If more evidence were needed? SRRI use in pregnancy is a burning issue.
The in utero phase of life is a risky time and the risks of SSRIs in
early pregnancy are clear. While in this study the hazards were clearest
for citalopram and sertraline, there are other unpublished data on
paroxetine indicating it carries similar harms, supporting a class effect.
A meta-analysis of all epidemiologically robust studies of paroxetine use
in the first trimester of pregnancy, conclusively shows increased
prevalence of both cardiac malformations OR 1.46 (95% CI 1.17-1.82) and
total malformations OR 1.24 (95% CI 1.08-1.43) Figures 1 and 2. This meta-
analysis, study number WEUSRTP2280, is available on GlaxoSmithKline’s
website.1
The point about the link between spontaneous and induced abortions
and assessment of teratogenic effects is important. As the authors
suggest, one of the best signals of teratogenicity is an increased rate of
spontaneous abortions and a key reason for induced abortion is congenital
malformations. Data on SSRIs from as early as 1998 indicated problems in
this area, showing the rate of abortion (spontaneous and induced) was
nearly twice that in those who had taken SSRIs in the first trimester of
pregnancy - OR 1.7 (95% CI 1.1, 2.9).2
The statement that depression affects up to one fifth of pregnant
women is misleading in an article about pharmacotherapy. While studies
using symptom scores find a high prevalence of depressive symptoms in this
group, just as they would in medical students about to sit exams, this
does not equate to the subset of women with major depression of moderate
to serious severity in whom an antidepressant might be considered. The
point prevalence of major depression is between 3.1% and 4.9% at the end
of each trimester.3
It is time to stop fiddling. Given the limited evidence for
effectiveness and these data on potential hazards for the unborn child,
the risk benefit equation is not favourable for use of SSRIs in pregnancy.
The numbers affected are small but prescribing is widespread in the
reproductive years and the consequences devastating for families. In
contrast to the US recommendations referred to in the accompanying
editorial,4 the NICE guidelines on pharmacotherapy for depression and
anxiety in pregnancy5 are consistent with the evidence. NICE recommends
stopping SSRIs, paroxetine in particular, in pregnancy (or preferably
before) and using other treatment alternatives, recommending tricyclic
antidepressants if pharmacotherapy is unavoidable. As the difficulties of
stopping SSRIs may lead to unavoidable early exposure of the unborn child
to these drugs and the risks of birth defects and abortion, informed
consent prior to starting SSRIs in women who may contemplate future
pregnancies should cover both of these issues.
Figure 1 Cardiac Malformations with First Trimester Paroxetine Use1
Figure 2 Total Congenital Malformations with First Trimester
Paroxetine Use1
2. Kulin NA, Pastuszak A, Sage SR, Schick-Boschetto B, Spivey G,
Feldkamp M, et al. Pregnancy Outcome Following Maternal Use of the New
Selective Serotonin Reuptake Inhibitors: A Prospective Controlled
Multicenter Study. JAMA 1998;279(8):609-610.
3. Gavin NI, Gaynes BN, Lohr KN, Meltzer-Brody S, Gartlehner G, T. S.
Perinatal depression: a systematic review of prevalence and incidence.
Obstet Gynecol 2005;106(5 Pt 1):1071-83.
5. NHS National Institute for Clinical Excellence. Antenatal and
Postnatal Mental Health. Clinical Guideline: Developed by the National
Collaborating Centre for Mental Health, 2007.
Competing interests:
DM is an expert witness for the plaintiff in cases involving Paxil and birth defects. She is also principal investigator in a New Zealand Health Research Council funded RCT of SSRI cessation in primary care. She is a member of and previously on the management committee of Healthy Skepticism. She has been an invited speaker on aspects of rational prescribing at conferences, some of which were sponsored by pharmaceutical companies
Competing interests:
No competing interests
28 September 2009
Derelie Mangin
Associate Professor, Director Primary Care Research Unit
Department of Public Health and General Practice. University of Otago, Christchurch
Rapid Response:
If more evidence were needed? SRRI use in pregnancy is a burning issue.
The in utero phase of life is a risky time and the risks of SSRIs in
early pregnancy are clear. While in this study the hazards were clearest
for citalopram and sertraline, there are other unpublished data on
paroxetine indicating it carries similar harms, supporting a class effect.
A meta-analysis of all epidemiologically robust studies of paroxetine use
in the first trimester of pregnancy, conclusively shows increased
prevalence of both cardiac malformations OR 1.46 (95% CI 1.17-1.82) and
total malformations OR 1.24 (95% CI 1.08-1.43) Figures 1 and 2. This meta-
analysis, study number WEUSRTP2280, is available on GlaxoSmithKline’s
website.1
The point about the link between spontaneous and induced abortions
and assessment of teratogenic effects is important. As the authors
suggest, one of the best signals of teratogenicity is an increased rate of
spontaneous abortions and a key reason for induced abortion is congenital
malformations. Data on SSRIs from as early as 1998 indicated problems in
this area, showing the rate of abortion (spontaneous and induced) was
nearly twice that in those who had taken SSRIs in the first trimester of
pregnancy - OR 1.7 (95% CI 1.1, 2.9).2
The statement that depression affects up to one fifth of pregnant
women is misleading in an article about pharmacotherapy. While studies
using symptom scores find a high prevalence of depressive symptoms in this
group, just as they would in medical students about to sit exams, this
does not equate to the subset of women with major depression of moderate
to serious severity in whom an antidepressant might be considered. The
point prevalence of major depression is between 3.1% and 4.9% at the end
of each trimester.3
It is time to stop fiddling. Given the limited evidence for
effectiveness and these data on potential hazards for the unborn child,
the risk benefit equation is not favourable for use of SSRIs in pregnancy.
The numbers affected are small but prescribing is widespread in the
reproductive years and the consequences devastating for families. In
contrast to the US recommendations referred to in the accompanying
editorial,4 the NICE guidelines on pharmacotherapy for depression and
anxiety in pregnancy5 are consistent with the evidence. NICE recommends
stopping SSRIs, paroxetine in particular, in pregnancy (or preferably
before) and using other treatment alternatives, recommending tricyclic
antidepressants if pharmacotherapy is unavoidable. As the difficulties of
stopping SSRIs may lead to unavoidable early exposure of the unborn child
to these drugs and the risks of birth defects and abortion, informed
consent prior to starting SSRIs in women who may contemplate future
pregnancies should cover both of these issues.
Figure 1 Cardiac Malformations with First Trimester Paroxetine Use1
Figure 2 Total Congenital Malformations with First Trimester
Paroxetine Use1
1. www.gsk-clinicalstudyregister.com/files/pdf/24089.pdf last
accessed 26 September 2009.
2. Kulin NA, Pastuszak A, Sage SR, Schick-Boschetto B, Spivey G,
Feldkamp M, et al. Pregnancy Outcome Following Maternal Use of the New
Selective Serotonin Reuptake Inhibitors: A Prospective Controlled
Multicenter Study. JAMA 1998;279(8):609-610.
3. Gavin NI, Gaynes BN, Lohr KN, Meltzer-Brody S, Gartlehner G, T. S.
Perinatal depression: a systematic review of prevalence and incidence.
Obstet Gynecol 2005;106(5 Pt 1):1071-83.
4. Chambers C, Selective serotonin reuptake inhibitors and congenital
malformations. BMJ 2009; 339:b3525.
5. NHS National Institute for Clinical Excellence. Antenatal and
Postnatal Mental Health. Clinical Guideline: Developed by the National
Collaborating Centre for Mental Health, 2007.
Competing interests:
DM is an expert witness for the plaintiff in cases involving Paxil and birth defects. She is also principal investigator in a New Zealand Health Research Council funded RCT of SSRI cessation in primary care. She is a member of and previously on the management committee of Healthy Skepticism. She has been an invited speaker on aspects of rational prescribing at conferences, some of which were sponsored by pharmaceutical companies
Competing interests: No competing interests