Implications of Fetal Exposure to Selective Serotonin Reuptake Inhibitors

Invited Commentary

Invited Commentary

Neurodevelopmental Implications of Fetal Exposure

to Selective Serotonin Reuptake Inhibitors and Untreated
Maternal Depression
Weighing Relative Risks
Lee S. Cohen, MD; Ruta Nonacs, MD, PhD

The last 20 years has seen an extensive examination of relevant research questions regarding the reproductive safety of
selective serotonin reuptake inhibitors (SSRIs). These have included studies describing the risk of developing teratogenesis (overall and specific
malformations), 1 transient
neonatal adaptation synRelated article
dromes, and problems such
as persistent pulmonary hypertension of the newborn (PPHN).2
As an example of the evolution of interest in perinatal psychiatry, more than several hundred articles have been published during the last decade on the risk associated with first
trimester exposure to SSRIs during pregnancy; the vast
majority of these reports do not support a significant teratogenic risk.
Few would argue that one of the critical missing pieces of
information needed to weigh relative risks of psychotropic drug
use during pregnancy is information regarding the effect of fetal SSRI exposure and untreated depression on long-term neurodevelopmental outcomes. To date, studies regarding longterm effects of fetal exposure to SSRIs have been limited to
relatively small cohort studies. Comorbid substance use, such
as alcohol or tobacco during pregnancy, is a critical variable
in the model vis--vis neurodevelopmental outcomes, yet
accurate data on fetal exposure to these agents are frequently
absent. In addition, the use of structured and consistent child
development assessments in studies has been lacking.3
One of the major advances of reports regarding the reproductive safety of antidepressants over the last decade has been
an appreciation of the need to account for other relevant exposures during pregnancy, such as the effect of untreated maternal psychiatric illnesses on obstetrical, neonatal, and longterm behavioral outcomes.4 This is particularly relevant given
the multiple articles demonstrating adverse effects of untreated depression on a host of obstetrical and neonatal outcomes and the effect of maternal psychiatric illness on child
development. Perhaps one of the most critical unanswered
questions in maternal and child health is the extent to which
untreated depression during pregnancy affects fetal brain development and whether or how untreated psychiatric illness
during pregnancy modulates risk for neurodevelopmental dysregulation or risk for the development of psychopathology in
children over the long-term.5
In this issue of JAMA Psychiatry, Brown et al6 examine the
critical question of whether SSRI exposure during pregnancy
is associated with disorders of speech, language, scholastic
jamapsychiatry.com

achievement, and neuromotor function in children observed

through early adolescence. With a very substantial sample of
845 345 pregnant women from a Finnish database, the authors describe a greater risk of speech/language disorders in
the SSRI-exposed group (ie, offspring exposed to SSRIs during pregnancy) as well as in the unmedicated group (ie, offspring with no SSRI exposure but with mothers diagnosed as
having a depression-related psychiatric disorder during pregnancy based on diagnosis coding in a health service register)
compared with nonexposed offspring.6 Comparing offspring
exposed to SSRIs with those exposed to maternal depression
yielded no differences in any of the neurodevelopmental outcomes studied. However, a difference was seen between infants exposed to SSRIs and infants not exposed to SSRIs (but
whose mothers were diagnosed as having a depressionrelated psychiatric disorder) when a greater number of SSRI
prescriptions were purchased during pregnancy.
Given the obvious methodologic limitations that are associated with analysis of big data from administrative databases, which are not specifically designed to provide answers to the questions for which we decide to probe, what are
the clinical implications of the data presented? While these
studies yield large sample sizes, we are forced to deal with some
fuzziness of data with regard to diagnosis, precise duration of
exposures, and severity of illness as well as whether medication is even taken. Should treatment of depression during pregnancy shift based on the findings noted in Table 2,6 where absolute risks vs relative risks are provided? The frequency of
speech/language problems following referral to specialized
health care services (without specific criteria for such referral) are relatively small; disorders occurred in 1.6% of patients from the SSRI-exposed group, 1.9% from the unmedicated group, and 1.0% from the nonexposed group.6 Are the
data presented a signal of concern requiring further study or
just background noise? Is it also possible that the finding of increased risk for speech/language disorders among those who
purchased more SSRIs during pregnancy reflects a group of
women who have more severe depression during pregnancy
compared with those who had a diagnosis of depression at
some point in the year before pregnancy or across pregnancy
but who did not take antidepressants?
Residual confounding is a major methodologic quagmire
for studies7 such as the one presented by Brown et al,6 and the
authors note clearly that numerous unmeasured variables may
affect the neurodevelopmental trajectory of children, particularly when assessments of that trajectory occur across an age
(Reprinted) JAMA Psychiatry Published online October 12, 2016

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: http://jamanetwork.com/ by Khaled Hassan on 10/13/2016

E1

Invited Commentary

Implications of Fetal Exposure to Selective Serotonin Reuptake Inhibitors

continuum from birth to 14 years. Critical unanswered questions in the current study are: How many children aged 4 to 5
years, for example, noted to have speech or developmental disorders still are noted to have these disorders at 14 years? And
is there any hypothesis to explain why a neurodevelopmental signal would be found along the domain of speech/
language disorder vs the other domains of scholastic performance or motor function when there was no finding across the
different groups examined? Is there something specific about
serotonergic neuromodulation during developmentally sensitive periods that would confer risk for dysregulation across
one domain of neurobehavioral function and not another? Despite the authors very careful look at a cutting-edge area of
scientific inquiry, questions linger about the clinical implications of the findings.
Brown et al6 have identified a very important research
question, and systematic research, preliminary findings, and
scientific replication may lead to greater delineation of the risk-

ARTICLE INFORMATION
Author Affiliations: Ammon-Pinizzotto Center for
Womens Mental Health, Department of Psychiatry,
Massachusetts General Hospital, Harvard Medical
School, Boston.
Corresponding Author: Lee S. Cohen, MD,
Department of Psychiatry, Massachusetts General
Hospital, Harvard Medical School, 185 Cambridge
St, Simches Research Blg, Boston, MA 02114
(lcohen2@mgh.harvard.edu).
Published Online: October 12, 2016.
doi:10.1001/jamapsychiatry.2016.2705
Conflict of Interest Disclosures: Dr Cohen has
received research support from Cephalon, Takeda/
Lundbeck Pharmaceuticals, GlaxoSmithKline, and
JayMac Pharmaceuticals and support for the
National Pregnancy Registry for Atypical
Antipsychotics from Alkermes Biopharmaceuticals,
AstraZeneca Pharmaceuticals, Bristol-Myers
Squibb/Otsuka Pharmaceuticals, Forest/Actavis

E2

benefit decision for the use of antidepressants during pregnancy. Data suggest a prevalence of SSRI use of 5% to 10% during pregnancy, and regardless of the current reproductive safety
data for SSRIs, even women with highly recurrent or longterm depression invariably prefer to avoid fetal exposure to
these medications if at all possible. But the current report does
not answer whether exposure to SSRIs or untreated depression during pregnancy are in equipoise with respect to neurodevelopmental toxicity or if, over the long-term, one confers greater risk. Given the extent to which depression
during pregnancy predicts risk for postpartum depression
with its attendant morbidity, and in light of the robust data
describing the adverse effects of maternal psychiatric morbidity on long-term child development, clinicians will need
to broaden the conceptual framework used to evaluate relative risk of SSRI use during pregnancy as they navigate this
clinical arena with patients making individual decisions to
match patient wishes.

Pharmaceuticals, Ortho-McNeil Janssen

Pharmaceuticals, and Sunovion Pharmaceuticals.
No other disclosures were reported.

patterns are differentially related to prenatal

maternal major depressive disorder and serotonin
reuptake inhibitor treatment. Depress Anxiety.
2011;28(11):1008-1019.

REFERENCES

5. Rifkin-Graboi A, Bai J, Chen H, et al. Prenatal

maternal depression associates with microstructure
of right amygdala in neonates at birth. Biol Psychiatry.
2013;74(11):837-844.

1. Huybrechts KF, Palmsten K, Avorn J, et al.

Antidepressant use in pregnancy and the risk of
cardiac defects. N Engl J Med. 2014;370(25):23972407.
2. Huybrechts KF, Bateman BT, Palmsten K, et al.
Antidepressant use late in pregnancy and risk of
persistent pulmonary hypertension of the
newborn. JAMA. 2015;313(21):2142-2151.
3. Suri R, Lin AS, Cohen LS, Altshuler LL. Acute and
long-term behavioral outcome of infants and
children exposed in utero to either maternal
depression or antidepressants: a review of the
literature. J Clin Psychiatry. 2014;75(10):e1142-e1152.
4. Salisbury AL, Wisner KL, Pearlstein T, Battle CL,
Stroud L, Lester BM. Newborn neurobehavioral

6. Brown AS, Gyllenberg D, Malm H, et al.

Association of selective serotonin reuptake
inhibitor exposure during pregnancy with speech,
scholastic, and motor disorders in offspring
[published online October 12, 2016]. JAMA Psychiatry.
doi:10.1001/jamapsychiatry.2016.2594
7. Palmsten K, Hernndez-Daz S. Can
nonrandomized studies on the safety of
antidepressants during pregnancy convincingly
beat confounding, chance, and prior beliefs?
Epidemiology. 2012;23(5):686-688.

JAMA Psychiatry Published online October 12, 2016 (Reprinted)

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: http://jamanetwork.com/ by Khaled Hassan on 10/13/2016

jamapsychiatry.com