRI=selective serotonin reuptake inhibitor. Percentages were calculated from nonmissing data. Missing values were as follows: place of residence, N=64 (0.1%);
marital status, N=2,693 (4.7%); previous births, N=17 (,0.1%); smoking during pregnancy, N=1,458 (2.6%); body mass index (available only from 2004 onward),
N=19,804 (34.9%).
b
The “other”category included students, housewives, entrepreneurs, and unemployed.
c
Other psychiatric drugs included anxiolytics, sedative-hypnotics, and antiepileptic drugs.
d
Other chronic diseases, drawn from the Special Reimbursement Register, included the following, recorded at any time: thyroid insufficiency, posttransplantation
conditions, disseminated connective tissue diseases (including rheumatoid arthritis), chronic asthma, chronic obstructive pulmonary disease, chronic hyper-
tension, and inflammatory bowel diseases.
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problems, but not hospital stay at 7 days of age. Compared
with the unexposed group, the SSRI group had a higher riskof
all neonatal problems, including hospital stay at 7 days age.
Compared with the unexposed group, the psychiatric
diagnosis/no medication group had a higher risk of late
preterm and very preterm birth, need for monitoring in
a neonatal care unit, and hospital stay at 7 days of age. Twelve
infants in the SSRI group (0.1%) had a diagnosis of persistent
pulmonary hypertension, compared with three (,0.1%) in the
psychiatric diagnosis/no medication group (odds ratio=2.49,
95% CI=0.71–8.70) and 21 (0.1%) in the unexposed group (odds
ratio=1.14, 95% CI=0.56–2.33).
In subanalyses in which the SSRI group included only
women with two or more SSRI purchases, comparison with
the psychiatric diagnosis/no medication group yielded ad-
justed results similar to those obtained for women with any
SSRI purchases for all outcomes except that the risk of hy-
pertension of pregnancy was now marginally higher (odds
ratio=1.16, 95% CI=1.01–1.35, p=0.04) and the lower risk of
urgent or emergency cesarean section was now insignificant
(see Table S3 in the data supplement). There was also
a tendency for slightly higher risks than those observed in the
overall SSRI group for 5-minute Apgar score ,7, neonatal
breathing problems, and needing monitoring in a neonatal
care unit (see Table S3).
In the trimester-specific analyses comparing the subgroup
of mothers with SSRI use during the first trimester with the
psychiatric diagnosis/no medication group, SSRI use was
associated with a lower risk of preterm birth (,37 weeks)
(Table 4), but the association was marginally insignificant
after second- and/or third-trimester exposure. The risks of
neonatal problems and major congenital anomalies were not
higher after first-trimester exposure, but exposure during the
second and/or third trimester was associated with a higher
risk of neonatal problems, including 5-minute Apgar score
,7, neonatal breathing problems, and monitoring in a neo-
natal care unit, with odds ratios higher than those observed
for SSRI use at any time during pregnancy. A subanalysis that
was restricted to full-term infants and compared second-
and/or third-trimester fluoxetine or paroxetine use with
use of other SSRIs revealed no significant differences for
5-minute Apgar score ,7, neonatal breathing problems, or
monitoring in a neonatal care unit.
DISCUSSION
We found that SSRI use during pregnancy is associated with
a lower risk of late preterm and very preterm birth compared
with women who had a psychiatric diagnosis but were not
treated with antidepressants during pregnancy. To our
knowledge, this is a novel finding. We also observed a lower
risk of cesarean section in SSRI users. In addition, we con-
firmed an increased risk of a 5-minute Apgar score ,7,
neonatal breathing problems, and need for monitoring in
a neonatal care unit.
TABLE 2. Comparisons of Pregnancy and Delivery Diagnoses, by Exposure Group, in a Study of Prenatal Exposure to SSRIs or Maternal
Psychiatric Disorders
a
SSRI Group
(N=15,729)
Psychiatric
Diagnosis/
No
Medication
Group
(N=9,652)
Unexposed
Group
(N=31,394)
SSRI Group Versus
Psychiatric
Diagnosis/No
Medication Group
SSRI Group Versus
Unexposed Group
Psychiatric Diagnosis/
No Medication
Group Versus
Unexposed Group
Outcome N % N % N % Odds Ratio 95% CI OddsRatio 95% CI Odds Ratio 95% CI
Hypertension of
pregnancy
813 5.2 434 4.5 1,413 4.5
Crude 1.13* 1.00–1.28 1.13** 1.03–1.24 1.00 0.89–1.12
Adjusted 1.10 0.97–1.26 1.09 0.98–1.20 0.99 0.87–1.11
Cesarean section 3,004 20.9 2,387 26.5 4,984 17.3
Crude 0.77*** 0.73–0.82 1.22*** 1.16–1.29 1.58*** 1.49–1.67
Adjusted 0.70*** 0.66–0.75 1.18*** 1.11–1.25 1.68*** 1.57–1.79
Cesarean section,
emergency or
urgent
1,600 12.3 977 12.9 2,869 10.7
Crude 0.96 0.88–1.05 1.13*** 1.06–1.21 1.17*** 1.08–1.27
Adjusted 0.88 ** 0.80–0.97 1.05 0.97–1.14 1.19*** 1.09–1.30
Bleeding during or
after delivery
520 3.3 342 3.5 903 2.9
Crude 0.88 0.77–1.01 1.15* 1.03–1.29 1.31* 1.15–1.49
Adjusted 0.83* 0.71–0.96 1.07 0.95–1.21 1.29*** 1.13–1.48
a
SSRI=selective serotonin reuptake inhibitor. Percentages were calculated from nonmissing data. Crude odds ratios were adjusted for sex and birth period
(1996–2000, 2001–2005, and 2006–2010). Adjusted odds ratios were adjusted for sex, birth period, maternal age at delivery, place of residence, marital status,
parity, smoking, socioeconomic status, purchase of anxiolytics, sedative-hypnotics, or antiepileptic drugs, prepregnancy diabetes, and other chronic diseases (see
Table 1 footnotes). For cesarean section, the reference group was those with vaginal cephalic delivery.
*p,0.05. **p,0.01. ***p,0.001.
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MALM ET AL.

The risk of preterm birth was 16% lower, and the risk of
very preterm birth nearly 50% lower, for women using SSRIs
during pregnancy compared with mothers who had a psy-
chiatric diagnosis but no medication use. This finding
remained even when we restricted the analyses to women
with two or more SSRI purchases, a sign of continuous use
and greater adherence. Given that less than 0.1% of women in
the whole birth cohort purchased the first-generation anti-
psychotics prochlorperazine and dixyrazine, used for treating
morning sickness during pregnancy, a condition associated
with a reduced risk of preterm birth (25), their use is unlikely to
have biased the results.
Preterm birth is the single most important cause of neo-
natal and infant death and is associated with long-term
neurological disabilities in surviving infants (26). Several
previous studies have reported an increased risk of preterm
birth associated with SSRI use during pregnancy (3–8). Al-
though SSRI use usually occurs in the context of maternal
depressive and anxiety disorders, only a few studies have
adjusted for these factors, yielding conflicting results (5, 6, 8,
20, 21). Three of these studies were prospective; one observed
a twofold higher risk of preterm birth in SSRI users (N=329)
(5), and another reported similarly elevated risks of preterm
birth between SSRI users (N=48) and women with untreated
depression (6). The third study, a population-based study
from Norway, reported a 50% higher risk of preterm birth in
SSRI users (N=572), but the risk was no longer significant
after adjustment for maternal depressive symptoms (20). Yet
another study, based on pharmacy records (N=221), reported
an increased risk of preterm birth in SSRI users compared
with women who had a psychiatric illness but no SSRI use (8).
Methodological limitations of previous studies include small
sample sizes (5, 6, 8) and selection bias. Underestimation of
SSRI exposure and maternal psychiatric illness (8) and low
response rates (20) may also have biased the findings. An-
other population-based study found an increased risk of
preterm birth in SSRI users (N=1,500), but after adjusting for
depression severity, the risk became nonsignificant, sug-
gesting that maternal depression confounded the association
(21). None of the previous studies that controlled for maternal
TABLE 3. Comparisons of Neonatal Outcomes, by Exposure Group, in a Study of Prenatal Exposure to SSRIs or Maternal
Psychiatric Disorders
a
SSRI Group
(N=15,729)
Psychiatric
Diagnosis/No
Medication
Group
(N=9,652)
Unexposed
Group
(N=31,394)
SSRI Group
Versus Psychiatric
Diagnosis/No
Medication Group
SSRI Group
Versus
Unexposed
Group
Psychiatric Diagnosis/
No Medication
Group Versus
Unexposed Group
Outcome N % N % N % Odds Ratio 95% CI Odds Ratio 95% CI Odds Ratio 95% CI
Preterm birth
32–36 weeks 741 4.7 515 5.4 1,193 3.8
Crude 0.89* 0.79–1.00 1.24*** 1.13–1.37 1.40*** 1.26–1.57
Adjusted 0.84* 0.74–0.96 1.07 0.96–1.20 1.27*** 1.13–1.44
,32 weeks 80 0.5 93 1.0 186 0.6
Crude 0.53*** 0.39–0.72 0.85 0.65–1.11 1.60*** 1.23–2.08
Adjusted 0.52*** 0.37–0.74 0.78 0.57–1.07 1.50** 1.12–2.01
Small for
gestational age
393 2.5 245 2.5 673 2.2
Crude 1.00 0.85–1.17 1.17* 1.03–1.33 1.17* 1.01–1.36
Adjusted 0.92 0.77–1.10 0.86* 0.74–0.99 0.93 0.79–1.10
5-minute Apgar
score ,7
376 3.9 113 2.3 383 2.1
Crude 1.72*** 1.39–2.13 1.96*** 1.70–2.27 1.14 0.92–1.41
Adjusted 1.68*** 1.34–2.12 1.72*** 1.46–2.02 1.02 0.81–1.28
Breathing problems 763 4.9 310 3.2 874 2.8
Crude 1.50*** 1.31–1.72 1.77*** 1.60–1.96 1.18* 1.04–1.35
Adjusted 1.40*** 1.20–1.62 1.60*** 1.43–1.79 1.15 1.00–1.32
Neonatal care unit 2,405 15.3 1,160 12.0 3,032 9.7
Crude 1.31 *** 1.22–1.42 1.68*** 1.58–1.78 1.28*** 1.19–1.38
Adjusted 1.24*** 1.14–1.35 1.38*** 1.29–1.48 1.12** 1.03–1.21
In hospital at
7 days of age
1,315 8.4 821 8.6 1,760 5.6
Crude 0.98 0.89–1.08 1.53*** 1.42–1.65 1.56*** 1.43–1.71
Adjusted 0.89* 0.80–0.99 1.22*** 1.12–1.33 1.37*** 1.24–1.51
a
SSRI=selective serotonin reuptake inhibitor. Percentages were calculated from nonmissing data. Crude odds ratios were adjusted for sex and birth period
(1996–2000, 2001–2005, and 2006–2010). Adjusted odds ratios were adjusted for sex, birth period, maternal age at delivery, place of residence, marital status,
parity, smoking, socioeconomic status, purchase of anxiolytics, sedative-hypnotics, or antiepileptic drugs, prepregnancy diabetes, and other chronic diseases (see
Table 1 footnotes). Five-minute Apgar scores were available from 2004 to 2010. For preterm (32–36 weeks) and very preterm (,32 weeks) birth, the reference
group was birth at $37 gestational weeks.
*p,0.05. **p,0.01. ***p,0.001.
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PREGNANCY COMPLICATIONS FOLLOWING PRENATAL EXPOSURE TO SSRIS OR PSYCHIATRIC DISORDERS

psychiatric illness found a protective effect of SSRI use on
preterm birth.
Prenatal stress, associated with maternal depression,
affects regulation of the hypothalamic-pituitary-adrenal axis,
resulting in increased corticosteroid production and release
of vasoactive amines, potentially reducing umbilical blood
flow and predisposing to hypoxia and preterm birth (27).
Hence, the protective effect observed in our cohort could be
related to relief of symptoms and stress secondary to the
antidepressant effect of SSRIs, and it may be consistent with
the increased risk of preterm birth in mothers with untreated
depression, which was also observed in our study.
Our findings also suggest that treating maternal depression
with SSRIs may lower the risk of cesarean section; we observed
a 30% lower risk in SSRI users compared with mothers who
had a psychiatric diagnosis but were not treated with anti-
depressants. Although one previous study observed an increased
risk of cesarean section in women using antidepressants, the
authors did not control for maternal depression (4).
A recent study in low-income women (10) reported a 40%
higher risk of postpartum hemorrhage in women using SSRIs
close to delivery,controlling for maternal depression severity.
Contrary to this, we found a marginally protective effect of
SSRI use compared with the psychiatric diagnosis/no
medication group, and SSRI use during the second and/or
third trimester was not associated with bleeding even when
compared with the unexposed group (odds ratio=1.10, 95%
CI=0.95–1.28). These findings are in line with the observed
lower risk of cesarean section because these two outcomes
are strongly related. These findings are also consistent with
a recent population-based study from Norway that reported
no increased risk for postpartum hemorrhage, controlling for
maternal depression (28). While SSRI use may increase the
risk of some bleeding events due to drug-induced platelet
dysfunction, normal hemo-
static mechanisms after delivery,
including uterine contractions
and uterine sinus thrombosis,
are unlikely to be affected by
SSRIs (29).
Regardingotherkeypreg-
nancy and neonatal com-
plications, hypertension of
pregnancy (including pre-
eclampsia) was not more
common among SSRI users
compared with either of the
comparison groups. The risk
became marginally signifi-
cant in women with two or
more SSRI purchases (see
Table S3), suggesting no ma-
jor effect, in linewith a recent
study controlling for mater-
nal depression (30). Also in
line with previous research
was that therisk of congenital anomalieswas not increased and
that SSRI use was associated with an increased risk for several
neonatal problems, including low Apgar score, breathing
problems, and need for monitoring in a neonatal care unit (4,
11–13, 31, 32). Becausethe study was based on register data, we
did not have information on whether these symptoms resulted
from drug toxicity or from drug withdrawal (33). Conse-
quently, the results do not provide information on how best to
treat these infants.It is possible that increased vigilance based
on the knowledge that the mother had been treated with an
SSRI led to increased identification of neonatal maladaptation
in the SSRI-exposed group. Our results suggest that the
symptoms are relatively short-lived. Even in this large study,
we could not confirm anincreasedriskof persistentpulmonary
hypertension of the newborn.
Strengths of this study include comprehensive pro-
spectively acquired data in a large national birth cohort and
inclusion of a comparison group of women with a psychiatric
diagnosis related to SSRI use but no antidepressant medi-
cation during pregnancy. The prevalence of SSRI use and
several of the examined outcomes in our study were com-
parable to those reported in other countries (2, 14, 28, 30, 34,
35), suggesting that the results are generalizable to other
populations. The register data allowed us to adjust for a large
number of meaningful potential confounders. Moreover,
exposures, outcomes, and covariates in the registers have
been validated, and the quality of ascertainment of these
variables is high (22, 23, 36).
One limitation of the study is that we had no information on
illness severity. The Hospital Discharge Register includes
comprehensive data on diagnoses but no data on symptom
levels. We had information only on maternal psychiatric
disorders diagnosed in inpatient or outpatient specialized
care. Hence, we cannot directly evaluate the effect of SSRI
TABLE 4. Comparison of Pregnancy and Neonatal Outcomes Between SSRI-Exposed Mothers and
Those With a Psychiatric Diagnosis But No AntidepressantUse, By Gestational Period of SSRI Exposure
a
SSRI Exposure During First
Trimester Only (N=7,069)
SSRI Exposure at Least During Second
and/or Third Trimester (N=8,660)
Outcome Odds Ratio 95% CI Odds Ratio 95% CI
Hypertension of pregnancy 1.04 0.89–1.21 1.16 1.00–1.35
Cesarean section 0.66*** 0.61–0.72 0.73*** 0.67–0.79
Cesarean section, emergency
or urgent
0.84** 0.75–0.95 0.90 0.81–1.01
Bleeding during or after delivery 0.82* 0.69–0.99 0.84* 0.71–1.00
Preterm birth ,37 weeks
b
0.71*** 0.61–0.83 0.87 0.76–1.01
Small for gestational age 0.89 0.72–1.11 0.96 0.78–1.17
5-minute Apgar score ,7 1.04 0.77–1.40 2.15*** 1.68–2.74
Breathing problems 0.99 0.82–1.19 1.76*** 1.50–2.07
Neonatal care unit 0.97 0.87–1.07 1.51*** 1.37–1.66
In hospital at 7 days of age 0.73*** 0.64–0.83 1.03 0.92–1.16
Major congenital anomaly
c
1.03 0.88–1.20
a
SSRI=selective serotonin reuptake inhibitor. Odds ratios were adjusted for sex, birth period, maternal age at delivery,
place of residence, marital status, parity, smoking, socioeconomic status, purchase of anxiolytics , sedative-hypnotics, or
antiepileptic drugs, prepregnancy diabetes, and other chronic diseases (see Table 1 footnotes).
b
Preterm birth ,37 weeks only was included because very preterm birth (,32 weeks) would exclude the possibility of
purchasing SSRIs at later gestational weeks.
c
Only first-trimester exposures to SSRIs were assessed.
*p,0.05. **p,0.01. ***p,0.001.
ajp in Advance ajp.psychiatryonline.org 7
MALM ET AL.

treatment on the reduction of psychiatric symptom burdenand
its relationship with perinatal outcomes, although we were
able to adjust for several covariates that are correlated with
illness severity, including smoking (37), socioeconomic status,
and use of other psychiatric drugs, including mood stabilizers.
Our findings should stimulate further research on samples of
pregnant mothers, treated and untreated with SSRIs, for
whom information on symptom severity is available.
Another limitation is thepossibility of residual confounding
by behavioral factors,such as alcohol and illicit drug use,which
were not available in the register data. Use of these substances
is strongly correlated with smoking, however, which was
accounted for in the analyses. For preterm delivery, one lim-
itation is that information was not available on the respective
proportions with spontaneous and elective preterm births.
Further limitations include those commonly present in
register-based studies, including lack of assessment of medi-
cation adherence and possible misclassification of timing of
exposure. However, our results were consistent whenanalyses
were restricted to women with two or more SSRI purchases
during pregnancy, indicating greater adherence.
CONCLUSIONS
We have provided novel evidence that SSRI use is associated
with a lower risk of preterm birth and cesarean section, com-
pared with presence of a psychiatric diagnosis but no antide-
pressant treatment, and we confirmed the results from previous
research of a higher risk for several neonatal problems. These
divergent findings reinforce the view that the decision on
whether to prescribe an SSRI during pregnancy should be in-
dividualized to the mother’s medical and psychiatric history.
AUTHOR AND ARTICLE INFORMATION
From the Teratology Information Service, University of Helsinki and
Helsinki University Hospital, Helsinki; the Department of Clinical Phar-
macology, University of Helsinki and Helsinki University Hospital, Helsinki;
the Department of Child Psychiatry, University of Turku, and the Research
Center for Child Psychiatry, Turku Brain and Mind Center, Turku, Finland;
the Department of Medical Genetics, Helsinki University, Helsinki; the
Department of Psychiatry, Columbia University College of Physicians and
Surgeons, and New York State Psychiatric Institute, New York; the National
Institute for Health and Welfare, Helsinki; the Nordic School of Public
Health, Gothenburg, Sweden; and the Department of Epidemiology,
Columbia University, Mailman School of Public Health, New York.
Address correspondence to Dr. Malm (heli.malm@hus.fi).
Supported by NIH grant P50MH090966.
Dr. Gyllenberg has received research grants from the Sigrid Juselius
Foundation, the Foundation for Pediatric Research (Finland), and the
Finnish Medical Foundation. The other authors report no financial rela-
tionships with commercial interests.
Received December 21, 2014; revisions received March 11 and May 4,
2015; accepted May 11, 2015.
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