Major congenital malformations following prenatal exposure to serotonin reuptake inhibitors and benzodiazepines using population-based health data

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DOI: 10.1002/bdrb.20144 · Source: PubMed
Abstract
To determine a population-based incidence of congenital anomalies following prenatal exposure to serotonin reuptake inhibitor (SRI) antidepressants used alone and in combination with a benzodiazepines (BZ). Population health data, maternal health, and prenatal prescription records were linked to neonatal records, representing all live births (British Columbia, Canada, N=119,547) during a 39-month period (1998-2001). The incidence and risk differences (RD) for major congenital anomalies (CA) and congenital heart disease (CHD), including ventricular and atrial septal defects (VSD, ASD), from infants of mothers treated with an SRI alone, a benzodiazepine (BZ) alone, or SRI+BZ in combinationcompared to outcomesno exposure. Risk for a CA or CHD did increase following combined SRI+BZ exposure compared with no exposure. However, using a weighted regression model, controlling for maternal illness characteristics, combination therapy risk remained significantly associated only with CHD. The risk for an ASD was higher following SRI monotherapy compared with no exposure, after adjustment for maternal covariates. Dose/day was not associated with increased risk. Infants exposed to prenatal SRIs in combination with BZs had a higher a incidence of CHD compared to no exposure, even after controlling for maternal illness characteristics. SRI monotherapy was not associated with an increased risk for major CA, but was associated with an increased incidence of ASD. Risk was not associated with first trimester medication dose/day.
Original Article
Major Congenital Malformations Followin g Prenatal
Exposure to Serotonin Reuptake Inhibitors and
Benzodiazepines Using Population-Based Health Data
Tim F. Oberlander,
1,2
William Warburton,
2
Shaila Misri,
3
Wayne Riggs,
4
Jaafar Aghajanian,
2
and Clyde Hertzman
2
1
Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada
2
Human Early Learning Partnership, University of British Columbia, Vancouver, BC, Canada
3
Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada
4
Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada
BACKGROUND: To determine a population-based incidence of congenital anomalies following prenatal exposure to
serotonin reuptake inhibitor (SRI) antidepressants used alone and in combination with a benzodiazepines (BZ).
METHODS: Population health data, maternal health, and prenatal prescription records were linked to neonatal records,
representing all live births (British Columbia, Canada, N 5 119,547) during a 39-month period (1998–2001). The incidence
and risk differences (RD) for major congenital anomalies (CA) and congenital heart disease (CHD), including ventricular
and atrial septal defects (VSD, ASD), from infants of mothers treated with an SRI alone, a benzodiazepine (BZ) alone, or
SRI1BZ in combinationcompared to outcomesno exposure. RESULTS: Risk for a CA or CHD did increase following
combined SRI1BZ exposure compared with no exposure. However, using a weighted regression model, controlling for
maternal illness characteristics, combination therapy risk remained significantly associated only with CHD. The risk for
an ASD was higher following SRI monotherapy compared with no exposure, after adjustment for maternal covariates.
Dose/day was not associated with increased risk. CONCLUSIONS: Infants exposed to prenatal SRIs in combination
with BZs had a higher a incidence of CHD compared to no exposure, even after controlling for maternal illness
characteristics. SRI monotherapy was not associated with an increased risk for major CA, but was associated with
an increased incidence of ASD. Risk was not associated with first trimester medication dose/day. Birth Defects Research
(Part B) 83:68–76, 2008. r 2008 Wiley-Liss, Inc.
Key words: serotonin reuptake inhibitors (SRIs); benzodiazepines (BZs);
congenital malformations; prenatal exposure
INTRODUCTION
Recent scientific and public attention has focused on
studies reporting an increased risk for congenital mal-
formations, particularly cardiac anomalies following 1st
trimesterto serotonin reuptake inhibitor (SRI) antidepres-
sant medications (Alwan et al., 2007; GlaxoSmithKline,
2006; Louik et al., 2007). While SRIs are commonly used
to manage depression during pregnancy (Oberlander
et al., 2006), some studies have reported an increased risk
for congenital (Alwan et al., 2007; Chambers et al., 1996;
Wogelius et al., 2006) and cardiac anomalies (Diav-Citrin
et al., 2005; GlaxoSmithKline, 2006; Malm et al., 2005)
while others have failed to find such an association
(Altshuler et al., 1996; Einarson et al., 2005; Ericson et al.,
1999; Hendrick et al., 2003; Ka
¨
lle
´
n et al., 2007; Simon
et al., 2002). Recently, Berard et al. (2007) reported an
increased risk for congenital and cardiac anomalies also
being associated with an increasedtrimester paroxetine
dose. Concerns about prenatal exposure led Health
Canada (2004) and the FDA (US Food and Drug
Administration, Medwatch, 2005) to issue warnings
about paroxetine use during pregnancy.
To date, a variety of cohort and population-based study
designsbeen used to assess relationships between gesta-
tional exposure and risk for anomalies (Berard et al., 2007;
Ericson et al., 1999; GlaxoSmithKline, 2006; Ka
¨
lle
´
n et al.,
2007; Simon et al., 2002; Wogelius et al., 2006). However,
outcomes have been conflicting and our understanding of
neonatal risk in this setting remains uncertain due to a
number of key methodological challenges (Hines et al.,
Published online in Wiley InterScience (www.interscience.wiley.com)
DOI: 10.1002/bdrb.20144
*Correspondence to: Tim F. Oberlander, MD, FRCPC, Early Human
Experience Unit, Centre for Community Child Health Research, Room
L408, 4480 Oak St., Vanco uver, BC V6H 3V4 Canada.
E-mail: toberlander@cw.bc.ca
Received 17 October 2007; Revised 19 November 2007; Accepted 16
December 2007
Contract grant sponsors: BC Ministry of Children and Family Develop-
ment; The Michael Smith Foundation for Health Research.
Birth Defects Research (Part B) 83:68–76 (2008)& 2008 Wiley-Liss, Inc.
2004). While the need for large study populations is
frequently acknowledged, congenital anomalies typically
occur at very low incidences and these studies have
been challenged by uncertainty abouttiming of gestatio-
nalexposure, maternal recall bias, lack of precise defini-
tions distinguishing major from minor anomalies,
controlling for the impact of depression itself, or other
maternal illness that may be associated with congenital
anomalies and the lack of matched pharmacological
and related maternal health data (Alwan et al., 2007;
Louik et al., 2007). Moreover, studies have not investi-
gated the effects of combined psychotropic medication
exposure and have only controlled for such exposures by
eliminating them from analysis (GlaxoSmithKline,
2006; Wogelius et al., 2006). In particular, studies have
not examined neonatal outcomes following prenatal
SRI use in combination with benzodiazepines, accounting
for the impact of maternal illness severity or the length of
1st trimester use.
To address these gaps in the literature, we undertook a
population-level study using health data linking all
maternal health data with records for prescriptions
dispensed during pregnancy and birth outcomes for their
infants over a 39-month period in our province (British
Columbia) to study whether the risk for major congenital
malformations and congenital heart defects differs
between first trimester SRI1BZ exposure and no ex-
posure at all. Secondarily, we also compared neonatal
outcomes following monotherapy SRI exposure with
outcomes with no exposure. We also sought to determine
whether risk for congenital anomalies is associated with
first trimester SRI medication dose controlling for length
of first trimester exposure and maternal illness severity,
which might have also contributed to increasing neonatal
risk. We expected that neonatal risk would increase with
poly-psychotropic drug exposure beyond no exposure,
even when controlling for maternal illness characteristics.
METHODS
This study was undertaken with approval from the
University of British Columbia (UBC) Research Ethics
Board, the Children’s and Women’s Health Centre of
British Columbia Research Review Committee, the
BC Ministry of Health Services, and the BC College
of Pharmacists. Data analysis was undertaken by T.O.,
J.A., and W.W.
Data Set Compilation
Data used in this study came from five administrative
sources housed in the BC Linked Health Database
(Chamberlayne et al., 1998) (BC registry of births,
hospital separation records, the PharmaCare registry of
subsidized prescriptions; the Medical Services Plan
physician billing records; and the registry of Medical
Services Plan subscribers) linked to PharmaNet, a
province-wide network recording all prescriptions dis-
pensed by BC pharmacists outside hospitals. These data
were processed by the Centre for Health Services and
Policy Research (CHSPR), UBC; PharmaNet provided
records with the same unique, non-identifying study ID
as was provided by CHSPR to enable data linkage. The
cohorts used in this study were assembled from records
of 203,520 registered live births (hospital and home
births) in British Columbia occurring between April 1,
1997 and March 31, 2002. To ensure accurate matching
between all data sets, and accounting for data entry
errors and records for multiple births, the final
study cohort comprised records related to 119,547 live
births, representing 92.7% of the live births in British
Columbia (previously described in Oberlander et al.,
2006). Of the total 356,727 prescriptions for psychotropic
medications in the PharmaNet data set, we identified
75,456 for one of the following SRIs: citalopram,
fluoxetine, fluvoxamine, paroxetine, sertraline, and
venlafaxine. The file identified the drug by brand name
and generic name, the date that the drugs were
dispensed, and the number of days supplied together
with a unique study number for the mother.
To account for maternal illnesses that may have also
contributed to congenital anomalies, physician billing
data were used to determine whether the mothers had
diseases and complications related to pregnancy (ICD9
codes from 640 to 648, Complications Mainly Related to
Pregnancy). In addition, any diagnosis of epilepsy or
seizures was also identified from maternal records
regardless of timing of exposure.
Hospital discharge records report gestational age based
on last menses. We define exposure in the first trimester
to have occurred if the period for which SRIs and/or
benzodiazepines were dispensed (i.e., days of dosing
covered by the prescription) overlapped with the period
from the LMP to LMP plus 90 days (first trimester). To
avoid any confounding effect from anticonvulsant ex-
posure, and the inherent multiple maternal diagnoses and
neonatal risks associated with these medications, 359
records were removed where neonates had first trimester
exposure to this class of medication. We define poly-drug
exposure to have occurred if both an SRI and a BZ were
dispensed for the same day during the first trimester.
Study Group Identification
Information on diagnosis of maternal mood was
obtained from Ministry of Health Services, Medical
Services Plan billing records (ICD9 diagnostic code). To
define a diagnosis of depression, all ICD9 codes that
explicitly referred to depression (National Centre for
Health Statistics, 2006; Teleplan Record Specifications
version 4.0,2004) were selected (Oberlander et al., 2006).
Exposure groups were defined as SRI monotherapy
and SRI1benzodiazepines (BZ) used in combination.
Outcomes were compared between infants exposed to
SRI monotherapy and SRI1BZ combination with infants
with no exposure to either of these drugs in the first
trimester, respectively.
Neonatal Outcomes
Based on previous studies (Berard et al.,
2007; GlaxoSmithKline, 2006; Wogelius et al., 2006),
neonatal outcomes were identified using ICD9 codes
for major congenital anomalies (codes: 740.0 to 759.9),
and the subset of cardiovascular defect (745.0–747.9)). We
excluded the following congenital anomalies, which
were defined as minor by Berard et al. (2007) (743.6,
744.1, 744.2–744.4, 744.8, 744.9, 747.0, 747.5, 750.0, 752.4,
752.5, 754.6, 755.0, 755.1, 757.2–757.6, 757.8, 757.9, 758.4).
Specific codes for ventricular septal defects (VSD) (745.4),
and atrial septal defects (ASD) (745.5) were also used.
69PRENATAL EXPOSURE TO SRIs AND BZs
Birth Defects Research (Part B) 83:68–76, 2008
Data Analysis
Data analysis was undertaken using four approaches:
First, given that congenital anomalies are rare events
within large populations, where odds ratios can be very
large when the numerator is close to zero, we report risks
and risk differences (RDs; 95% confidence intervals),
rather than odds ratios (Davies et al., 1998; Kraemer et al.,
2003). Confidence intervals for incidence were calculated
using Newcombe and Altman’s method (Newcombe and
Altman, 2000) and confidence intervals for the risk
difference were calculated using Newcombe’s method
ten (Newcombe, 1998).
Second, because linked-population level health data do
not permit randomization between exposure groups
enabling us to control for maternal risk factors that could
have either directly or indirectly contributed to a risk for
congenital anomalies, we supplemented the comparisons
of raw differences with regression models to control for
maternal characteristics that could have also contributed
to neonatal risk. We used weighted linear probability
models (corrected for heteroskedasticity) to provide
estimates of risk differences. In these models, we
controlled for maternal illness characteristics, diseases,
and complications of pregnancy diagnosed more than 60
days before birth, depression in the first trimester, and a
dummy variable indicating that the mother filled a
prescription after she knew that she was pregnant (see
below), plus a variable indicating whether the patient
had been prescribed methadone. Methadone use during
pregnancy was used as a proxy marker for other
maternal health characteristics, such as poor nutrition
and other drug use, which could also contribute to an
increased risk for congenital anomalies (but were
unmeasured in our administrative health data). Namely,
if mothers, who were also treated with methadone and
had related health risk factors, were also more likely to be
taking an SRI, this would bias our results.
Third, compliance among patients starting antidepres-
sant therapy has been frequently noted (A
˚
kerblad et al.,
2003; Reis et al., 2004) and non-compliance could mask
associations (i.e., bias the relationships towards zero),
and therefore might alter the significance of any
exposure-outcome relationships. To control for non-
compliance, we constructed a variable that indicated
that the mother had filled a prescription more than 50
days after the LMP and included it in the regression
analyses. It was assumed that mothers, except possibly
the hidden non-compliers, who took the trouble to fill a
prescription, would have used the previously dispensed
pills.
Fourth, to study the relationship between first trime-
ster medication dose and congenital anomalies, we
developed indicators of whether the dose was low,
medium, or high in two steps. First, because of
differences in dose range inherent to each SRI and BZ
medication, each dispensed medication dose was con-
verted to a z score. Second, we classified the dose for SRI
monotherapy as low if the z score was less than 0.5,
medium if the z score was between 0.5 and 0.5, and
high if the z score was greater than 0.5. For combined BZ
and SRI, we used cutoffs of 0.75 and 0.75. For some
patients, dose changed over time. In these cases, we used
the dose in effect on the estimated date of conception.
Differences in the rates of anomalies associated with high
doses (compared with medium and low doses) and for
high and medium doses (compared with low doses) for
both SRI monotherapy and for SRI1BZ were assessed
using Fisher’s exact test and logistic regression analysis.
In the regression analysis, we controlled for the variables
described above, and in a separate analysis we addition-
ally controlled for days of exposure to SRI medication.
We calculated the incidence of anomalies (and 95%
confidence intervals) associated with each specific SRI
both when used individually and when used in
combination with a BZ. We calculated the difference in
incidence (risk difference) compared with no exposure,
and the associated 95% confidence intervals for the
difference. We also produced estimates of the risk
difference after controlling for potential confounders
described above using a weighted linear probability
model. We tested the null hypothesis that the risk
difference was the same for all SRI’s using an F-test.
To ensure robustness of our regression results, we
conducted sensitivity analyses by controlling for (1)
exposure to clonazepam or clobazam since these drugs
are sometimes used as anticonvulsants; (2) restricting the
period of exposure to the period of organogenesis; (3)
controlling for exposure to antipsychotics since these
drugs and/or the attendant illness may present risk to
the fetus, and to non-SRI antidepressants; and (4) by
using logistic regression and probit regression to estimate
the parameters of the models.
Confidence intervals using Newcombe’s and Altman’s
methods were computed by the authors. All other
statistical analysis was conducted using Stata SE 10
(STATA SE10, 2006).
RESULTS
Maternal Demographic Characteristics
Cohort and medication exposure group characteristics
are tabulated in Table 1. Paroxetine was the most
commonly prescribed SRI, and lorazepam and clonaze-
pam the most frequent benzodiazepines prescribed
during the first trimester. Key differences in maternal
characteristics emerged between exposure groups.
Mothers who had received an SRI alone had 1.8 times
more family physician visits, were three times more
likely to have had drugs subsidized through the welfare
system, and were 16 times more likely to have been
diagnosed as depressed in the year before LMP with the
‘no exposure group’ (i.e., not depressed and not
receiving an SRI during pregnancy).
Major Congenital Anomalies
When an SRI was used in combination with BZ, the
crude risk difference for CA relative to no exposure was
2.43 percentage points (0.49 to 5.31%). However, after
adjustment for potential confounders, the risk difference
was no longer statistically significant (Table 2a). Com-
pared with no exposure, SRI monotherapy did not
increase the risk for major CAs.
Congenital Heart Disease (CHD)
An SRI used in combination with a BZ increased the
risk of CHD by 1.19 percentage points compared with no
exposure. The risk difference remained statistically
significant after adjustment for potential confounders,
70 OBERLANDER ET AL.
Birth Defects Research (Part B) 83:68–76, 2008
adjusted RD 5 1.18% (0.18 to 2.18%) (Table 2b). SRI
monotherapy did not increase the risk for CHD overall
compared with no exposure. The risk for VSD did
not increase with poly-drug exposure (Table 2c), while
the risk for an atrial septal defect (ASD) (Table 2d)
increased with SRI monotherapy compared with
no exposure RD 5 0.16% (0.03 to 0.43%). This difference
remained statistically significant after adjustment
for potential confounders, adjusted RD 5 0.21% (0.05
to 0.36%).
Specific SRI Exposure and Risk for Anomalies
No differences between SRI medications were ob-
served for the risk of major anomalies (Table 3a,b). An
increased risk for cardiovascular defects was observed
following exposure to citalopram (n 5 3; 2.97%; 95% CI
(1.02–8.37); RD 2.49% (0.54–7.89) when compared to no
exposure. While this risk difference remained statisti-
cally significant after controlling for potential confoun-
ders, the F-test did not reject the null hypothesis that the
risk difference did not differ across SRI mono-therapies.
Specific CHDs identified in the 3 citalopram-exposed
neonates are listed in Table 3b.
An increased risk for both CA and CHD was observed
following exposure to fluoxetine1BZ compared with
no exposure (Table 3c, Table 3d). The risk difference
for CA remained statistically significant after control-
ling for potential confounders, but the risk difference
for CHD did not. The F-test did not reject the
null hypothesis that risk differences did not differ
across SRI’s when they were used in combination
with BZ.
Impact of First Trimester Dose
There was no association between increased first
trimester dose and risk for major congenital anomalies
or congenital heart disease in the simple comparisons or
in the regression models, for SRI1BZ or SRI mono-
therapy even controlling for length of time of medication
use and maternal illness characteristics.
Table 1
Maternal Demographic Characteristics: First Trimester Exposure
Maternal medication group
Mean
maternal
age
Prenatal
care visits
(all trimesters)
Average number
of diagnoses
of depression
in the year
before LMP
Average number
of visits to
a psychiatrist
in the year
before LMP
Average number
of visits to
a physician
in the year
before LMP
Depression exposure alone (n 5 7,883) 29.6 11.3 0.9 0.3 15.3
SRIs only (n 5 2,25)
a
29.6 11.0 3.2 0.9 21.3
Benzodiazepines only (n 5 968)
b
30.1 10.8 1.5 0.7 23.8
SRIs1benzodiazepines (n 5 392) 29.9 10.6 4.9 2.9 31.6
No exposure (n 5 10,720) 29.5 10.8 0.2 0.0 11.5
Frequency of particular drug use in a specific therapeutic class in the first trimester:
SRIs:
Drug Frequency of use (%)
Paroxetine 37.0
Sertraline 24.3
Fluoxetine 24.2
Venlafaxine 7.1
Fluvoxamine 4.6
Citalopram 2.8
Benzodiazepines:
Drug Frequency of use (%)
Lorazepam 44.0
Clonazepam 21.4
Oxazepam 15.0
Alprazolam 6.8
Temazepam 5.1
Diazepam 5.0
Clobazam 1.6
Bromazepam 0.3
Triazolam 0.3
chlordiazepoxide hcl 0.2
flurazepam hcl 0.2
Nitrazepam 0.1
Clorazepate dipotassium 0.0
71PRENATAL EXPOSURE TO SRIs AND BZs
Birth Defects Research (Part B) 83:68–76, 2008
Table 2a
Major congenital Anomalies (incidence, 95% CI and RD compared with risk associated with no exposure.)
Exposure group
Major congenital
anomalies (N)
Incidence (95%
confidence interval)
Unadjusted Risk
Difference (95%
confidence interval)
Regression adjusted
Risk Difference (95%
confidence interval)
No exposure (n 5 107,320) 3,369 3.14 (3.04–3.25)
SRI’s only (n 5 2,625) 75 2.86 (2.29–3.57) 0.28 (0.86–0.43) 0.61 (1.44–0.21)
Benzodiazepines only (n 5 968) 31 3.20 (2.27–4.51) 0.06 (0.88–1.37) 0.41 (1.51–0.69)
SRI’s 1 benzodiazepines (n 5 359) 20 5.57 (3.63–8.45) 2.43 (0.495.31) 1.65 (0.49–3.79)
Table 2b
Cardiovascular Congenital Defects
Exposure group
Cardiovascular
defect (N)
Incidence (95%
confidence interval)
Unadjusted Risk
Difference (95%
confidence interval)
Regression adjusted
Risk Difference (95%
confidence interval)
No exposure (n 5 107,320) 512 0.48 (0.44–0.52)
SRI’s only (n 5 2,625) 17 0.65 (0.40–1.03) 0.17 (0.08–0.56) 0.21 (0.14–0.56)
Benzodiazepines only (n 5 968) 5 0.52 (0.22–1.20) 0.04 (0.26–0.73) 0.13 (0.55 to 0.29)
SRI’s1benzodiazepines (n 5 359) 6 1.67 (0.77–3.60) 1.19 (0.293.12) 1.18 (0.182.18)
Table 2c
Ventricular Septal Defects (VSD)
Exposure group VSD (N)
Incidence (95%
confidence interval)
Unadjusted Risk
Difference (95%
confidence interval)
Regression adjusted
Risk Difference (95%
confidence interval)
No exposure (n 5 107,320) 219 0.20 (0.19–0.25)
SRI’s only (n 5 2,625) 6 0.23 (0.13–0.55) 0.02 (0.09–0.33) 0.10 (0.12–0.33)
Benzodiazepines only (n 5 968) 3 0.31 (0.11–0.91) 0.11 (0.11–0.69) 0.05 (0.26–0.36)
SRI’s 1 benzodiazepines (n 5 359) 2 0.56 (0.15–2.01) 0.35 (0.07–1.09) 0.35 (0.26–0.96)
Table 2d
Atrial Septal Defects (ASD)
Exposure group ASD (N)
Incidence (95%
confidence interval)
Unadjusted Risk
Difference (95%
confidence interval)
Regression adjusted
Risk Difference (95%
confidence interval)
No exposure (n 5 107,320) 75 0.07 (0.06–0.09)
SRI’s only (n 5 2,625) 6 0.23 (0.10–0.50) 0.16 (0.030.43) .21 (0.05–0.36)
Benzodiazepines only (n 5 968) 1 0.10 (0.02–0.58) 0.03 (0.05–0.51) 0.02
(0.16–0.20)
SRI’s 1 benzodiazepines (n 5 359) 0 0.00 (0.00–1.06) 0.07 (0. 09–0.99) 0.01 (0.31–0. 30)
Notes to Tables 2a–d:
Major congenital anomalies refers to ICD9 codes from 740 to 759 excluding minor anomalies (743.6, 744.1, 744.2–744.4, 744.8, 744.9,
747.0, 747.5, 750.0, 752.4, 752.5, 754.6, 755.0, 755.1, 757.2–757.6, 757.8, 757.9, 758.4).
Cardiovascular congenital defects refers to ICD9 codes from 745 to 747 excluding 747.0 patent ductus arteriosus and 747.5 Absence or
hypoplasia of umbilical artery.
VSD refers to ICD9 code 745.4.
ASD refers to ICD9 code 745.5.
Table excludes pregnancies with exposure to an anticonvulsant during the first trimester (357 observations) and pregnancies with
exposure to both SRI & BZ in the first trimester, but not at the same time (35 observations).
Regression analysis controls for characteristics listed in Table 1, diseases and complications of pregnancy diagnosed more than 60
days before birth, depression in the first trimester and a dummy variable indicating that the mother filled a prescription after she knew
that she was pregnant. Sample includes 7,883 depressed, not medicated mothers, N 5 119,155.
We report results from the weighted least squares regression analysis. We repeated the analysis using logistic regression analysis. The
conclusions regarding statistical significance were unaffected. The OR for cardiovascular congenital defects for SRI1BZ was 3.077 95%
CI (1.22–7.78).
72 OBERLANDER ET AL.
Birth Defects Research (Part B) 83:68–76, 2008
Table 3a
SRI Monotherapy Major Congenital Anomalies (incidence, 95% CI and RD compared with risk associated with no
exposure.)
Exposure group
Major congenital
anomalies (N)
Incidence (95%
confidence interval)
Unadjusted Risk
Difference (95%
confidence interval)
Regression adjusted
Risk Difference (95%
confidence interval)
No exposure (n 5 107,320) 3,369 3.14 (3.04–3.25)
Citalopram (n 5 101) 4 3.96 (1.55–9.74) 0.82 (1.59–6.61) 0.40 (3.13–3.93)
Fluoxetine (n 5 638) 21 3.29 (2.16–4.98) 0.15 (0.98–1.84) 0.26 (1.68–1.17)
Fluvoxamine (n 5 119) 2 1.68 (0.46–5.92) 1.46 (2.68–2.78) 1.52 (4.02–0.98)
Paroxetine (n 5 993) 29 2.92 (2.04–4.16) 0.22 (1.10–2.49) 0.56 (1.70–0.59)
Sertraline (n 5 608) 19 3.13 (2.01–4.83) 0.01 (1.13–1.69) 0.41 (1.84–1.02)
Venlafaxine (n 5 250) 6 2.40 (1.10–5.14) 0.74 (2.04–2.00) 1.18 (3.20–0.84)
Table 3b
SRI Monotherapy Cardiovascular Congenital Defects
Exposure group
Major congenital
anomalies (N)
Incidence (95%
confidence interval)
Unadjusted Risk
Difference (95%
confidence interval)
Regression adjusted
Risk Difference (95%
confidence interval)
No exposure (n 5 107,320) 512 0.48 (0.44–0.52)
Citalopram (n 5 101) 3* 2.97 (1.02–8.37) 2.49 (0.547.89) 2.28 (0.194.36)
Fluoxetine (n 5 638) 5 0.78 (0.34–1.82) 0.31 (0.14–1.35) 0.08 (0.54–0.70)
Fluvoxamine (n 5 119) 0 0.00 (0.00–3.13) 0.48 (0.52–2.65) 0.55 (1.45–0.36)
Paroxetine (n 5 993) 7 0.70 (0.34–1.45) 0.23 (0.14–0.97) 0.12 (0.38–0.62)
Sertraline (n 5 608) 3 0.49 (0.17–1.44) 0.02 (0.31–0.96) 0.09 (0.65–0.47)
Venlafaxine (n 5 250) 1 0.40 (0.07–2.23) 0.08 (0.41–1.75) 0.01 (0.77–0.79)
*CHD for infants with citalopram exposure: Infant 1: 745.4 Ventricular septal defect. Infant 2: 747.0 Patent ductus arteriosus; 745.5
Ostium secundum type atrial septal defect; 746.8 Other specified anomalies of heart; 746.6 Congenital mitral insufficiency. Infant 3: 745.5
Ostium secundum type atrial septal defect; 745.4 Ventricular septal defect.
Table 3c
Individual SRI1BZ Major Congenital Anomalies (incidence, 95% CI and RD compared with risk associated
with no exposure.)
Exposure group
Major congenital
anomalies (N)
Incidence (95%
confidence interval)
Unadjusted Risk
Difference (95%
confidence interval)
Regression adjusted
Risk Difference (95%
confidence interval)
No exposure (n 5 107,320) 3,369 3.14 (3.04–3.25))
Citalopram (n 5 25) 1 4.00 (0.71–19.54) 0.86 (2.43–16.41) 1.78 (8.24–4.67)
Fluoxetine (n 5 81) 7 8.64 (4.25–16.78) 5.50 (1.1113.64) 5.18 (0.3010.07)
Fluvoxamine (n 5 25) 2 8.00 (2.22–24.97) 4.86 (0.92–21.83) 4.84 (3.67–13.35)
Paroxetine (n 5 141) 7 4.96 (2.43–9.89) 1.83 (.72–7.75) 0.98 (2.30–4.26)
Sertraline (n 5 84) 4 4.76 (1.87–11.61) 1.62 (1.27%–8.48) 1.11 (3.03–5.25)
Venlafaxine (n 5 38) 1 2.63 (0.47–13.50) 0.51 (2.68–10.36) 0.46 (5.39–4.47)
Table 3d
Individual SRI1BZ Cardiovascular Congenital Defects
Exposure group
Major congenital
anomalies (N)
Incidence (95%
confidence interval)
Unadjusted Risk
Difference (95%
confidence interval)
Regression adjusted
Risk Difference (95%
confidence interval)
No exposure (n 5 107,320) 512 0.48 (0.44–0.52)
Citalopram (n 5 25) 0 0.00 (0.00–13.32) 0.48 (0.52–12.84) 0.89 (3.00–1.22)
Fluoxetine (n 5 81) 2 2.47 (0.68–8.56) 1.99 (0.208.09) 1.94 (0.30–4.18)
Fluvoxamine (n 5 25) 0 0.00 (0.00–13.32) 0.48 (0.52–12.84) 0.63 (2.62–1.36)
Paroxetine (n 5 141) 2 1.42 (0.39–5.02) 0.94 (0.09–4.55) 0.70 (0.79–2.19)
Sertraline (n 5 84) 1 1.19 (0.21–6.44) 0.71 (0.27–5.96) 0.82 (0.95–2.58)
Venlafaxine (n 5 38) 1 2.63 (0.47–13.50) 2.15 (0.01–13.02) 1.90 (1.41–5.22)
This table is based on the 3,423 mothers who, in the first 90 days of pregnancy, had been exposed to an antidepressant but had not been
exposed to an anticonvulsant, antipsychotic or benzodiazepine.
73PRENATAL EXPOSURE TO SRIs AND BZs
Birth Defects Research (Part B) 83:68–76, 2008
Sensitivity Analysis
The conclusions were unaffected by any of the
sensitivity analyses with one notable exception. The
increased risk associated with citalopram monotherapy
did not remain statistically significant when we
restricted exposure to the period of organogenesis.
DISCUSSION
When SRIs were used in combination with a BZ, risk
for CA and CHD increased over risks associated with no
exposure. However, when controlling for maternal illness
characteristics, using a weighted regression model, only
an increased risk for CHD remained. With the exception
of an increased risk for CHDs following citalopram
exposure, monotherapy SRI or BZ exposure was not
associated with an overall increased risk for CA or CHD.
Risk for major congenital anomalies was not associated
with the dose of medication used per day during the first
trimester, even controlling for length of first trimester
medication use. SRI1BZ exposure increased the risk for
CA when the exposure included fluoxetine. However, the
numbers of fluoxetine1 BZ with a CA and citalopram-
exposed neonates with a CHD were very small (n 5 7
and n 5 3, respectively). Moreover, given that the
majority of VSDs and ASDs are frequently considered
clinically insignificant (Hoffman et al., 2002), the clinical
relevance of these anomalies (Table 3b) could not be
determined, nor could we attribute a causal relationship
between these exposures and these anomalies.
A surveillance or diagnostic bias associated with prenatal
mental maternal mental illness, SRI and BZ treatment
leading to an increased observation of these anomalies
could not be ruled out. SRIs have been associated with
increased admission to special care nurseries and an
increased risk for all investigations (i.e., clinical exams,
cardiac echocardiograms etc) inherent to care in that
setting. Importantly, the risk for major congenital
anomalies associated with exposure to
depressed maternal mood alone was not significantly
different from no exposure.
Comparing our findings with previously reported
outcomes remains confusing and contradictory due to
multiple study designs, outcomes, drug exposures, and
the impact of maternal illness itself. Some population-
based studies have reported an increased risk for
omphalocele and craniosynostosis following paroxetine
exposure (Alwan et al., 2007), while others found no
increase in risk for congenital malformations (Ericson
et al., 1999; Simon et al., 2002). An increased risk for
ventricular and atrial septal defects was reported by
Ka
¨
lle
´
n et al. (2007) using population level data following
paroxetine exposure. Furthermore, using a case control
study design (Louik et al., 2007) and unpublished
propriety industry surveillance data (GlaxoSmithKline,
2006) indicate that first trimester paroxetine exposure
increases the risk for congenital malformations and
cardiac defects (OR 1.82; 95% CI 1.17–2.82). However,
when controlling for other exposures, an increased
risk for cardiovascular malformations was not observed
(OR 1.54, 95% CI 0.81–2.92) (GlaxoSmithKline, 2006).
In contrast to previous reports (Berard et al., 2007;
GlaxoSmithKline, 2006; Wogelius et al., 2006), we
specifically sought to advance our understanding
of the teratogenic risk associated with prenatal SRI
exposure by distinguishing risk differences between SRI
1BZ poly-drug exposure and no exposure, accounting
for rare outcomes in large data sets and control for
the impact of maternal illness characteristics that could
have also influenced neonatal risk. Our study found
that the risk for cardiac anomalies increasedwhen SRIs
were used in combination with a benzodiazepine
medication, even when controlling for maternal age,
illness, and income, beyond the risk associated
with mono-drug exposure. Such findings might reflect
a poly-drug interaction (competitive inhibition) and a
possible pharmacological mechanism associated with the
increased risk. SRI monotherapy exposure was only
associated with an increasedfor atrial septal defects.poly-
drug-associated risk was also higher than the risk
associated with exposure to depressed maternal
mood alone. Finally, using regression models, including
length of prenataltrimester exposure, we were not able to
identify an increased risk associated with an increased
SRI dose/day.
From the outset, we were aware that we needed to
overcome a number of key methodological limitations
that have faced previous work in this field. These
included the risk for mis-reporting confidence intervals
inherent to studies of very rare events in large popula-
tions, the variety and overlap between neonatal diag-
nostic outcomes, imprecision on length and timing of 1st
trimester exposure, and the impact of maternal illness
itself. To deal with these challenges, we applied the
following strategies: First, to obtain measures of timing
and duration of 1st trimester SRIs and benzodiazepines
exposure, we used the date of the LMP and the actual
date on which the drugs were dispensed. Second, using
ICD9 diagnostic codes, we were able to define mutually
exclusive neonatal outcomes for major anomalies. Third,
because these anomalies occur very rarely, even in large
populations, we report risk differences and confidence
intervals using Newcombe’s and Altman’s methods
rather than reporting odds ratios and p values produced
by standard statistical approaches. Fourth, given that
maternal illness itself may carry a risk for anomalies but
that key aspects of maternal health can not be directly
assessed using population level health data, we used
characteristics of maternal illness severity (i.e., times
visiting a psychiatrist in the year before LMP, number of
times receiving a diagnosis of depression in the year
before LMP, etc.) in a regression model to assess whether
maternal illness severity was also associated with
increased risk for anomalies. Finally, given that risk
may be associated with increased 1st trimester dose, but
that inherent to SRI and BZ dose is length of exposure,
we also examined the impact of dose accounting for
duration of exposure and maternal illness severity.
The increased risk associated with poly-drug exposure
was not altogether unexpected. Benzodiazepines have
been used to manage anxiety during pregnancy and have
been associated with cleft palate, musculoskeletal ab-
normalities, and cardiovascular abnormalities (ASD)
(Iqbal et al., 2002), though results have not been
consistent (Tikkanen and Heinonen, 1992; Zierler Roth-
man, 1985) and typically benzodiazepines are not
considered teratogenic. As well, multi-drug interactions
or increased maternal plasma concentrations resulting
from combinations of clonazepam and phenobarbital
74 OBERLANDER ET AL.
Birth Defects Research (Part B) 83:68–76, 2008
have been associated with increased risk for congenital
heart disease and hip dislocation (Czeizel et al., 1992).
The increased risk for anomalies observed with SRI1 BZ
exposure suggests similar mechanisms might account for
increased risk with poly-drug exposures.
Previously, we observed significantly increased parox-
etine levels in neonates of mothers treated with SRI
medication and the benzodiazepine clonazapine (Ober-
lander et al., 2004), findings that may have reflected
competitive inhibition of the hepatic metabolic isoezyme,
CYP3A4. These findings also raise the question of
whether such increased SRI drug levels may increase
risk for congenital anomalies associated with poly-drug
exposure where pharmacological factors may lead to
increased drug levels and associated neonatal risk.
During gestation, serotonin and related receptors play
key roles as trophic factors in the development of the
monoamine-dependent cardiac structures and functions
(Nebigil and Maroteaux, 2001). It is conceivable that
changing prenatal intrasynaptic levels of serotonin by
altering drug levels, could change this trophic role,
leading to an increased risk for congenital anomalies and
cardiac malformations (Nebigil et al., 2001). Moreover,
multi-drug interactions may lead to increased drug levels
secondary to a competitive inhibition for common
metabolic pathways shared by both SRIs and BZs.
Moreover, increased parent drug or metabolite levels,
or the generation of reactive intermediates, are all
possible mechanisms. Increased maternal 3rd trimester
and delivery paroxetine plasma levels have also been
reported following the use of this SRI with the
benzodiazepine clonazepam (Oberlander et al., 2004);
this may reflect competitive inhibition of the hepatic
CYP450 3A4 isoenzyme that metabolizes both medica-
tions. Other examples of pertinent drug-drug interac-
tions include increased plasma concentrations of
alprazolam and diazepam by fluvoxamine, and increased
serum concentrations of lorazepam by valproic acid
(Hemeryck and Belpaire, 2002; Perucca, 2002).
A number of limitations associated with the use of
administrative health data need to be mentioned. While
our data set was able to identify the congenital anomalies
diagnosed, we were not able to verify the exact time at
which the diagnosis was made or whether it was verified
by echocardiogram evaluations or other imaging tests.
The incidence of congenital anomalies and CHD in our
population is consistent with other reports, though there
are substantial variations depending on the severity
of the anomaly and population studied. The occurrence
of CHDs between studies ranges from 4/1,000–50/1,000
with the incidence of moderate to severe forms at about
6/1,000 (Hoffman and Kaplan, 2002). Isolated VSDs
vary from 2 to 5% (Roguin et al., 1995) and ASDs range
from 0.03–0.1% (mean 0.09%) (Hoffman and Kaplan,
2002). The clinical significance or severity of the anomaly
could not be verified in our current study and many
VSDs and ASDs are minor and resolve without
any clinical sequeala (Hoffman and Kaplan, 2002). While
we attempted to control for maternal health (i.e.,
diabetes, etc.) and severity of illness, which could
have potentially contributed to congenital anomalies,
the use of tobacco and alcohol during pregnancy or
maternal weight gain, illicit drug use, or maternal parity
could not be directly studied with these administrative
data sets.
Using population-based linked health cohort data, we
report an increased risk for cardiac malformations when
first trimester SRIs medication use was combined with
benzodiazepines. The risk associated with SRI mono-
therapy did not increase beyond exposure to depression
or no drug/no depression. Risk for anomalies in SRI
monotherapy was not associated with maternal doses/
day, maternal age, nor measures of illness severity. These
results highlight the importance of considering the
competitive interactions or toxicity associated with
poly-psychotropic drug exposure. While poly-drug ex-
posure increased the risk for all anomalies, the risk
associated with combined exposures remained very low
and the clinical significance of the anomalies remains to
be determined. Moreover, the added risk associated with
SRI medication exposure should be evaluated in the
context of depressed maternal mood during pregnancy.
The identification and treatment of depression during
pregnancy is an urgent health care concern for mothers,
their families, and health care professionals. Antenatal
depression is by itself a risk factor for maternal and fetal/
neonatal health that might require pharmacological
management and these findings only highlight one
aspect of the risks associated with medical management
of perinatal depression. None of these findings should
diminish the urgency to identify and manage maternal
mental illness during pregnancy. This decision should be
made by an informed patient with her physician
as risk needs to be assessed on a case-by-case basis
(Wisner et al., 1999).
ACKNOWLEDGMENTS
The researchers gratefully acknowledge funding from
the BC Ministry of Children and Family Development
through the Human Early Learning Partnership. The
authors also acknowledge the financial support of The
Michael Smith Foundation for Health Research. T.F.O. is
supported by a HELP Senior Career Award and is the R.
Howard Webster professor in Child Development (UBC,
Faculty of Graduate Studies). We are also grateful to
Colleen Fitzgerald for her administrative help and to
Ursula Brain and Tracey Weir for their editorial com-
ments. The views presented in the article are solely those
of the authors and do not represent the policy of HELP or
the Province of British Columbia. Dr. Oberlander has had
full access to all of the data in the study and takes
responsibility for the integrity of the data and the
accuracy of the data analysis. None of the authors has a
conflict of interest with these data or our findings. As the
corresponding author, I have had full access to all the
data in the study and had final responsibility for the
decision to submit for publication (T.F.O.).
REFERENCES
A
˚
kerblad AC, Bengtsson F, Ekselius L, von Knorring L. 2003. Effects of an
educational compliance enhancement programme and therapeutic
drug monitoring on treatment adherence in depressed patients
managed by general practitioners. Int Clin Psychopharmacol 18:
347–354.
Altshuler LL, Cohen L, Szuba MP, Burt VK, Gitlin M, Mintz J. 1996.
Pharmacologic management of psychiatric illness during pregnancy:
dilemmas and guidelines. Am J Psychiatry 153:592–606.
Alwan S, Reefhuis J, Rasmussen SA, Olney RS, Friedman JM. 2007. Use of
selective serotonin-reuptake inhibitors in pregnancy and the risk of
birth defects. N Engl J Med 356:2684–2692.
75PRENATAL EXPOSURE TO SRIs AND BZs
Birth Defects Research (Part B) 83:68–76, 2008
Berard A, Ramos E, Rey E, Blais L, St-Andre M, Oraichi D. 2007. First
trimester exposure to paroxetine and risk of cardiac malformations in
infants: the importance of dosage. Birth Defects Res B Dev Reprod
Toxicol 80:18–27.
Chamberlayne R, Green B, Barer ML, Hertzman C, Lawrence WJ,
Sheps SB. 1998. Creating a population-based linked health database:
a new resource for health services research. Can J Public Health
89:270–273.
Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones KL. 1996. Birth
outcomes in pregnant women taking fluoxetine. New Engl J Med
335:1010–1015.
Czeizel AE, Bod M, Halasz P. 1992. Evaluation of anticonvulsant drugs
during pregnancy in a population-based Hungarian study. Eur J
Epidemiol 8:122–127.
Davies HT, Crombie IK, Tavakoli M. 1998. When can odds ratios mislead?
BMJ 316:989–991.
Diav-Citrin O, Shechtman S, Weinbaum D, Arnon J, di Gianantonio E,
Clementi M, Ornoy A. 2005. Paroxetine and fluoxetine in pregnancy:
a multicenter, prospective, controlled study. Reprod Toxicol 20:459.
Einarson TR, Einarson A. 2005. Newer antidepressants in pregnancy and
rates of major malformations: a meta-analysis of prospective
comparative studies. Pharmacoepidemiol Drug Saf 14:823–827.
Ericson A, Ka
¨
lle
´
n B, Wiholm BE. 1999. Delivery outcome after the use of
antidepressants in early pregnancy. Eur J Clin Pharmacol 55:503–508.
GlaxoSmithKline. 2006. Clinical trail register. http://ctr gsk co uk/
welcome asp.
Health Canada advises of potential adverse effects of SSRIs and other
anti-depressants on newborns. 2004. http://www.hc-sc.gc.ca/eng-
lish/protection/warnings/2004/2004_44.htm 7-9-2004. http://
www.hc-sc.gc.ca/english/protection/warnings/2004/2004_44.htm.
Hemeryck A, Belpaire FM. 2002. Selective serotonin reuptake inhibitors
and cytochrome P-450 mediated drug-drug interactions: an update.
Curr Drug Metab 3:13–37.
Hendrick V, Smith LM, Suri R, Hwang S, Haynes D, Altshuler L. 2003.
Birth outcomes after prenatal exposure to antidepressant medication.
Am J Obstet Gynecol 188:812–815.
Hines RN, Adams J, Buck GM, Faber W, Holson JF, Jacobson SW, Keszler
M, McMartin K, Segraves RT, Singer LT, Sipes IG, Williams PL. 2004.
NTP-CERHR Expert Panel Report on the reproductive and devel-
opmental toxicity of fluoxetine. Birth Defects Res B Dev Reprod
Toxicol 71:193–280.
Hoffman JIE, Kaplan S. 2002. The incidence of congenital heart disease.
J Am Coll Cardiol 39:1890–1900.
Iqbal MM, Sobhan T, Ryals T. 2002. Effects of commonly used
benzodiazepines on the fetus, the neonate, and the nursing infant.
Psychiatr Serv 53:39–49.
Ka
¨
lle
´
n BA, Otterblad Olausson P. 2007. Maternal use of selective
serotonin re-uptake inhibitors in early pregnancy and infant
congenital malformations. Birth Defects Res A Clin Mol Teratol
79:301–308.
Kraemer HC, Measelle JR, Ablow JC, Essex MJ, Boyce WT, Kupfer DJ.
2003. A new approach to integrating data from multiple informants
in psychiatric assessment and research: mixing and matching
contexts and perspectives. Am J Psychiatry 160:1566–1577.
Louik C, Lin AE, Werler MM, Hernandez-Diaz S, Mitchell AA. 2007.
First-trimester use of selective serotonin-reuptake inhibitors and the
risk of birth defects. N Engl J Med 356:2675–2683.
Malm H, Klaukka T, Neuvonen PJ. 2005. Risks associated with selective
serotonin reuptake inhibitors in pregnancy. Obstet Gynecol 106:
1289–1296.
National Centre for Health Statistics. 2006. International classification of
Diseases, ninth revision, clinical modification (ICD-9-CM). http://
www cdc gov/nchs/about/otheract/icd9/abticd9.htm.
Nebigil CG, Maroteaux L. 2001. A novel role for serotonin in heart. Trends
Cardiovasc Med 11:329-335.
Nebigil CG, Hickel P, Messaddeq N, Vonesch JL, Douchet MP, Monassier
L, Gyorgy K, Matz R, Andriantsitohaina R, Manivet P, Launay JM,
Maroteaux L. 2001. Ablation of serotonin 5-HT(2B) receptors in mice
leads to abnormal cardiac structure and function. Circulation
103:2973–2979.
Newcombe RG. 1998. Interval estimation for the difference between
independent proportions: comparison of eleven methods. Stat Med
17:873–890.
Newcombe RG, Altman DG. 2000. Proportions and their differences. In:
Altman DG, Machin M, Bryant D, and Gardner TN, editors. Statistics
with confidence. Bristol, UK: British Medical Journal Books. p 45–56.
Oberlander TF, Misri S, Fitzgerald CE, Kostaras X, Rurak D, Riggs W.
2004. Pharmacologic factors associated with transient neonatal
symptoms following prenatal psychotropic medication exposure.
J Clin Psychiatry 65:230–237.
Oberlander TF, Warburton W, Misri S, Aghajanian J, Hertzman C. 2006.
Neonatal outcomes after prenatal exposure to selective serotonin
reuptake inhibitor antidepressants and maternal depression using
population-based linked health data. Arch Gen Psychiatry 63:898–906.
Perucca E. 2002. Pharmacological and therapeutic properties of valproate: a
summary after 35 years of clinical experience. CNS Drugs 16:695–714.
Reis M, A
˚
berg-Wistedt H, A
˚
gren AC, A
˚
kerblad AC, Bengtsson F. 2004.
Compliance with SSRI medication during 6 months of treatment for
major depression: an evaluation by determination of repeated serum
drug concentrations. J Affect Disord 82:443–446.
Roguin N, Du ZD, Barak M, Nasser N, Hershkowitz S, Milgram E. 1995.
High prevalence of muscular ventricular septal-defect in neonates.
J Am Coll Cardiol 26:1545–1548.
Simon GE, Cunningham ML, Davis RL. 2002. Outcomes of prenatal
antidepressant exposure. Am J Psychiatry 159:2055–2061.
STATA SE10. 2006 http://www stata com.
Teleplan Record Specifications version 4.0. 2004. http://
www.hlth.gov.bc.ca/msp/infoprac/teleplanspecs/ch1.pdf, page 27.
http://www hlth gov bc ca/msp/infoprac/teleplanspecs/ch1 pdf,
page 27.
Tikkanen J, Heinonen OP. 1992. Risk-factors for conal malformations of
the heart. Eur J Epidemiol 8:48–57.
US Food and Drug Administration.Medwatch. 2005 http://www fda
gov/medwatch/safety/2005/safety05 htmxPaxil2.
Wisner KL, Gelenberg AJ, Leonard H, Zarin D, Frank E. 1999.
Pharmacologic treatment of depression during pregnancy. JAMA
282:1264–1269.
Wogelius P, Norgaard M, Gislum M, Pedersen L, Munk E, Mortensen PB,
Lipworth L, S^rensen HT. 2006. Maternal use of selective serotonin
reuptake inhibitors and risk of congenital malformations. Epidemiol-
ogy 17:701–704.
Zierler S, Rothman KJ. 1985. Congenital heart disease in relation to
maternal use of Bendectin and other drugs in early pregnancy.
N Engl J Med 313:347–352.
76 OBERLANDER ET AL.
Birth Defects Research (Part B) 83:68–76, 2008
    • "The same study, along with several other population-based studies, reported a specific association between prenatal sertraline exposure and septal heart defects [25, 28, 30, 32]. However, in other well-powered studies, including the NBDPS case–control study [31, 45], and several cohort studies [21, 24, 26, 27, 29, 48] , no association was noted with septal defects following maternal sertraline treatment in early pregnancy. It is important to note that, unlike in other studies, the diagnoses in the Danish study [28] were taken from hospital discharge registers, which may have led to differential increased ascertainment if SSRI-exposed infants were more often transferred to neonatal intensive care units and therefore could have been evaluated more intensely. "
    [Show abstract] [Hide abstract] ABSTRACT: Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressant medications worldwide. However, over the past decade, their use during pregnancy, a period of extreme vulnerability to the onset of depression, has become highly concerning to patients and their healthcare providers in terms of safety to the developing fetus. Exposure to SSRIs in pregnancy has been associated with miscarriage, premature delivery, neonatal complications, birth defects-specifically cardiac defects-and, more recently, neurodevelopmental disorders in childhood, specifically autism spectrum disorders. Studies addressing the effect of individual SSRIs indicate a small but higher risk for birth defects with maternal fluoxetine and paroxetine use. Though the excess in absolute risk is small, it may still be of concern to some patients. Meanwhile, antenatal depression itself is associated with adverse perinatal outcomes, and discontinuing antidepressant treatment during pregnancy is associated with a high risk of relapse of depression. Whether the observed adverse fetal effects are related to the mother's medication use or her underlying maternal illness remains difficult to determine. It is important that every pregnant woman being treated with an SSRI (or considering such treatment) carefully weighs the risks of treatment against the risk of untreated depression for both herself and her child. The importance of recognizing a higher risk for the development of adverse outcomes lies in the potential for surveillance and possibly a timely intervention. Therefore, we recommend that pregnant women exposed to any SSRI in early pregnancy be offered options for prenatal diagnosis through ultrasound examinations and fetal echocardiography to detect the presence of birth defects. Tapering off or switching to other therapy in early pregnancy, if appropriate for the individual, may also be considered on a case-by-case basis.
    Full-text · Article · May 2016
    • "Nordic countries including 2763 exposed first-trimester pregnancies [10]. The remaining studies are from the Czech Republic (10 exposed) [23] and Canada (413 exposed) [24,25]. In summary, we identified 3186 exposed infants of whom 107 were born with major malformations, resulting in a malformation rate of 3.36%. "
    [Show abstract] [Hide abstract] ABSTRACT: Major depressive disorder is common among women in childbearing age, and medical treatment is subject to substantial discussions and controversies. For Selective Serotonin Reuptake Inhibitors, SSRIs, a vast amount of data is available. For the newer antidepressant group of serotonin and noradrenaline reuptake inhibitors, SNRIs, significantly less data are available. Following the PRISMA guideline for systematic reviews, we performed a systematic search on the risk of major congenital malformations after first-trimester in utero exposure to venlafaxine or duloxetine. We identified 8 cohort studies reporting on the outcome upon in utero exposure to venlafaxine or
    Full-text · Article · Oct 2015
    • "Maternal exposure to any SSRI were found to be associated with a two-fold increase in the risk of CHD overall (AOR 2.01 (95% CI 1.60-2.53)). Several studies from other countries have also suggested an association between maternal SSRI-use and CHD, but the results regarding specific types of SSRIs are conflicting121314151617181920212223. In our study, the overall risk estimate for CHD was close to unity and not statistically significant, but for severe CHD the risk estimate was high and statistically significant (4.03 (1.75-9.26)). "
    [Show abstract] [Hide abstract] ABSTRACT: Background Previous studies suggest a possible association between maternal use of selective serotonin-reuptake inhibitors (SSRIs) during early pregnancy and congenital heart defects (CHD). The purpose of this study was to verify this association by using validated data from the Danish EUROCAT Register, and secondary, to investigate whether the risk differs between various socioeconomic groups. Methods We conducted a cohort study based on Danish administrative register data linked with the Danish EUROCAT Register, which includes all CHD diagnosed in live births, fetal deaths and in pregnancies terminated due to congenital anomalies. The study population consisted of all registered pregnancies (n = 72,280) in Funen, Denmark in the period 1995–2008. SSRI-use was assessed using The Danish National Prescription Registry, information on marital status, maternal educational level, income, and country of origin from Statistics Denmark was used as indicators of socioeconomic situation, and the CHD were studied in subgroups defined by EUROCAT. Logistic Regression was used to investigate the association between redeemed prescriptions for SSRIs and CHD. Results The risk of severe CHD in the offspring of the 845 pregnant women who used SSRIs during first trimester increased four times (AOR 4.03 (95% CI 1.75-9.26)). We found no increased risk of septal defects. Socioeconomic position did not modify the association between maternal SSRI-use during pregnancy and severe CHD. Conclusion This study, which is based on data with high case ascertainment, suggests that maternal use of SSRIs during first trimester increases the risk of severe CHD, but does not support findings from previous studies, based on administrative register data, regarding an increased risk of septal defects. The study was unable to document an interaction between socioeconomic status and maternal SSRI-use on the risk of severe CHD.
    Full-text · Article · Sep 2014
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