RESEARCH ARTICLE
Ma e nal dep essi e symp oms du ing and
a e p egnancy a e associa ed wi h a en ion-
de ici /hype ac i i y diso de symp oms in
hei 3- o 6-yea -old child en
Elina Wol o d
1
*, Ma ius Lah i
1,2
, Soile Tuo inen
1
, Ja i Lah i
1,3,4
, Ja i Lipsanen
1
,
Ka i Sa olainen
1
, Ka i Heinonen
1
, Esa Ha
¨ma
¨la
¨inen
5
, Ee o Kajan ie
6,7,8
, Anu-
Ka iina Pesonen
1
, Pia M. Villa
9
, Hannele Lai uo i
10,11,12,13
, Rebecca M. Reynolds
2
,
Ka i Ra
¨ikko
¨nen
1
1Depa men o Psychology and Logopedics, Facul y o Medicine, Uni e si y o Helsinki, Helsinki, Finland,
2Uni e si y/B i ish Hea Founda ion Cen e o Ca dio ascula Science, Queen’s Medical Resea ch
Ins i u e, Uni e si y o Edinbu gh, Edinbu gh, Uni ed Kingdom, 3Helsinki Collegium o Ad anced S udies,
Uni e si y o Helsinki, Helsinki, Finland, 4Folkha
¨lsan Resea ch Cen e, Helsinki, Finland, 5Depa men o
Clinical Chemis y, Uni e si y o Helsinki, Helsinki, Finland, 6Na ional Ins i u e o Heal h and Wel a e,
Helsinki, Finland, 7Child en’s Hospi al, Helsinki Uni e si y Hospi al and Uni e si y o Helsinki, Helsinki,
Finland, 8PEDEGO Resea ch Uni , MRC Oulu, Oulu Uni e si y Hospi al and Uni e si y o Oulu, Oulu,
Finland, 9Obs e ics and Gynaecology, Uni e si y o Helsinki and Helsinki Uni e si y Hospi al, Helsinki,
Finland, 10 Facul y o Medicine and Li e Sciences, Uni e si y o Tampe e, Tampe e, Finland, 11 Depa men
o Obs e ics and Gynecology, Tampe e Uni e si y Hospi al, Tampe e, Finland, 12 Medical and Clinical
Gene ics, Uni e si y o Helsinki and Helsinki Uni e si y Hospi al, Helsinki, Finland, 13 Ins i u e o Molecula
Medicine Finland, Helsinki Ins i u e o Li e Science, Uni e si y o Helsinki, Helsinki, Finland
*elina.wol o d@helsinki. i
Abs ac
Ma e nal dep essi e symp oms du ing p egnancy ha e been associa ed wi h child beha-
iou al symp oms o a en ion-de ici /hype ac i i y diso de (ADHD) in ea ly childhood. How-
e e , i emains unclea i dep essi e symp oms h oughou p egnancy a e mo e ha m ul o
he child han dep essi e symp oms only du ing ce ain imes, and i ma e nal dep essi e
symp oms a e p egnancy add o o media e any p ena al e ec s. 1,779 mo he -child dyads
pa icipa ed in he P edic ion and P e en ion o P e-eclampsia and In au e ine G ow h
Res ic ion (PREDO) s udy. Mo he s illed in he Cen e o Epidemiological S udies Dep es-
sion Scale biweekly om 12+0–13+6 o 38+0–39+6 weeks+days o ges a ion o deli e y,
and he Beck Dep ession In en o y-II and he Conne s’ Hype ac i i y Index a he child’s
age o 3 o 6 yea s (mean 3.8 yea s, s anda d de ia ion [SD] 0.5). Ma e nal dep essi e
symp oms we e highly s able h oughou p egnancy, and child en o mo he s wi h consis-
en ly high dep essi e symp oms showed highe a e age le els (mean di e ence = 0.46 SD
uni s, 95% Con idence In e al [CI] 0.36, 0.56, p<0.001 compa ed o he low g oup), and
p opo ion (32.1% s. 14.7%) and odds (odds a io = 2.80, 95% CI 2.20, 3.57, p<0.001)
o clinically signi ican ADHD symp oms. These associa ions we e no explained by he
e ec s o ma e nal dep essi e symp oms a e p egnancy, which bo h added o and pa ially
media ed he p ena al e ec s. Ma e nal dep essi e symp oms h oughou p egnancy a e
associa ed wi h inc eased ADHD symp oma ology in young child en. Ma e nal dep essi e
PLOS ONE | h ps://doi.o g/10.1371/jou nal.pone.0190248 Decembe 21, 2017 1 / 13
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OPEN ACCESS
Ci a ion: Wol o d E, Lah i M, Tuo inen S, Lah i J,
Lipsanen J, Sa olainen K, e al. (2017) Ma e nal
dep essi e symp oms du ing and a e p egnancy
a e associa ed wi h a en ion-de ici /hype ac i i y
diso de symp oms in hei 3- o 6-yea -old
child en. PLoS ONE 12(12): e0190248. h ps://doi.
o g/10.1371/jou nal.pone.0190248
Edi o : Ma ianna Mazza, Uni e si a Ca olica del
Sac o Cuo e Sede di Roma, ITALY
Recei ed: Augus 23, 2017
Accep ed: Decembe 11, 2017
Published: Decembe 21, 2017
Copy igh : ©2017 Wol o d e al. This is an open
access a icle dis ibu ed unde he e ms o he
C ea i e Commons A ibu ion License, which
pe mi s un es ic ed use, dis ibu ion, and
ep oduc ion in any medium, p o ided he o iginal
au ho and sou ce a e c edi ed.
Da a A ailabili y S a emen : The PREDO S udy
da a con ain sensi i e and po en ially iden i ying
pa ien in o ma ion, e en a e social secu i y
numbe s and names ha e been emo ed om he
da a se . The use and sha ing o such da a a e
s ic ly con olled by se e al clauses o he Finnish
law, designed o ensu e he p o ec ion o p i acy.
The esea che s in e es ed in using he da a mus
ob ain app o al om he PREDO S udy Boa d. The
S udy Boa d is accoun able o he na ional egis e
au ho i y ( he Finnish Na ional Ins i u e o Heal h
symp oms a e p egnancy add o, bu only pa ially media e, he p ena al e ec s. P e en-
i e in e en ions sui ed o he p egnancy pe iod may bene i bo h ma e nal and o sp ing
men al heal h.
In oduc ion
A en ion-de ici /hype ac i i y diso de (ADHD) is cha ac e ized by a pe sis en pa e n o
ina en ion, impulsi i y, and hype ac i i y. I is one o he mos p e alen neu ode elopmen al
diso de s in child en wi h p e alence a es a ying om 5.9 o 7.1% [1,2]. These symp oms
may no only be associa ed wi h impai men s in academic, socioeconomic and social domains
[3], bu also p edic p ema u e mo ali y [4].
In he ecen decade, he p e alence a es o ADHD ha e shown a nea ly 30% inc ease [5].
As ou gene ic makeup has no changed, his inc ease canno be a ibu ed o gene ic ac o s.
E en hough inc easing a ailabili y o se ices, ecogni ion o , and sc eening o ADHD may
pa ly unde lie his inc ease [6], ano he con ibu ing ac o may lie in he exposu e o en i-
onmen al ad e si ies in he p ena al s age o li e. Among hese ad e si ies a e exposu e o
ma e nal p e-p egnancy obesi y and hype ensi e and diabe ic p egnancy diso de s. They
complica e an inc easing numbe o p egnancies and ha e been linked wi h an inc eased isk
o ADHD symp oma ology in he child [7–10]. They a e also among he majo unde lying
causes o p e e m bi h and low bi hweigh , which p e ious s udies ha e also linked wi h an
inc eased isk o ADHD symp oma ology [11–13].
Ye , al hough ex ensi e esea ch on he e ec s o ma e nal dep ession on o sp ing ou -
comes has s a ed o eme ge [14,15], ela i ely li le a en ion has been de o ed o he associa-
ion wi h o sp ing ADHD symp oma ology. I has been es ima ed ha 7 o 20% o women
expe ience clinically signi ican le els o dep essi e symp oms a di e en s ages o p egnancy
[16,17]. We a e awa e o only one la ge-scale e ospec i e s udy which has shown ha he
mo he s o 2-11-yea -old child en wi h an ADHD diagnosis we e mo e likely o be diagnosed
wi h dep ession he yea be o e he bi h o he child [18]. Two addi ional p ospec i e s udies
ha e shown ha ma e nal dep essi e symp oms epo ed a ges a ional week 20 we e associ-
a ed wi h a highe isk o child a en ion p oblems a 3 yea s o age [19], and when epo ed
a ges a ional weeks 18 and 32, hey we e associa ed wi h a highe isk o child a en ion and
hype ac i i y p oblems a 4 and 11 yea s o age [19,20].
These s udies a e, howe e , limi ed by a numbe o easons. Fi s , hey measu ed dep essi e
symp oms “du ing he pas se en days o las wo weeks” a one o wo ime poin s du ing
p egnancy no co e ing he en i e p egnancy [19,20]. Second, while wo o hese s udies
accoun ed o ma e nal dep ession a e p egnancy [19,20], none o he s udies es ed i ma e -
nal dep ession a e p egnancy added o o media ed ei he ully o pa ially he p ena al
e ec s. Finally, he s udies ailed o accoun o ma e nal p e-p egnancy obesi y and common
p egnancy diso de s, which in addi ion o inc easing he child’s ADHD isk [8–10], may o en
also accompany ma e nal dep ession [21].
Hence, we es ed, in a la ge sample o p egnan Finnish women, i dep essi e symp oms,
measu ed biweekly om ges a ional week 12 onwa ds un il e m o deli e y, we e associa ed
wi h ADHD symp oms in hei 3- o 6-yea -old child en. The biweekly assessmen s allowed us
o add ess ges a ion-week and imes e -speci ic e ec s, and ma e nal e- a ings o dep essi e
symp oms a he ime o a ing he 3- o 6-yea -old child allowed us o add ess i any e ec s
we e speci ic o he p ena al s age. Ou s udy also es ed i ma e nal dep essi e symp oms a e
Ma e nal dep essi e symp oms du ing p egnancy and child a en ion-de ici /hype ac i i y diso de symp oms
PLOS ONE | h ps://doi.o g/10.1371/jou nal.pone.0190248 Decembe 21, 2017 2 / 13
and Wel a e) and o he e hics commi ees which
ha e app o ed he s udy p o ocol ( he E hics
Commi ees o Obs e ics and Gynaecology,
Child en’s Diseases and Psychia y, and Women,
Child en and Psychia y o he Hospi al Dis ic o
Helsinki and Uusimaa and by he pa icipa ing
hospi als in Finland). Collabo a ion in da a analysis
is possible h ough speci ic esea ch p oposals
sen o he PREDO S udy Boa d [p edo.
[email p o ec ed]] o p ima y in es iga o s Ka i
Ra¨ikko¨nen [ka i. aikkonen@helsinki. i] o Hannele
Lai uo i [[email p o ec ed]].
Funding: The PREDO s udy is unded by he
Academy o Finland, E aNe , EVO (a special s a e
subsidy o heal h science esea ch), Uni e si y o
Helsinki Resea ch Funds, he Signe and Ane
Gyllenbe g Founda ion, he Emil Aal onen
Founda ion, he Finnish Medical Founda ion, he
Jane and Aa os E kko Founda ion, he No o
No disk Founda ion, he Pa¨i ikki and Saka i
Sohlbe g Founda ion, he Sig id Juselius
Founda ion, and he Si Jules Tho n Cha i able
T us . The unde s had no ole in s udy design,
da a collec ion and analysis, decision o publish, o
p epa a ion o he manusc ip .
Compe ing in e es s: The au ho s ha e decla ed
ha no compe ing in e es s exis wi h No o
No disk Founda ion (an independen ounda ion
wi h co po a e in e es s) o any o he unde s. This
does no al e ou adhe ence o PLOS ONE policies
on sha ing da a and ma e ials.
p egnancy added o o media ed any o he p ena al e ec s. Finally, we es ed i ma e nal p e-
p egnancy obesi y, hype ensi e p egnancy diso de s, and ges a ional diabe es, o ma e nal
ADHD symp oms accoun ed o any obse ed e ec s. We ha e p e iously demons a ed in
his coho associa ions be ween ma e nal dep essi e symp oms and child in e nalizing, ex e -
nalizing, and o al p oblems, including DSM IV-o ien ed ADHD p oblems [16] as measu ed
by he Child Beha iou Checklis (CBCL) [22]. This s udy adds o hese indings by es ing
associa ions wi h he Conne s’ Hype ac i i y Index (CHI) [23], which has been shown o be
alid in iden i ying child en 3 yea s and olde wi h ADHD [23,24]. CHI is a comp ehensi e
measu e o ADHD symp oms in child en 3 yea s and olde , including aspec s o ina en ion,
hype ac i i y, and emo ional labili y [23–25], while he ADHD p oblems scale o he CBCL is
sui able o child en 1.5 yea s and olde and ocuses mo e on hype ac i e-impulsi e and ina -
en i e symp oms [22].
Ma e ials and me hods
Pa icipan s
The P edic ion and P e en ion o P e-eclampsia and In au e ine G ow h Res ic ion
(PREDO) s udy comp ises al oge he 4,777 mo he s and hei single on o sp ing bo n ali e in
Finland be ween 2006 and 2010 [26]. The women we e ec ui ed when hey a ended he i s
ul asound sc eening be ween 12+0–13+6 weeks+days o ges a ion in an ena al clinics a one
o he en s udy hospi als in Sou he n and Eas e n Finland. O hem, 3,402 (71.2%) assessed
hei dep essi e symp oms biweekly du ing p egnancy.
In 2011–2012 we in i ed 4,586 mo he -child dyads ( h ee child en had died be o e he ol-
low-up, 33 had no da a in he Finnish Medical Bi h Regis e (MBR), 55 women declined pa -
icipa ion in a ollow-up, and o 100 women, add esses we e no aceable), and 2,667 (58.2%)
pa icipa ed. O hem 2,312 (68.0% o hose wi h da a on dep essi e symp oms du ing p eg-
nancy) had p egnancy as well as ollow-up da a a ailable a he child’s age o 1.9 o 6.3 yea s
(50.6% boys). Since he CHI is alida ed o child en who a e 3 yea s and olde [23], we
excluded 533 child en om he analy ic sample. Hence, he cu en s udy comp ised o 1,779
mo he -child pai s who had bo h p egnancy as well as ollow-up da a a ailable a he child’s
mean age o 3.8 yea s (S anda d De ia ion (SD) = 0.5 yea s, ange 3.0 o 6.3 yea s; 51.5% boys).
Compa ed o he women who we e in i ed bu did no pa icipa e in he ollow-up
(n= 2,274), he women who pa icipa ed and whose child en in he ollow-up we e 3 yea s
and olde (n= 1,779) we e olde a deli e y (31.9 s. 31.1 yea s, p<0.001), had mo e o en
a e ia y educa ion (61.6% s. 54.1%, p<0.001), we e less o en single (1.5% s. 3.6%,
p<0.001), we e less o en mul ipa ous (57.7% s. 64.4%, p<0.001), smoked less o en
h oughou p egnancy (2.6% s. 7.5%, p<0.001), and epo ed less o en a his o y o a dep es-
sion diagnosis (9.0% s. 12.6%, p= 0.002).
The PREDO s udy p o ocol was app o ed by he E hics Commi ees o Obs e ics and
Gynaecology, Child en’s Diseases and Psychia y, and Women, Child en and Psychia y o he
Hospi al Dis ic o Helsinki and Uusimaa and by he pa icipa ing hospi als. All pa icipa ing
women signed in o med consen o ms and all p ocedu es con ibu ing o his wo k comply
wi h he Helsinki Decla a ion o 1975, as e ised by he 59 h WMA Gene al Assembly, Seoul,
Republic o Ko ea, Oc obe 2008.
Child ADHD symp oms
A he child’s age o 3 o 6 yea s, hei mo he s a ed he en CHI ques ions on he child’s beha-
iou al symp oms o ADHD on a scale o “no a all” (0) o “ e y much” (3) [23]. A sum-sco e
o 10 o abo e indica es clinically signi ican ADHD symp oms [27]. The scale has good
Ma e nal dep essi e symp oms du ing p egnancy and child a en ion-de ici /hype ac i i y diso de symp oms
PLOS ONE | h ps://doi.o g/10.1371/jou nal.pone.0190248 Decembe 21, 2017 3 / 13
in e nal consis ency [24,25] and disc iminan alidi y [24,25]. In ou sample, i showed high
in e nal consis ency (α= .91).
Ma e nal dep essi e symp oms du ing and a e p egnancy
Dep essi e symp oms we e epo ed biweekly up o 14 imes h oughou p egnancy s a ing
om 12+0–13+6 o 38+0–39+6 weeks+days ges a ion o deli e y using he Cen e o Epide-
miological S udies Dep ession Scale (CES-D) [28]. The CES-D has 20 ques ions a ed on a
scale o none o he ime (0) o all he ime (3) du ing he pas week, wi h highe sco es indica -
ing mo e equen symp oms o dep ession, and a sum-sco e o 16 indica ing a isk o clini-
cal dep ession [28].
In he ollow-up, dep essi e symp oms we e epo ed using he Beck Dep ession In en-
o y-II (BDI-II) [29]. This scale comp ises 21 ou -s a emen se s (sco ed om 0 o 3) wi h
each s a emen e lec ing inc easing se e i y o dep essi e symp oms du ing he pas wo
weeks [29]. A sum-sco e o 14 indica es a leas mild dep essi e symp oms [29].
Bo h dep ession scales ha e good psychome ic p ope ies [28–30], and he CES-D has
been used ex ensi ely and alida ed also in p egnan popula ions [30]. We ha e p e iously
shown ha in ou sample he CES-D (C onbach‘s α= .88 o .92 in he 14 biweekly measu e-
men poin s) and he BDI-II (α= .91) showed high in e nal consis ency [16].
Ma e nal p e-p egnancy obesi y and p egnancy diso de s
Ma e nal p e-p egnancy obesi y (BMI, 30 kg/m
2
), ges a ional diabe es (yes s. no) and
hype ensi e p egnancy diso de s (p e-eclampsia, ges a ional hype ension; yes s. no) we e
ex ac ed om he MBR and/o om medical eco ds independen ly e i ied by a clinical ju y.
Co a ia es
These included ma e nal his o y o physician-diagnosed dep ession which was epo ed in a
ques ionnai e a 12+0–13+6 weeks+days o ges a ion. Ques ions on ma e nal ADHD p oblems
we e embedded in he Adul Sel -Repo (ASR) [31], which he mo he s comple ed in he ol-
low-up (T-sco e 65 poin s indica es bo de line signi ican p oblems). Ma e nal age a deli -
e y (yea s), an idep essan use (yes s. no), psycho opic medica ion use (yes s. no), smoking
du ing p egnancy (did no smoke/ qui du ing he i s imes e / smoked h oughou p eg-
nancy), pa i y (p imipa ous s. mul ipa ous), p e-p egnancy/ch onic hype ension (yes s.
no), ype 1 diabe es (yes s. no), child’s sex, ges a ional leng h (weeks), bi hweigh (g) adjus ed
o sex and ges a ion leng h, and amily s uc u e (cohabi a ing/ma ied s. single) a child-
bi h we e de i ed om he MBR, and ma e nal alcohol use (yes s. no) and educa ion (sec-
onda y o less, uppe seconda y, lowe e ia y, uppe e ia y) we e mo he - epo ed du ing
p egnancy, and child’s age a he ollow-up.
S a is ical analyses
We i s examined ma e nal dep essi e symp oms p o iles du ing p egnancy wi h a la en p o-
ile analysis. We compa ed solu ions wi h wo o eigh clus e s, and iden i ied he mos op imal
one by using Akaike In o ma ion C i e ion, sample size-adjus ed Bayesian In o ma ion C i e-
ion, and Vuong-Lo-Mendell-Rubin Likelihood Ra io Tes and Lo-Mendell-Rubin Adjus ed
Likelihood Ra io Tes s. We hen es ed i he child ADHD symp om sco es, ea ed as a con in-
uous ou come a iable, and he p opo ion o child en wi h clinically signi ican ADHD symp-
oms, ea ed as a dicho omous a iable using he ADHD symp om sco e 10 o abo e as a
clinical cu o [27], di e ed be ween he g oups o mo he s wi h di e en dep essi e symp om
Ma e nal dep essi e symp oms du ing p egnancy and child a en ion-de ici /hype ac i i y diso de symp oms
PLOS ONE | h ps://doi.o g/10.1371/jou nal.pone.0190248 Decembe 21, 2017 4 / 13
p o iles du ing p egnancy. These g oup di e ences a e p esen ed as mean di e ences (MD)
and odds a ios (OR) and hei 95% Con idence In e als (CI) om linea (con inuous ADHD
symp om sco es) and logis ic eg ession analyses (ADHD symp om sco es dicho omized a
clinical cu o ), espec i ely.
We also examined i he associa ions be ween ma e nal dep essi e symp oms du ing p eg-
nancy and child ADHD symp oms we e ges a ion-week- o imes e -speci ic. In hese es s,
we used linea eg ession analysis when we ea ed child ADHD symp oms as con inuous and
logis ic eg ession analysis when we dicho omized child ADHD symp oms sco es a he clini-
cal cu o . Fu he , in hese analyses ma e nal dep essi e symp om sco es (biweekly alues;
i s imes e alue, mean alues o he second and hi d imes e alues; imes e -weigh ed
mean alue) we e squa e oo ans o med o imp o e linea model i ing.
In all o he abo e analyses we i s made adjus men s o child’s sex and age a ollow-up
(model 1). The ea e , we addi ionally adjus ed o ma e nal age a childbi h, pa i y, amily
s uc u e, educa ion le el, ype 1 diabe es, ch onic hype ension, his o y o physician-diag-
nosed dep ession, an idep essan and o he psycho opic medica ion use, alcohol use and
smoking du ing p egnancy, and ges a ion leng h and weigh a bi h adjus ed o sex and ges-
a ion leng h (model 2); o ma e nal p e-p egnancy obesi y, ges a ional diabe es, ges a ional
hype ension, and p e-eclampsia (model 3); o ma e nal ADHD p oblems (model4); and
inally, o all o he abo e and ma e nal dep essi e symp oms a ollow-up pa allel o a ing
he child (model 5).
We also es ed i ma e nal dep essi e symp oms a e p egnancy added o he p ena al
e ec s wi h an in e ac ion e m o ma e nal imes e -weigh ed mean dep essi e symp oms
du ing p egnancyma e nal dep essi e symp oms a e p egnancy ha was added o he linea
(con inuous ADHD symp om sco es) and logis ic eg ession models (ADHD symp oms
sco es dicho omized a he clinical cu o ). In addi ion, we es ed i ma e nal dep essi e symp-
oms a e p egnancy media ed he e ec s o ma e nal imes e -weigh ed mean dep essi e
symp oms du ing p egnancy using he PROCESS mac o o media ion in SPSS 24 wi h 5000
boo s apping e-samples wi h bias-co ec ed CIs [32,33]. Finally, we conduc ed sensi i i y
analyses by unning he linea eg ession analyses sepa a ely in g oups acco ding o ma e nal
p e-p egnancy obesi y and p egnancy diso de s, child’s sex, ma e nal his o y o physician-
diagnosed dep ession, and ma e nal ADHD p oblems. We used MPLUS and SPSS 24 da a
packages o he analyses.
Resul s
Cha ac e is ics o he s udy pa icipan s a e in S1 Table. Co ela ions be ween he co a ia es
wi h child ADHD symp oms a e in S2 Table. Ma e nal biweekly, imes e -speci ic and imes-
e -weighed mean alues o dep essi e symp oms du ing p egnancy we e signi ican ly co e-
la ed (Pea son ’s anged om .51 o .92, all p- alues <.001) and we e also signi ican ly
co ela ed wi h dep essi e symp oms a e p egnancy (Pea son ’s anged om 0.36 o 0.46, all
p- alues <0.001) [16]. The median numbe o consecu i e dep essi e symp om measu e-
men s du ing p egnancy in he en i e sample was 13 and he in e qua ile ange was 12 o 14.
The e we e al oge he 879 (49.4%) women wi h da a on all 14 measu emen poin s du ing
p egnancy and only 334 (18.8%) women had mo e han wo missing alues du ing p egnancy.
Ma e nal dep essi e symp oms du ing p egnancy and child ADHD
symp oms
Fig 1 (Panel A) shows ha he mos op imal la en p o ile solu ion (in compa ison o solu ions
wi h h ee o eigh g oups) iden i ied wo g oups o women wi h consis en ly low and high
Ma e nal dep essi e symp oms du ing p egnancy and child a en ion-de ici /hype ac i i y diso de symp oms
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le els o dep essi e symp oms h oughou p egnancy (Akaike In o ma ion C i e ion =
147821.10, sample-size-adjus ed Bayesian In o ma ion C i e ion = 147920.30, Vuong-Lo-
Mendell-Rubin LRT and Lo-Mendell-Rubin-adjus ed likelihood a io es p- alues <0.001).
Fo he wo la en p o ile g oups, he pe cen age o women wi h da a on all 14 measu emen
poin s compa ed o he ones wi h a leas one missing alue was no signi ican ly di e en
(50.9% in he low and 45.9% in he high dep essi e symp om le el g oup had all 14 measu e-
men poin s, p= 0.051 o g oup di e ence). Fig 1 (Panels B and C) also shows ha child
Fig 1. La en p o ile analysis showing he mos op imal, wo g oup, solu ion o mo he s wi h
consis en ly low and high sco es on he Cen e o Epidemiological S udies Dep ession Scale (CES-D)
h oughou p egnancy (Panel A), and he child’s beha iou al symp oms o a en ion-de ici /
hype ac i i y diso de on he Conne s’ Hype ac i i y Index (CHI) es ima ed ma ginal mean sco es
(Panel B), and p opo ion o child en wi h sco es abo e he clinical cu o (10) in he CHI (Panel C).
E o ba s e e o he 95% Con idence In e als (95% CI), and numbe s o mean di e ence (MD) (Panel B)
and odds a io (OR) (Panel C) and hei 95% CIs in model 1, and p- alues o models 1–5. Fo di e en
adjus men models, please see oo no e in Table 1.
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ADHD symp oms and he p opo ion o and odds o child en wi h clinically signi ican
ADHD symp oms we e highe in he g oup o women who had consis en ly high dep essi e
symp oms h oughou p egnancy.
Fu he , highe ma e nal biweekly, imes e -speci ic (S3 Table) and imes e -weigh ed
mean dep essi e symp om sco es (Table 1) we e signi ican ly associa ed wi h highe ADHD
symp om sco es and highe odds o clinically signi ican ADHD symp oms (Table 1) in chil-
d en. These associa ions we e signi ican ac oss all adjus men models wi h all co a ia es,
including ma e nal ADHD symp oms.
Addi i e e ec s o ma e nal dep essi e symp oms du ing and a e
p egnancy on child ADHD symp oms
Fig 2 (Panels A and B) shows ha ma e nal dep essi e symp oms a e p egnancy added o he
e ec o ma e nal dep essi e symp oms du ing p egnancy (bo h p- alues o in e ac ions = 0.03
o dep essi e symp oms du ing p egnancydep essi e symp oms a e p egnancy in e ac ion
on child con inuous and clinically signi ican ADHD symp oms sco es). Ac oss all adjus men
models, child ADHD symp om sco es and p opo ion o child en wi h clinically signi ican
symp oms we e he highes i he mo he epo ed dep essi e symp oms abo e he clinical cu -
o bo h du ing and a e p egnancy (Fig 2).
Media ion o ma e nal dep essi e symp oms du ing p egnancy on child
ADHD symp oms ia ma e nal dep essi e symp oms a e p egnancy
Fig 3 shows, ha he e ec o ma e nal dep essi e symp oms du ing p egnancy on child
ADHD symp oms was pa ially media ed ia ma e nal dep essi e symp oms a e p egnancy.
The model also shows ha ma e nal dep essi e symp oms du ing p egnancy s ill had a di ec
and signi ican e ec on child ADHD symp oms a e adjus ing o dep essi e symp oms a e
p egnancy. Toge he , dep essi e symp oms du ing and a e p egnancy accoun ed o 11.4%
o he a ia ion o he child’s ADHD symp oms.
Table 1. Associa ion be ween ma e nal dep essi e symp oms du ing p egnancy and child beha iou al symp oms o a en ion-de ici /hype ac i -
i y diso de on he Conne s’ Hype ac i i y Index a age 3.5 yea s.
Ma e nal Cen e o Epidemiological S udies Dep ession
Scale imes e -weigh ed mean sco e du ing p egnancy
Child’s Conne s’
Hype ac i i y Index Sum
sco e
Child’s Conne s’ Hype ac i i y
Index Sum sco e10
B (95%CI) pOR (95%CI) p
Model 1 0.26 (0.22, 0.31) <0.001 1.83 (1.62, 2.08) <0.001
Model 2 0.25 (0.21, 0.30) <0.001 1.85 (1.62, 2.11) <0.001
Model 3 0.26 (0.21, 0.30) <0.001 1.86 (1.63, 2.12) <0.001
Model 4 0.24 (0.20, 0.29) <0.001 1.77 (1.55, 2.03) <0.001
Model 5 0.15 (0.10, 0.20) <0.001 1.49 (1.29, 1.73) <0.001
B indica es he S anda d De ia ion (SD) inc ease in child ADHD symp oms when ma e nal dep essi e symp oms inc ease by 1 SD.
OR (Odds Ra io) indica es he isk o clinically signi ican ADHD symp oms pe 1 SD uni inc ease in ma e nal dep essi e symp oms du ing p egnancy.
Model 1: adjus ed o child sex and age a ollow-up
Model 2: adjus ed o model 1 + ma e nal age a childbi h, pa i y, amily s uc u e, educa ion le el, ype 1 diabe es, p e-p egnancy/ch onic hype ension,
his o y o physician-diagnosed dep ession, an idep essan and o he psycho opic medica ion use, alcohol use and smoking du ing p egnancy, and
ges a ion leng h and in an ’s bi hweigh adjus ed o sex and ges a ion leng h
Model 3: adjus ed o model 2 + ma e nal p e-p egnancy obesi y, ges a ional diabe es, ges a ional hype ension and p e-eclampsia
Model 4: adjus ed o model 3 + ma e nal ADHD p oblems
Model 5: adjus ed o model 4 + ma e nal dep essi e symp oms a e p egnancy
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Ma e nal dep essi e symp oms du ing p egnancy and child a en ion-de ici /hype ac i i y diso de symp oms
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Fig 2. Es ima ed ma ginal means (Panel A) o he child’s beha iou al symp oms o a en ion-de ici /hype ac i i y
diso de on he Conne s’ Hype ac i i y Index (CHI) and p opo ion o child en wi h sco es abo e he clinical cu o
(10) in he CHI (Panel B) acco ding o he ma e nal Cen e o Epidemiological S udies Dep ession Scale (CES-D)
imes e -weigh ed mean sco e (16) du ing p egnancy and Beck Dep ession In en o y-II (BDI-II) sum sco e (14)
a e p egnancy abo e and below he clinical cu o s. E o ba s e e o 95% Con idence In e als (95% CI), and numbe s
o mean di e ences (MD) (Panel A) and odds a ios (OR) (Panel B) and hei 95% CIs in model 1, and p- alues o models 1–4.
Women who sco ed below he clinical cu o in bo h he CES-D du ing p egnancy and in he BDI-II a e p egnancy we e used as
he compa ison g oup. Fo di e en adjus men models, please see oo no e in Table 1.
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Fig 3. Media ion model o he e ec s o ma e nal dep essi e symp oms du ing p egnancy on child’s beha iou al
symp oms o a en ion-de ici /hype ac i i y diso de on he Conne s’ Hype ac i i y Index ia ma e nal dep essi e
symp oms a e p egnancy. Numbe s e e o uns anda dized eg ession coe icien s (B) and hei 95% Con idence In e als om
models adjus ed o child’s age and sex, and o he p opo ion (R
2
) ma e nal dep essi e symp oms du ing and a e p egnancy
explain o he child’s ADHD symp oms.
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Ma e nal dep essi e symp oms du ing p egnancy and child a en ion-de ici /hype ac i i y diso de symp oms
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Sensi i i y analyses
S4 Table shows ha ma e nal p e-p egnancy obesi y and p egnancy diso de s, child’s sex,
ma e nal his o y o physician-diagnosed dep ession, o ma e nal ADHD p oblems had no
e ec s on he indings: ac oss all g oups, he associa ions be ween ma e nal dep essi e symp-
oms du ing p egnancy and child ADHD symp oms we e signi ican .
Discussion
Ou s udy showed, i s , ha ma e nal dep essi e symp oms h oughou p egnancy a e associ-
a ed wi h child ADHD symp oms. We also showed ha ma e nal dep essi e symp oms du ing
p egnancy we e highly s able, and child en o mo he s wi h consis en ly high dep essi e symp-
oms du ing p egnancy showed highe le els o ADHD symp oms a he age o 3 o 6 yea s.
These child en also showed a highe p opo ion (o e 32%) and 2.8- imes highe odds o clin-
ically signi ican ADHD symp oms. I was he e o e no su p ising ha we ound no ges a-
ion-week o imes e -speci ic associa ions be ween ma e nal dep essi e symp oms du ing
p egnancy and child ADHD symp oms. None o hese associa ions we e accoun ed o by a
numbe o pe ina al, ma e nal and neona al cha ac e is ics, and a se ies o sensi i i y analyses
demons a ed ha he associa ions did no ei he a y by ma e nal p e-p egnancy obesi y,
hype ensi e p egnancy diso de s, o ges a ional diabe es, child’s sex, ma e nal his o y o phy-
sician-diagnosed dep ession, o ma e nal ADHD p oblems.
Ou s udy also showed ha highe le els o ma e nal dep essi e symp oms a e p egnancy
we e associa ed wi h highe child ADHD symp om sco es. These highe le els o dep essi e
symp oms a e p egnancy only pa ially accoun ed o he p ena al e ec s as ma e nal dep es-
si e symp oms du ing p egnancy also had a signi ican di ec e ec on he child’s ADHD
symp oms when adjus ing o he symp oms a e p egnancy. They did, howe e , add o he
p ena al e ec s, such ha child ADHD symp om sco es and he p opo ion and odds o chil-
d en wi h clinically signi ican ADHD symp oms we e he highes among hose women wi h
clinically signi ican dep essi e symp oms bo h du ing and a e p egnancy. Toge he ma e nal
dep essi e symp oms du ing and a e p egnancy accoun ed o 11% o he a ia ion in he
child’s ADHD symp oms.
Ou indings co espond wi h he De elopmen al O igins o Heal h and Disease (DOHaD)
amewo k sugges ing ha p ena al exposu e o en i onmen al ad e si y may ca y endu ing
e ec s on b ain de elopmen al sequelae, including isk o ADHD symp oma ology
[12,13,34]. Ou indings a e also in alignmen wi h ou own ecen s udy on psychia ic beha -
iou p oblems [16], and he o he wo p e ious p ospec i e s udies based on he ALSPAC and
he Gene a ion-R coho s on child a en ion and hype ac i i y p oblems [19,20] showing ha
ma e nal dep essi e symp oms du ing p egnancy a e associa ed wi h child ADHD symp oms.
Also in alignmen wi h he ALSPAC s udy, ou s udy showed ha ma e nal dep essi e symp-
oms a e p egnancy did no en i ely accoun o he e ec s o ma e nal dep essi e symp oms
du ing p egnancy on child’s ADHD symp oms. In con as , in he Gene a ion-R s udy ma e -
nal dep essi e symp oms a e p egnancy ende ed he p ena al e ec s on child a en ion p ob-
lems non-signi ican [19]. While ou s udy is o ou knowledge he i s o o mally es o
media ion, bo h he ALSPAC and Gene a ion-R indings poin o media ion: he ALSPAC
indings poin o pa ial and he Gene a ion-R indings poin o ull media ion o he p ena al
dep ession e ec s ia he dep ession e ec s a e p egnancy.
An ob ious s udy limi a ion is ha we a e no able o speci y he b ain s uc u al o unc-
ional no biological o beha iou al unde lying mechanisms. Exis ing li e a u e sugges s ha
highe ma e nal dep essi e symp oms and/o sali a y co isol le els du ing p egnancy a e
linked wi h al e ed o sp ing b ain s uc u e and unc ional connec i i y [35], and wi h co ical
Ma e nal dep essi e symp oms du ing p egnancy and child a en ion-de ici /hype ac i i y diso de symp oms
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