Nej Mo a 1301449

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T h e NE W E NGL A ND JOU R NA L o f M E DICINE

ORIGINAL ARTICLE

Use of Selective Serotonin Reuptae In!i"itors

#urin$ %re$nanc& an# Ris of Autis' Anders Hviid, Dr.Med.Sci., Mads Melbye, M.D., Dr.Med.Sci.,

and Björn Pasternak, M.D., Ph.D.

A(S TR AC T

From the Department o !pidemiolo"y

#e$search, Statens Ser%m &nstit%t,

'openha$"en. Address reprint re(%ests

to Dr. Hviid at the Department o

!pidemiolo"y #esearch, Statens Ser%m&nstit%t, Artillerivej ), *+ 'openha"en

S, Denmark, or at aii-ssi.dk.

N Engl J Med 2013;369:2406-

15. DOI:

10.1056/NEJMoa1301449

Copyright © 2013 Massachusetts MedicalSociety.

BAC!"O#ND

Stu#ies

!ave raise#

concern

a"out anassociation

"et)een

t!e use of

selective

sero*tonin

reuptae

in!i"itors

+SSRIs,

#urin$

pre$nanc&

an# an

increase#ris of

autis'

spectru'

#isor#ers in

t!e

offsprin$-

ME$%OD&

We

con#ucte#

a co!ort

stu#& of all

sin$leton

live "irt!s

in Den'ar

fro' .//0

t!rou$!

1223

+0104563

"irt!s,4

)it!

follo)*up

t!rou$!122/-

Usin$

Danis!

popula*tion re$istries4 )e

line# infor'ation on 'aternal

use of SSRIs "efore an# #urin$

pre$nanc&4 autis' spectru'

#isor#ers #ia$nose# in t!e

offsprin$4 an# a ran$e of

potential confoun#ers- We use#a survival anal&sis of t!e ti'e

to #ia$nosis in t!e offsprin$

)it! %oisson re$ression to

esti'ate rate ratios of autis'

spectru' #isor#ers accor#in$ to

'aternal use of SSRIs-

"E'$&

Durin$ 342364151 person*&ears of

follo)*up4 )e i#entifie# 75/1

cases of autis' spec*tru'

#isor#er +inci#ence rate4 66-2 per .224222 person*&ears,- A total of

31 cases #urin$ 814822 person*

&ears of follo)*up involve#

offsprin$ of )o'en )!o )ere

e9pose# to SSRIs #urin$ t!eir

pre$nanc& +inci#ence rate4 .11-0

per .224222 person*&ears,- As

co'pare# )it! no use of SSRIs

"ot! "efore an# #urin$

pre$nanc&4 use #urin$ pre$nanc&

)as not associate# )it! a

si$nificantl& increase# ris of

autis' spectru' #isor#ers +full&

a#:uste# rate ratio4 .-12; /3<

confi#ence interval =CI>4 2-/2 to

.-0.,- A'on$ )o'en )!o

receive# SSRIs "efore pre$nanc&

"ut not #urin$ pre$nanc&4 t!e

correspon#in$ full& a#:uste# rate

ratio )as .-80 +/3< CI4 .-.6 to

.-5.,-

CONC'#&ION&

We #i# not #etect a si$nificant

association "et)een 'aternal

use of SSRIs #urin$ pre$nanc&

an# autis' spectru' #isor#er in

8/9/2019 Nej Mo a 1301449

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t!e offsprin$- On t!e "asis of

t!e upper "oun#ar& of t!e

confi#ence interval4 our stu#&

coul# not rule out a relative

ris up to

.-0.4 an#

t!erefore

t!e

association )arrants furt!er

stu#&- +?un#e# "& t!e Danis!

@ealt! an# Me#icines

Aut!orit&-,

1820 !/0 1 M!D+234*) !1M.5#/

D!'!MB

!# 63, *6+

The New England Journal of Medicine

Downloaded from nejm.org on

February 4,

2015. Forpersonal use

only. No other

uses without

permission.

C

o

p

y

r

i

gh

t

©

2013

Massac

husetts

Medical

Society.

All

rightsreserved

.

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SSRI USE DURING %REGNANC AND RISB O? AUTISM

SELECTIESEROTONINREU%TABEIN@I(I*tors+SSRIs, are

increasin$l& use#in t!e treat'ent of

#epression an#an9iet& #is or#ers-

Currentl&4 SSRIs

appear to provi#et!e "est "alance "et)een efficac&an# safet& an# aret!e preferre# first*

line treat'ent-Depression is

co''on #urin$ pre$nanc&4 an#

$iven t!e riss of untreate#

#epression to'ot!er an#

fetus4.41

p!ar'acolo$ictreat'ent is

)arrante#4 often)it! SSRIs-

7

@o)ever4 SSRIscross t!e placenta4

an# a nu'"er of safet& concerns

!ave "een raise#-

8

T!ese inclu#econcerns a"out

"irt! #efects4 a#*verse o"stetrical

an# neonataloutco'es4 an# ef*fects on co$nitive

an# "e!avioral#evelop'ent in

c!il#!oo#-

Recentl&4

autis' spectru'

#isor#ers !ave

"een line# to

'aternal use of

SSRIs #urin$

pre$nanc&- In acasecontrol stu#&

involvin$ 1/5

c!il#ren )it!

autis' spectru'

#isor#ers4 t!e use

of SSRIs "& t!e

'ot!er #urin$

pre$nanc& )as

s!o)n to "e

associate# )it! a

ris of autis'

spectru' #is or#er

t!at )as increase#

"& a factor of 1-3

A causal

association is

plausi"le-

Increase# "loo#

levels of t!e

neurotrans'itter

serotonin !ave

"een o"serve# in

persons )it!

autis' spectru'

#isor#ers-0 ?ur*

t!er'ore4 t!is

neurotrans'itter

appears to pla& an

i'portant role in

earl& "rain

#evelop'ent4

an#

'anipulation of

serotonin

!o'eostasis can

alter

neuroanato'ical

an#neurop!&siolo$i

cal #evelop'ent

an# pro#uce

en#urin$

"e!avioral

c!an$es in

ani'al 'o#els-6*

/ @o)ever4

'ore re*searc!

inclu#in$

lar$e

o"servationalstu#ies

involvin$

!u'ans is

nee#e# to

a##ress a po*

tential

association-

Usin$ #ata fro'

t!e Danis!

!ealt! re$istries4

)e con#ucte# a

nation)i#e co*

!ort stu#& of

SSRI use #urin$

pre$nanc& an#

t!e ris of

autis' spectru'

#isor#ers in t!e

offsprin$-

MET@

ODS

&$#D(CO%O"$

We use# t!e

nation)i#e

Me#ical (irt!

Re$istr& to

construct a

co!ort of all live

"irt!s in Den*'ar #urin$ t!e

stu#& perio# of

Januar& .4 .//04

t!rou$!

Dece'"er 7.4

1223-.2

T!e

Me#ical (irt!

Re$istr&

contains recor#s

of all "irt!s in

Den*'ar4

inclu#in$

infor'ation ont!e personal

i#entification

nu'"er +a .2*

#i$it nu'"er

assi$ne# to all

Danis! resi#ents

an# use# in all

nation*)i#e

re$istries..

, of

t!e parents an#

t!e ne)*"orn4

t!e #ate of "irt!4)!et!er t!e

"irt! )as a

sin$le or

'ultiple "irt!4

t!e $estational

a$e4 vital status4

an# ot!er

p!&sical

c!aracteristics of

t!e

8/9/2019 Nej Mo a 1301449

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ne)"orn- T!e

stu#& )as

approve# "& t!e

Danis! Data

%rotection

A$enc&-

Approval "& an

institu*tional

revie) "oar# an#

infor'e# consent

are not reFuire#

for re$istr&*"ase#

researc! in Den*

'ar- T!e first

aut!or vouc!es

for t!e accurac&

an# co'pleteness

of t!e #ata-

We esti'ate#t!e "e$innin$ of

pre$nanc& "&su"tractin$ t!e

$estational a$efro' t!e #ate of

"irt!- T!e$estational a$e

recor#e# in t!eMe#i*cal (irt!

Re$istr& is "ase#on t!e self*reporte# first #a&

of t!e last'enstrual perio#

an# in 'ost casesis confir'e# "&

prenatalultrasono$*rap!&-

An esti'ate#/7< of all

pre$nant )o'enun#er)ent an

o"stetricalultrasoun#

e9a'ination in

1222-.1

We

inclu#e# onl&

"irt!s )it! ano)n

$estational a$ean# furt!er

restricte# t!eco!ort tosin$leton "irt!s-

?ro' t!e National %atient

Re$ister4.7

)e

o"taine#infor'ation on anu'"er of

$enetic

con#itions +t!efra$ile

s&n#ro'e4tu"erous

sclerosis4An$el'anHs

s&n#ro'e4Do)nHs s&n*

#ro'e4DiGeor$eHs

s&n#ro'e4neurofi"ro'ato

*sis4 an# t!e%ra#erWilli

s&n#ro'e, an#on t!e

con$enitalru"ellas&n#ro'e- All

t!ese con#i*tions are

associate# )it!

an in!erentincrease# ris of autis'4 an#

offsprin$ )it!an& of t!ese

con#itions )eree9clu#e# fro'

t!e co!ort-

T!e uniFue

personal

i#entification

nu'"ers for

'ot!er an#c!il# allo)e#

us to lin

infor'a*tion on

'aternal use of

SSRIs4

#ia$noses of

au*tis'

spectru'

#isor#ers

a'on$

offsprin$4 an#

potentialconfoun#in$

varia"les

relevant to t!e

"irt!s in t!e

co!ort-

E)*O"E$O &&"ID"#!&

Infor'ation on

SSRI

prescriptionsfille# "&

)o'en in t!e

co!ort )as

o"taine# fro'

t!e Na*tional

%rescription

Re$istr&-.8

T!is

re$ister con*

tains

in#ivi#ual*level

infor'ation on

all prescrip*tions #ispense#

at Danis!

p!ar'acies

since .//3-

Eac! recor#

inclu#es t!e

personal

i#entifi*cation

nu'"er of t!e

patient4 t!e #ate

t!e pre*

scription )asfille#4 t!e t&pe

of #ru$

accor#in$ to t!e

Anato'ical

T!erapeutic

C!e'ical

+ATC,

classification

s&ste'4 t!e

nu'"er of #ail&

#oses specifie#

in t!e prescription4

an# t!e nu'"er

of paca$es

o"taine#- We

inclu#e#

prescriptions

)it! t!e ATC

co#e N20A(

+selective

serotonin

reuptae

in!i"itors, t!at

)ere fille#

#urin$ t!e

perio# fro' 1

&ears "efore t!e

"e$innin$ of

t!e pre$nanc&

until #eliver&-

We use# t!e

#ate on )!ic! a

prescription

)as fille# to

in#icate initial

use of t!e

prescri"e#

#ru$-

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!/0 1 M!D +234*) !1M.5#/ D!'!MB!# 63, *6+ 1826

The

New

Engl

and

Journa

l of

Medici

ne

Downloaded from

nejm.org

on

February

4, 2015.

For

personal use only.

No other uses

without

permission.

Copyright © 2013

Massachusetts

Medical

Society. All

rights

reserved.

8/9/2019 Nej Mo a 1301449

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A#$I&M&*EC$"#MDI&O"DE"&

Infor'ation on

#ia$noses of

autis' spectru'

#is*or#er #urin$

t!e stu#& perio#

)as o"taine#

fro' t!e Danis!

%s&c!iatric

Central

Re$ister-.3

T!is

re$*ister inclu#es

#ia$noses 'a#e

an# #ia$nostic

co#es assi$ne#

"& c!il#

ps&c!iatrists an#

contains

infor'ation fro'

ps&c!iatric

!ospitals an#

ps&*c!iatric units

+inpatient an#

outpatient ,- T!e

co#*in$

classification

use# #urin$ t!e

stu#& perio# )as

t!e International

Classification of

Diseases, 10th Revision

+ICD*.2,- We

classifie# autis'

spectru'

#isor#ers in t)o

$roups autistic

#isor#er +ICD*.2

co#e ?58-2, an#

ot!er autis'

spectru'

#isor#ers +in*

clu#in$ at&pical

autis'4

Asper$erHs

s&n#ro'e4 an#

ot!er or

unspecifie#

pervasive

#evelop'ental

#is*or#er; ICD*

.2 co#es ?58-.4

?58-34 ?58-54

an# ?58-/,-

*O$EN$IA'CON+O#NDE"&

We selecte# a

priori a

nu'"er of

potential con*

foun#ers t!at

)ere plausi"le

ris factors for

ei*t!er autis'

or SSRI use

an# for )!ic!

infor'a*tion

)as availa"le

to us fro' t!e

nation)i#e

Danis! !ealt!

re$istries-

?ro' t!e

Me#ical (irt!

Re$istr& an#

t!e Danis!

Civil

Re$istration

S&s*te'..

+t!e

e& national

#e'o$rap!ic

re$istr& in

Den'ar, )e

o"taine#

infor'ation on

t!e &ear of t!e

"irt! an# on

'aternal

parit&4 a$e att!e onset of

pre$nanc&4

countr& of

ori$in4 place of

resi#ence at

t!e start of t!e

pre$nanc&4 an#

s'oin$ status

#urin$

pre$nanc&4 an#

)e line# t!is

infor'ation to

t!e co!ort-

?ro' t!e

Danis!

%s&c!iatric

Central

Re$ister an#

t!e National

%rescription

Re$istr& )e

o"taine#

infor'ation on

'aternal

ps&c!iatric

con#itions an#

selecte# #ru$s

ot!er t!an

SSRIs t!at

)ere use#

#urin$ t!e

pre$nanc&-

T!e Danis!

%s&c!iatric

Central Re$*

ister inclu#es

#ia$noses

'a#e in a ps&c!iatric

!ospital or

ps&c!iatric

unit +inpatient

or out patient,

"ut #oes not

inclu#e

#ia$noses

'a#e "& a

'e#ical

specialist in

t!e pri'ar&care settin$-

Infor'ation on

e'plo&'ent

status an# t!e

'ot!erHs level

of e#ucation

)as o"taine#

fro' Statistics

Den'ar-.0

&$A$I&$ICA'

ANA'(&I&We perfor'e# a

survival

anal&sis to

follo) up

c!il#ren fro'

"irt! until

Januar& .4

12.24 or until

t!e c!il#

reac!e# .2

&ears of a$e4

#ie# or )as lostto follo)*up4 or

receive# a

#ia$nosis of

autis'

spectru'

#isor#er

)!ic!ever

ca'e first-

T!e

resultin$

follo)*up

ti'es an#nu'"ers of

#ia$noses of

autis' +autis'

8/9/2019 Nej Mo a 1301449

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counts, )ere

a$*$re$ate#

accor#in$ to

'aternal use or

nonuse of

SSRIs #urin$

pre$nanc&- We

use# %oisson

re*$ression on

t!e autis'

counts )it! t!e

lo$a*rit!' of

t!e follo)*up

ti'es as t!e

offset ter'4

assu'in$ a

%oisson

#istri"ution for

t!e autis'

counts4 to

esti'ate

inci#ence rate

ratios an# /3<

confi#ence

intervals so

t!at )e coul#

co'*pare t!e

rates of autis'spectru'

#isor#er

a'on$ t!e

offsprin$ of

)o'en )!o

!a# "een

e9pose# to

SSRIs #urin$

pre$nanc&

)it! t!e rates

a'on$ t!e

offsprin$ of )o'en )!o

!a# not "een

e9pose# to

SSRIs #urin$

pre$nanc&-.6

T!e re$ression

anal&sis )as

perfor'e#

)it! t!e use of

t!e %ROC

GENMOD

proce#ure inSAS soft)are4

version /-.

+SAS

Institute,-T!e #ate t!e

prescription

)as fille# )as

con*si#ere# to

"e t!e #ate of

e9posure- T!e

use of SSRIs

#urin$ pre$nanc& )as

#efine# as use

#ur*in$ t!e

perio# 8 )ees

"efore t!e

"e$innin$ of

t!e pre$nanc&

until #eliver&-

We furt!er ana*

l&e# t!e use of

SSRIs

specificall& in

t!e firsttri'ester- To

evaluate t!e

potential for

con*foun#in$

"& in#ication

+i-e-4 t!e

possi"ilit& t!at

)o'en )it!

#epression or

ot!er

in#ications for

SSRI use )oul# "e 'ore liel&

to !ave c!il#ren

)it! autis'

spectru'

#isor#ers,4 )e

also looe# at

t!e use of

SSRIs #urin$

t!e perio# fro'

1 &ears until 0

'ont!s "efore

t!e "e$innin$of t!e pre$*

nanc&- T!is

allo)e# us to

i#entif& a $roup

of )o'en )!o

receive# SSRIs

#urin$ t!at

perio# "ut not

#urin$

pre$nanc& an#

t)o $roups of

)o'en )!oreceive# SSRIs

#urin$

pre$nanc&

t!ose )!o

receive# t!e

#ru$s "ot!

"efore an#

#urin$ t!e

pre$nanc& an#

t!ose )!o #i#

not receive t!e

#ru$s "eforet!e pre$nanc&

"ut #i# receive

t!e' #urin$ t!e

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pre$nanc&- In

all t!e anal&ses4

une9*pose#

pre$nancies

)ere consi#ere#

to "e pre$*

nancies in

)o'en )!o !a#

no e9posure to

SSRIs fro' 1&ears "efore t!e

"e$innin$ of

pre$nanc&

t!rou$! t!e en#

of t!e

pre$nanc&-

We e9plore#

)!et!er t!e

association

"et)een t!e

use of SSRIs

#urin$ pre$nanc& an#

autis'

spectru'

#isor#er

#iffere# in

su"$roups

#efine#

accor#in$ to

t!e c!il#Hs a$e

at t!e ti'e of

t!e follo)*up

assess'ent4t!e calen#ar

perio# #ur*in$

)!ic! t!e

follo)*up

assess'ent

)as per*

for'e#4 t!e

t&pe of SSRI

use#4 previous

ps&c!i*atric

#ia$noses in

t!e 'ot!er4ot!er #ru$s

use# #urin$

pre$nanc&4 an#

t!e t&pe of

autis' spec*

tru' #isor#er

in t!e

offsprin$- We

esti'ate#

cru#e rate

ratios4 rateratios a#:uste#

for a$e an#

calen#ar

perio#4 an#

full& a#:uste#

rate ratios t!at

inclu#e#4 in

a##ition to a$e

an# calen#ar

perio#4 all t!e

potential

confoun#ersliste#

1825

!/0 1

M!D +234*)!1M.5#/ D!'!MB!#

63, *6+



February 4,

2015. For

personal use

only. No other

uses without

permission.

Copyright©

2013

Massachusetts

Medical

Society. All

rights

reserved.

8/9/2019 Nej Mo a 1301449

9/24


a"ove- No 'oret!an 3< of t!evalues )ere'issin$ for an&of t!e potentialconfoun#ers4 an#)e t!erefore use#si'plei'putation4 in)!ic! 'issin$values )erereplace# )it! t!e'ost co''on

value-.5

T!ei'plications of t!is strate$& )eree9plore# insensitivit&anal&ses-

R E

SULT

S

&$#D( CO%O"$

We i#entifie#

0354633 live "irt!s

in Den'ar #urin$ t!e perio#

fro' Januar& .4

.//04 t!rou$!

Dece'"er 7.4

1223- We t!en

e9clu#e# "irt!s

)it!out a no)n

$estational a$e

+82.0,4 'ultiple

"irt!s +104310,4

an# "irt!s

resultin$ in

offsprin$ )it! t!e

con$enital ru"ella

s&n#ro'e or )it!

$e*netic

con#itions t!at are

associate# )it! an

in*!erent ris of

autis' +.775,-

T!is resulte# in a

final stu#& co!ort

of 0104563

c!il#ren +3.-7<

)ere "o&s,- A total

of 0205 'ot!ers

+.-2

8/9/2019 Nej Mo a 1301449

10/24

'entar&

Appen#i94

availa"le )it! t!e

full te9t of t!is

article at

NEJM-or$4 s!o)s

t!e association of

autis' spectru'

#isor#er )it!

ot!er ris factors4

inclu#in$ t!e a$e

of t!e c!il#4 t!e

calen#ar perio#4

an# 'aternal a$e

at t!e ti'e of

#eliver&-, Stron$

associations )ere

seen "et)een

autis' spectru'

#isor#er an#

'aternal ps&c!iatric

#ia$noses an# t!e

use of #ru$s ot!er

t!an SSRIs #urin$

pre$nan*c&- T!ese

associations

su$$est possi"le

confoun#*in$ "&

in#ication4

especiall& $iven

t!at 'ot!ers )it!

t!esec!aracteristics

)ere also 'ore

liel& to use

SSRIs #urin$

pre$nanc& +Ta"le

.,-

&&"I #&ED#"IN!*"E!NANC(AND "I& O+A#$I&M&*EC$"#MDI&O"DE"

Ta"le 7 s!o)s t!e

association

"et)een 'aternal

use of SSRIs

#urin$ pre$nanc&

an# t!e ris of

autis' spectru'

#isor#er in t!e

offsprin$- Dur*in$

814822 person*

&ears of follo)*

up4 )e i#enti*fie#

31 cases of

autis' spectru'

#isor#er a'on$

t!e offsprin$ of

)o'en )!o

)ere e9pose# to

SSRIs #urin$

pre$nanc&

+inci#ence rate4

.11-0 per .224222 person*

&ears,- ?or t!e

co'parison )it!

no use of SSRIs

"efore or #urin$

pre$nanc&4 t!is

rate

correspon#e# to

a cru#e rate ratio

of .-01 +/3<

confi#ence

interval =CI>4.-17 to 1-.7,-

@o)ever4 in a

full& a#:uste#

anal&sis4 t!e use

of SSRIs #urin$

pre$nanc&

+inclu#in$ use

"ot! "e*fore an#

#urin$

pre$nanc& an#

use onl& #urin$

pre$nanc&, )asnot associate#

)it! a si$nifi*

cantl& increase#

ris of autis'

spectru' #isor*

#er in t!e

offsprin$ +rate

ratio .-12; /3<

CI4 2-/2 to

.-0.,- Ta"le S1

in t!e

Supple'entar&

Appen#i9 s!o)s

t!e e9tent to

)!ic! eac!

potential con*

foun#er inclu#e#

in t!e full&

a#:uste# 'o#els

in*fluence# t!e

esti'ate- T!e

full& a#:uste#

rate ra*tio

associate# )it!

t!e use of SSRIs

in t!e first

tri'ester )as

.-73 +/3< CI4

2-/6 to .-56,4

)!ere*as t!e

full& a#:uste#

rate ratio in t!e

su"$roup of

)o'en )!o

receive# SSRIs#urin$

pre$nanc& "ut

not "efore

pre$nanc& )as

.-82 +/3< CI4

2-/1 to 1-.7,-

T!ese esti'ates

s!oul# "e

co'pare# )it!

t!e full&

a#:uste# rate

ratio of .-80+/3< CI4 .-.6 to

.-5., in t!e

su"$roup of

)o'en )!o !a#

use# SSRIs

"efore

pre$nanc& "ut

#i# not use t!ese

#ru$s #urin$

pre$nanc&-

Ta"le S7 int!e

Supple'entar&

Appen#i9 s!o)s

t!e association

"et)een t!e use

of SSRIs #urin$

pre$nanc& an#

t!e ris of

autis' spectru'

#isor*#er in

offsprin$

accor#in$ to

several

prespecifie#

c!aracteristics-

Alt!ou$! t!e

point esti'ates

su$*$este# t!at

in so'e

su"$roups of

)o'en t!e as*

sociation

#iffere# fro' t!efull& a#:uste#

rate ra*

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l of

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Copyright © 2013

Massachusetts

Medical

Society. All

rights

reserved.

8/9/2019 Nej Mo a 1301449

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tio of .-124

tests of

!o'o$eneit&

)ere

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no si$nificant

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Since )euse# a si'ple

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The New England

Journal of

Medicine


February 4,

2015. For

personal use

only. No other

uses without

permission. Copyright © 2013

Massachusetts Medical

Society. All rights reserved.

8/9/2019 Nej Mo a 1301449

15/24


t!e Danis!

re$istries

allo)e# t!e

lina$e "e*

t)een #ru$ use

#urin$

pre$nanc& an#

autis'spectru'

#isor#ers in t!e

offsprin$4 so

t!at )e )ere

a"le to

#eter'ine t!e

potential effect

of t!e #ru$s

later in

c!il#!oo#-

Secon#4 our

stu#& )ascon#ucte# on a

nation)i#e

level4 an#

t!ere*fore t!e

co!ort )as

lar$e4 )it!

0104563 live

"irt!s4

inclu#in$ 31

cases of autis'

spectru'

#isor#er in

offsprin$ of

)o'en )it!

SSRI e9po*sure

#urin$

pre$nanc&

'ore t!an t!ree

ti'es t!e

nu'"er of

cases a'on$

e9pose#

)o'en in t!e

stu#& "& Croen

an# collea$ues

or t!e S)e#*is!

stu#&- T!ir#4

)e use#

a#'inistrative

!ealt! re$istr&

#ata in a

!istoricall&

prospective

stu#&

#esi$n4 )it!in#epen#entascertain'entof e9*posurean# outco'e4t!us re#ucin$t!e poten*tialfor selectionan# recall "ias-

?inall&4 t!e National%rescriptionRe$istr&4 fro')!ic! )eo"taine# #ataon e9posure toSSRIs4 isconsi#*ere# to "e nearl&

co'plete.8

; all

Danis! p!ar*

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Our stu#&

also !as a

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?irst4 in our

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on February 4,

2015. For

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permission.

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Medical Society.

All rights

reserved.

8/9/2019 Nej Mo a 1301449

17/24


$a,le 2. ?Conned.@

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Schi?ophrenia 6) ),=32.)2 +.)2 8*.6=H).3:

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The New England

Journal of

Medicine


February 4,

2015. For

personal use

only. No other

uses without

permission. Copyright © 2013

Massachusetts Medical

Society. All rights reserved.

8/9/2019 Nej Mo a 1301449

19/24


$a,le 3. Aoaon ,eeen *eod o &&"I #e and A8 &

8/9/2019 Nej Mo a 1301449

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r uses

without

permissio

n.

Copyright

© 2013

Ma

ssa

chu

sett

s

Me

dic

al

Soc

iety

.

All

righ

ts

rese

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.

8/9/2019 Nej Mo a 1301449

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t!eir use rat!er

t!an an effect of

t!ese #ru$s- T!is

!i$!li$!ts t!e

potential effect of

confoun#*in$ "&

in#ication in our

stu#& an# si'ilar stu#ies of SSRIs

an# t!e

i'portance of

"ein$ a"le to

a#eFuatel& tae

t!is confoun#in$

into account in

t!e stu#& #esi$n-

As )it! all

o"servational

stu#*ies4 t!e

possi"le presenceof resi#ual an#

un'ea*sure#

confoun#in$ or

ascertain'ent

"ias )it! respect

to e9posure an#

outco'e a##s

to t!e

i'precision of

our esti'ates-

Interpretation

of our results

s!oul# tae t!is

factor into

account-

T!e vie)s an#conclusions

e9presse# in t!is

article are t!ose of

t!e aut!ors an#

s!oul# not "e

un#erstoo# or cite#

as "ein$ 'a#e on

"e!alf of or

reflectin$ t!e

position of t!e

Danis! @ealt! an#

Me#icines Aut!orit&-

Supporte# "&

t!e Danis!

@ealt! an#

Me#icinesAut!orit&-

Disclosure

for's provi#e#

"& t!e aut!ors

are availa"le

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t!e full te9t of t!is

article at NEJM-or$-

"E+E"ENCE&

1. Al#er J4?in N4 (iter

J4 @Ksli I4@ol $reve W-

Depression

an# an9iet&

#urin$

pre$nanc& a

ris factor for

o"stetric4 fetal

an# neonatal

outco'e A

critical revie)

of t!e

literature- J

Matern ?etal

Neonatal Me#

1226;12.5/*

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stress in pre$*

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MA4 (ro)n J4

et al- Use of anti#epressant

'e#ications

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et al- Safet&

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Copyright©

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Massachusetts

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All rights

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Documents

Nej Mo a 1301449