<div>Antidepressants are not safe during pregnancy and in women of child
bearing age.</div><div>Alain Braillon (1), Susan Bewley(2), Aubrey Blumsohn(3), Florian Naudet
(4) Jean-Louis Montastruc(5), Joel R Lexchin(6)</div><div>(1) Previously senior consultant, Amiens, France
braillon.alain@gmail.com</div><div>(2) Department of Women &amp; Children’s Health, King’s College London,
London, UK</div><div>(3) Previously Senior Lecturer in Medicine, University of Sheffield,
Sheffield, UK</div><div>(4) University of Rennes 1, Rennes, France Clinical Investigation Center
(INSERM 1414) and Adult Psychiatry Department, Rennes University
Hospital, Rennes, France</div><div>(5) Medical and Clinical Pharmacology, University Hospital-Faculty of
Medicine, Toulouse, France</div><div>(6) School of Health Policy and Management Faculty of Health, York
University, Toronto, Ontario, Canada</div><div>Correspondance</div><div>Alain Braillon, 27 rue Voiture, 80000 Amiens, France.
braillon.alain@gmail.com</div><div>757 w + 9 ref. (Limit 800 words + 10 references)</div><div>Keywords: risk minimization measures; drug safety; serotonin reuptake
inhibitors; teratogenicity; developmental disorders; post-partum
hemorrhage; EBM</div><div>No funding</div><div>CoI: Alain Braillon, JL and SB are among industry independent experts on
Jeanne Lenzer’s list
(https://jeannelenzer.com/list-independent-experts). SB chairs
Healthwatch, a charity promoting science and integrity in healthcare
(https://www.healthwatch-uk.org/) and her interests are declared
at https://www.whopaysthisdoctor.org/doctor/58/active. JL received
payments for writing a brief in an action for side effects of a drug for
Michael F. Smith, Lawyer and a second brief on the role of promotion in
generating prescriptions for Goodmans LLP in 2017-2020. He is a member
of the Foundation Board of Health Action International. He receives
royalties from University of Toronto Press and James Lorimer &amp; Co. Ltd.
for books he has written.</div><div>Cabaillot and colleagues’ pharmaco-epidemiological study of
antidepressants use during pregnancy in France raises a number of
questions about the validity of their conclusions.(1)</div><div>Firstly, what is their basis for making the claim that “[selective
serotonin-norepinephrine reuptake inhibitors] appear to be safe in
pregnant women”?(1) This claim ignores significant evidence to the
contrary:</div><div>a) the odds ratio for maternal use of serotonin reuptake inhibitor
antidepressants (SRIs) (we use SRI to refer to both
serotonin-norepinephrine reuptake inhibitors and so-called ‘selective’
serotonin reuptake inhibitors as selectivity is restricted to the
experimental setting) during the first trimester of pregnancy and the
presence of congenital heart defects is 1.57 (95% CI 1.25–1.97) for
paroxetine, 1.36 (95% CI 1.08–1.72) for fluoxetine and 1.29 (95% CI
1.14–1.45) for sertraline.(2) Further, observational studies reported
developmental disorders that are in line with experimental studies and
with human infant MRI studies: SRIs exposure has an association with
changes in brain structure, white matter microstructure, brain
connectivity, and cerebral metabolism, particularly in brain regions
critical to emotional processing;(3)</div><div>b) previous warnings about SRIs’ harms in core clinical journals were
overlooked;(4,5)</div><div>c) post-partum hemorrhage, a serious SRI complication acknowledged by
Cabaillot and colleagues, is a very serious issue; with cardiovascular
conditions it is the most common underlying causes of pregnancy-related
death.(6)</div><div>Secondly, Cabaillot et al misrepresent the references that they cite in
their statement that “[selective serotonin-norepinephrine reuptake
inhibitors] are recommended by the National Agency for Health and
Medicines (ANSM) and the 2018 International Cochrane Review
International Publications ”?(1)</div><div>a) the link for the recommendation (ref. 19 in Cabaillot et al) does not
work and the summary of product characteristics for fluoxetine warns
“Overall, the data suggest that the risk of cardiovascular malformation
in children after maternal exposure to fluoxetine is approximately 2/100
… Fluoxetine should not be used during pregnancy unless the
clinical condition of the patient requires treatment with fluoxetine and
justifies the potential risk to the fetus”.(7)</div><div>b) the Cochrane Review (ref. 20 in Cabaillot et al) is about postnatal
depression, not pregnancy. It concluded: “Due to the limitations of the
current evidence base, such as the low statistical power of the included
studies, it is not possible to draw any clear conclusions about the
effectiveness of antidepressants for the prevention of postnatal
depression.”</div><div>Thirdly, Cabaillot and colleagues should provide data (malformations,
deprescription) according to the various classes of antidepressants and
their princeps. The risk of malformations varies among antidepressant
classes and within classes, e.g., it is highest for SRIs containing
paroxetine.(2)</div><div>Fourthly, the widespread prescribing of antidepressants in France may be
the result of France’s universal healthcare scheme consistently refusing
to reimburse effective psychotherapy. In contrast is the 2008 Improving
Access to Psychological Therapies strategy in England that provides free
and direct access to psychotherapy without barriers.(8)</div><div>Overplaying benefits and downplaying harms are not serving the patient’s
interests. All prescribers must be warned that antidepressants have not
been shown to be risk free during pregnancy, either for the woman or her
fetus. Quantitative explanation of the degree of risk expressed in
easily understood terms such as number needed to harm must be provided,
not binary assertions of apparent “safety” based on a value judgment
only women should make. The well documented harms of SRIs during
pregnancy contrast with purported benefits _a limited effectiveness of
SRIs in the general population and no controlled trials during
pregnancy. Available SRI vs placebo trials are short-term (6-8 weeks)
and although the decreases in depression scores are statistically
significant, their clinical relevance is doubtful.(9) In contrast, many
patients with depression respond to judicious ‘watchful waiting’ and
psychotherapies successfully treat most episodes of even persistent
depression. These interventions are evidence-based in real-life
settings: their benefits persist over the long term (improving
self-esteem, agency, and social functioning and, they are safe.(9)
Evidence based psychosocial interventions must be the preferred initial
option in treating depression, especially in women of child bearing age
as many pregnancies are unintended.(4)</div><div>Regulatory agencies must implement and monitor a series of risk
minimization measures for SRIs as for other teratogens: a) an assessment
of each woman’s potential to become pregnant; b) shared decision making
about the risks of antidepressant treatment in general and specifically
during pregnancy, and an explanation about the need for effective
contraception throughout treatment; c) informed pregnancy testing before
and during treatment as needed; d) a ‘risk acknowledgement form’, in
which the woman and prescriber confirm that appropriate counselling has
been given and understood. Finally, prescription of antidepressants
during pregnancy should be recorded in specific registries to closely
monitor clinical outcomes.</div><div>References</div><div>1. Cabaillot A, Bourset A, Mulliez A et al. Trajectories of
antidepressant drugs during pregnancy: A cohort study from a
community-based sample. Br J Clin Pharmacol. 2021;87(3):965-987.</div><div>doi: 10.1111/bcp.14449.</div><div>2. De Vries C, Gadzhanova S, Sykes MJ, Ward M, Roughead E. A Systematic
Review and Meta-Analysis Considering the Risk for Congenital Heart
Defects of Antidepressant Classes and Individual Antidepressants. Drug
Saf. 2020;44(3):291-312.</div><div>doi: 10.1007/s40264-020-01027-x</div><div>3. Lugo-Candelas C, Cha J, Hong S, et al. Associations Between Brain
Structure and Connectivity in Infants and Exposure to Selective
Serotonin Reuptake Inhibitors During Pregnancy. JAMA Pediatr. 2018;
172(6):525-533. doi: 10.1001/jamapediatrics.2017.5227.</div><div>4. Braillon A, Bewley S. Prescribing in pregnancy shows the weaknesses
in pharmacovigilance. BMJ. 2018;361:k2334. doi: 10.1136/bmj.k2334.</div><div>5. Braillon A, Bewley S. The easy misuse of antidepressants during
pregnancy is depressing. Br J Clin Pharmacol. 2018;84(10):2445-2446.
doi: 10.1111/bcp.13713.</div><div>6. Davis NL, MPH, Smoots AN, Goodman, DA. Pregnancy-Related Deaths: Data
from 14 U.S. Maternal Mortality Review Committees, 2008-2017. Maternal
Mortality Review Data-Brief. 2019. Available at
https://www.cdc.gov/reproductivehealth/maternal-mortality/erase-mm/MMR-Data-Brief_2019-h.pdf
Accessed 27 May 2020.</div><div>7. French National Agency for Health and Medicines (ANSM). Fluoxetine:
Summary of Product Characteristics. 3 April 2016. Available at
http://agence-prd.ansm.sante.fr/php/ecodex/rcp/R0278605.htm
Accessed 27 May 2021.</div><div>8. Thornicroft G. Improving access to psychological therapies in
England. Lancet. 2018;391(10121):636-637. doi:
10.1016/S0140-6736(17)32158-X.</div><div>9. Braillon A, Lexchin J, Noble JH, Menkes D, M’sahli L, Fierlbeck K,
Blumsohn A, Naudet F. Challenging the promotion of antidepressants for
nonsevere depression. Acta Psychiatr Scand. 2019;139(3):294-295. doi:
10.1111/acps.13010.</div>