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Selective serotonin reuptake inhibitors in pregnancy and congenital malformations: population based cohort study

BMJ 2009; 339 doi: (Published 23 September 2009) Cite this as: BMJ 2009;339:b3569

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Authors' reply

Various very important points and questions have been raised in
response to our paper; ”selective serotonin reuptake inhibitors in
pregnancy and congenital malformations: population based cohort study”

Overall, caution is warranted in causal interpretation of
observational studies if the exposure in question is potentially
confounded by unobserved factors. We may have a strong potential
association between the degree of underlying psychiatric disease and use
of antidepressant medication. We have discussed this potential confounding
by indication in the paper but this paramount limitation deserves much
attention. With this in mind we still interpret the difference between the
different SSRIs as suggestive of a drug effect but other explanations
apply, as discussed in the paper, and further studies are needed. No
randomized controlled trials are possible on most types of malformations,
due to ethical and practical considerations, so we are stuck with the
fairly foggy results from epidemiological studies. We present such data
but believe that the results, interpreted with caution in the context of
the existing literature, represent important information in the evidence-
based treatment of depression during pregnancy.

Professor Einarson raises the important point of how data is
presented in the abstract. With English as a second language we are humble
to the fact that our wording could have been more elegant. However, we
still believe the conclusion in the abstract is in line with what our data
show. The estimate of the association between any SSRI and septal heart
defects is not solely based on sertraline and citalopram but also on the
(larger) association with the more than one type of SSRI. In the latter
group some women did not use sertraline or citalopram, hence the wording
“particularly sertraline and citalopram”. We do not present the result on
paroxetine in the abstract, as the OR 0.76 was based on only one case and
we were unable to consider dose as suggested by a previous study (2).

The study is based on information on malformation coded by hospital
physicians and we used data from the first year after birth (with an
additional analyses on malformations coded up to two years after birth).
Professor Hoffman’s questions are essential in the understanding of the
nature of the heart defects. The septal heart defects were defined as
defects of either the atrial or ventricular wall (or both), excluding the
atrioventricular canal defects (3). There was no routine use of
echocardiography during the period and, because the children were born
before the warning on the use of paroxetine, we expect no increased
clinical investigation of the SSRI exposed children. Unfortunately, we
have no further information on the nature of the septal heart defects.
Regardless, even if all the defects were small we believe that the
information is important to consider. Even ASDs with no symptoms for many
years might eventually cause atrial hypertrophy and potentially pulmonary
hypertension later in life. Importantly, more severe septal heart
malformations do mandate surgical treatment but further studies with a
larger sample size are needed to disentangle the potential differences in
severity of the outcome.


1. Pedersen LH, Henriksen TB, Vestergaard M, Olsen J, Bech BH.
Selective serotonin reuptake inhibitors in pregnancy and congenital
malformations: population based cohort study. BMJ 2009;339:b3569.

2. Berard A, Ramos E, Rey E, Blais L, St-Andre M, Oraichi D. First
trimester exposure to paroxetine and risk of cardiac malformations in
infants: the importance of dosage. Birth Defects Res.B Dev.Reprod.Toxicol.

3. Louik C, Lin AE, Werler MM, Hernandez-Diaz S, Mitchell AA. First-
trimester use of selective serotonin-reuptake inhibitors and the risk of
birth defects. N.Engl.J Med. 2007;356(26):2675-83.

Competing interests:
None declared

Competing interests: No competing interests

12 November 2009
Lars H Pedersen
Research Assistant (1); Resident (2)
Tine B. Henriksen, Mogens Vestergaard, Jorn Olsen, and Bodil H. Bech
(1) Dept. Epidemiology, Aarhus University; (2) Dept. ObGyn, Aarhus University Hospital, Denmark