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SCIENTIFIC RePoRTS | (2018) 8:791 | DOI:10.1038/s41598-017-19133-9
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Placen al Mo phology Is Associa ed
wi h Ma e nal Dep essi e
Symp oms du ing P egnancy and
Toddle Psychia ic P oblems
Ma ius Lah i-Pulkkinen
1,2,3, Melissa Jane Cudmo e2, E a Haeussne 4, Ch is oph Schmi z
4,
Anu-Ka iina Pesonen1, Esa Hämäläinen5, Pia M. Villa6, Susanna Meh älä7, Ee o Kajan ie3,8,9,
Hannele Lai uo i
7,10,11,12, Rebecca M. Reynolds2, Hans-Geo g F ank4 & Ka i Räikkönen1
Ma e nal dep essi e symp oms du ing p egnancy p edic inc eased psychia ic p oblems in child en.
The unde lying biological mechanisms emain unclea . Hence, we examined whe he al e a ions in
he mo phology o 88 e m placen as we e associa ed wi h ma e nal dep essi e symp oms du ing
p egnancy and psychia ic p oblems in 1.9–3.1-yea s old (Mean = 2.1 yea s) oddle s. Ma e nal
dep essi e symp oms we e a ed biweekly du ing p egnancy wi h he Cen e o Epidemiological S udies
Dep ession Scale (n = 86). Toddle psychia ic p oblems we e mo he - a ed wi h he Child Beha io
Checklis (n = 60). We ound ha highe ma e nal dep essi e symp oms h oughou p egnancy
[B = −0.24 S anda d De ia ion (SD) uni s: 95% Con idence In e al (CI) = −0.46; −0.03: P = 0.03; Mean
di e ence = −0.66 SDs; 95% CI = −0.08; −1.23: P = 0.03; be ween hose wi h and wi hou clinically
ele an dep essi e symp oms] we e associa ed wi h lowe a iabili y in he placen al illous ba ie
hickness o γ-smoo h muscle ac in-nega i e illi. This placen al mo phological change p edic ed
highe o al (B = −0.34 SDs: 95% CI = −0.60; −0.07: P = 0.01) and in e nalizing (B = −0.32 SDs:
95% CI = −0.56; −0.08: P = 0.01) psychia ic p oblems in oddle s. To conclude, ou indings sugges
ha bo h ma e nal dep essi e symp oms du ing p egnancy and oddle psychia ic p oblems may be
associa ed wi h lowe a iabili y in he illous memb ane hickness o pe iphe al illi in e m placen as.
This lowe he e ogenei y may comp omise ma e no- e al exchange, sugges ing a possible ole o
al e ed placen al mo phology in he e al p og amming o men al diso de s.
Ma e nal clinically ele an dep essi e symp oms complica e up o 10–20% o p egnancies1–5. Ma e nal dep es-
si e symp oms no only dis up he heal h o he p egnan woman4,6 bu also ha e ad e se consequences on
o sp ing men al heal h2,3,7–9. Se e al s udies ha e shown ha ma e nal dep essi e symp oms du ing p egnancy
p edic inc eased psychia ic p oblems in o sp ing, and hese e ec s a e no explained by ma e nal dep essi e
symp oms a e p egnancy2,3,7–9. Fo example, we showed among 2296 P edic ion and P e en ion o P eeclampsia
and In au e ine G ow h Res ic ion (PREDO)-s udy pa icipan s ha ma e nal dep essi e symp oms du ing
1Depa men o Psychology and Logopedics, Uni e si y o Helsinki, Helsinki, Finland. 2B 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. 3Ch onic Disease P e en ion Uni , Na ional Ins i u e o Heal h and Wel a e, Helsinki, Finland.
4Depa men o Ana omy II, LMU Munich, Munich, Ge many. 5HUSLAB and Depa men o Clinical Chemis y,
Helsinki Uni e si y Cen al Hospi al, Helsinki, Finland. 6Obs e ics and Gynaecology, Uni e si y o Helsinki and
Helsinki Uni e si y Hospi al, Helsinki, Finland. 7Medical and Clinical Gene ics, Uni e si y o Helsinki and Helsinki
Uni e si y Hospi al, Helsinki, Finland. 8PEDEGO Resea ch Uni , MRC Oulu, Oulu Uni e si y Hospi al and Uni e si y
o Oulu, Oulu, Finland. 9Child en’s Hospi al, Helsinki Uni e si y Hospi al and Uni e si y o Helsinki, Helsinki, Finland.
10Ins i u e o Molecula Medicine Finland, HiLIFE Uni , Uni e si y o Helsinki, Helsinki, Finland. 11Facul y o Medicine
and Li e Sciences, Uni e si y o Tampe e, Tampe e, Finland. 12Depa men o Obs e ics and Gynecology, Tampe e
Uni e si y Hospi al, Tampe e, Finland. Ma ius Lah i-Pulkkinen and Melissa Jane Cudmo e con ibu ed equally o his
wo k. Co espondence and eques s o ma e ials should be add essed o M.L.-P. (email: ma ius.lah i-pulkkinen@
helsinki. i)
Recei ed: 23 Oc obe 2017
Accep ed: 21 Decembe 2017
Published: xx xx xxxx
OPEN
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SCIENTIFIC RePoRTS | (2018) 8:791 | DOI:10.1038/s41598-017-19133-9
p egnancy p edic inc eased psychia ic p oblems in child en, independen ly o ma e nal dep essi e symp oms
a e p egnancy3. Howe e , he biological mechanisms unde lying hese associa ions emain la gely unknown.
Eme ging e idence sugges s ha ma e nal dep essi e symp oms du ing p egnancy may al e ma e nal
physiological homeos asis abo e and beyond al e a ions induced by he p egnancy i sel , leading o changes in
hypo halamic-pi ui a y-ad enoco ical axis, in lamma o y and au onomic ne ous sys em unc ioning, and in
oxida i e s ess and nu i ion le els2,6,9–14. These dep ession- ela ed physiological changes may al e he no mal
placen al adap a ion and emodelling which occu s o ensu e ha he equi emen s o oxygen, ho mones, nu i-
en s and was e emo al o he g owing e us a e me h oughou ges a ion15.
Abe a ions in placen al de elopmen and ma u a ion ha ad e sely a ec he capaci y o he placen a o
p o ide op imal ma e no- e al exchange can in luence e al heal h and p og am he e us o disease de elopmen
la e in li e16,17. A ma u e placen a comp ises an ex ensi e illous ee con aining a ne wo k o e al capilla -
ies ha ba hes in a pool o ma e nal blood18. The illous ee consis s o la ge s uc u al s em illi ha a bo-
ize o o m in e media e and e minal illi, wi h a γ-smoo h muscle ac in(SMA)-posi i e pe i ascula laye o
myo ib oblas -like cells ha abo ize in he ( hen myo ib oblas - ee and SMA-nega i e) pe iphe al pa o he
illous ee19. This pe iphe al pa o he illous ee acili a es mos ma e no- e al exchange20. The whole illous
ee is co e ed by a p incipally bi-laye ed epi helium wi h an a - e m la gely incomple e basal laye o cy o oph-
oblas s and an apical laye , called he syncy io ophoblas . The laye s om he apical aspec o he syncy io opho-
blas o he apical (luminal) su ace o he e al capilla y endo helium cons i u e he placen al illous memb ane21,
he illous ma e no- e al ba ie 15. As p egnancy p og esses and e al demand o gaseous and nu ien exchange
inc eases, he illous memb ane hickness becomes i egula 22. Some a eas become ex emely hin as locally
dila ed segmen s o e al capilla ies p o ude in o he ophoblas laye and some a eas emain hicke , whe e
syncy ial o ganelles and nuclei accumula e ou wi h hese hin ba ie a eas18,23. The a eas o ex emely hin il-
lous memb ane, as small as 1–2 mic ons, a e known as asculo-syncy ial memb anes (VSM) and a e he p ima y
ma e no- e al exchange si es24. Thus, a heal hy la e ges a ion placen a has high a iabili y in illous memb ane
hickness measu es and hence di usion dis ance e idenced by la ge s anda d de ia ions (SD:s)25. Inc eased VSM
hickness and a esul ing dec ease in illous memb ane hickness a iabili y has been shown in placen as om
p egnancies complica ed by p eeclampsia26 and ges a ional diabe es27.
P e ious s udies ha e shown ha ma e nal psychological dis ess du ing p egnancy may be associa ed wi h
al e ed placen al weigh and e oplacen al ci cula ion28,29, and al e a ions in placen al weigh and/o su ace a ea
may p edic psychia ic dis u bance in childhood and adolescence30, and ce ain pe sonali y diso de s31 and
ai s32 in adul hood. Ye , no p e ious s udies ha e es ed associa ions be ween ma e nal dep essi e symp oms
o child psychia ic p oblems and placen al mo phology. In his hypo hesis-gene a ing s udy, we es ed whe he
ma e nal dep essi e symp oms du ing p egnancy a e associa ed wi h al e a ions in he mo phology o e m pla-
cen as, and i e m placen al mo phology p edic s child psychia ic p oblems in oddle hood.
Resul s
Pa icipan Cha ac e is ics and Po en ial Con ounde s. Table1 shows he sample cha ac e is ics. In
ou s udy sample, ma e nal dep essi e symp oms showed high in e -indi idual s abili y ac oss p egnancy imes-
e s ( ’s om =0.63 o =0.84, P < 0.001). Toddle in e nalizing, ex e nalizing and o al psychia ic p oblems also
had high in e -co ela ions ( ’s om =0.63 o =0.88, P < 0.001). Supplemen a y TableS1 shows he in e co ela-
ions be ween he di e en placen al mo phology indica o s.
Ma e nal diabe ic and hype ensi e diso de s in p egnancy we e associa ed wi h smalle capilla y olumes
pe SMA-posi i e illi pe placen a (Mean Di e ence (MD) = 0.56: 95% Con idence In e al (CI) = 0.00;1.12:
P = 0.05). Gi ls had la ge capilla y olumes pe SMA-nega i e illi pe placen a han boys (MD = 0.41:
95%CI = 0.01;0.81: P = 0.05). Ges a ion leng h was posi i ely associa ed wi h olumes o SMA-nega i e
illi ( = 0.24; P = 0.02) and capilla ies pe SMA-nega i e illi ( = 0.27; P = 0.01) pe placen a. Ma e nal age,
p e-p egnancy body mass index (BMI), educa ion, o his o y o men al diso de s be o e p egnancy we e no
associa ed wi h placen al mo phology (P- alues ≥ 0.10).
Ma e nal Dep essi e Symp oms du ing P egnancy and Placen al Mo phology. Highe ma e -
nal dep essi e symp oms h oughou p egnancy (Table2) and du ing each p egnancy imes e (Table3) we e
associa ed wi h a signi ican ly smalle SD o he illous ba ie hickness o SMA-nega i e illi (indica ing less il-
lous ba ie hickness a iabili y) in unadjus ed and/o adjus ed eg ession analyses. Figu e1 shows ha simila
associa ions wi h a smalle SD o SMA-nega i e illi illous ba ie hickness we e ound when CES-D dep essi e
symp oms h oughou p egnancy we e abo e he clinical cu o sco e (Panel A), and when hese symp oms we e
mo e equen ly abo e he cu o du ing p egnancy imes e s (Panel B). The associa ions wi h his placen al
mo phology indica o we e mos consis en ac oss analy ic models o ma e nal dep essi e symp oms du ing he
i s p egnancy imes e (Table3).
Placen al Mo phology and Child Psychia ic P oblems. A smalle SD o he illous ba ie hickness
o SMA-nega i e illi p edic ed signi ican ly highe oddle o al and in e nalising psychia ic p oblems in unad-
jus ed and adjus ed eg ession models (Table4). A smalle SD o SMA-nega i e illi illous ba ie hickness also
p edic ed highe oddle sleep, a ec i e, anxie y, anxious/dep essed, emo ionally eac i e, pe asi e de elopmen-
al and opposi ional de ian p oblems in unadjus ed and/o adjus ed eg ession models (Supplemen a y TableS2).
Discussion
This explo a i e, hypo hesis-gene a ing s udy examined whe he ma e nal dep essi e symp oms du ing p eg-
nancy and subsequen oddle psychia ic p oblems we e associa ed wi h mo phology al e a ions o e m pla-
cen as. We ound ha bo h ma e nal dep essi e symp oms ac oss p egnancy and oddle o al and in e nalizing
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SCIENTIFIC RePoRTS | (2018) 8:791 | DOI:10.1038/s41598-017-19133-9
psychia ic p oblems we e associa ed wi h less a ia ion in SMA-nega i e illi illous ba ie hickness, sugges -
ing an associa ion wi h placen al ma u a ion. These associa ions we e independen o se e al ma e nal and od-
dle sociodemog aphic and pe ina al cha ac e is ics. The associa ions o ma e nal dep essi e symp oms wi h
placen al mo phology we e he mos consis en o dep essi e symp oms du ing he i s p egnancy imes e ,
and hey we e also independen o ma e nal his o y o physician-diagnosed men al diso de s be o e p egnancy.
The associa ions o placen al mo phology wi h oddle psychia ic p oblems we e also independen o ma e nal
dep essi e symp oms concu en ly o child assessmen .
The illous ba ie is he physical ba ie h ough which ma e nal- e al exchange o gases, nu ien s and was e
occu s. I s hickness di ec ly co ela es wi h exchange e iciency, hus i is a highly ele an physiological measu e-
men . As ges a ion p og esses he exchange demands placed on his ba ie inc ease and he illous ba ie o he
SMA-nega i e illi becomes mo e he e ogeneous in hickness. Fe al capilla ies, especially hei sinusoidal essels
in he e minal segmen s o he illous ee23, dila e in o anuclea a eas o he syncy ium leading o a eas o he
illous ba ie ha a e ex emely hin o maximize exchange e iciency24. Howe e , o accommoda e hese a eas o
Ma e nal Cha ac e is ics Da a
A ailable(N) Mean(SDa)/N(%)
Age a Deli e y (yea s) 88 31.5 (4.9)
Educa ion, Te ia y 88 57 (64.8%)
P e-P egnancy Body Mass Index (kg/m2) 88 24.0 (4.2)
Any Diabe ic o Hype ensi e Diso de in P egnancy ( ype 1 o ges a ional diabe es, ch onic o
ges a ional hype ension, p e-eclampsia), Yes 88 15 (17.0%)
His o y o Physician-Diagnosed Men al Diso de s Be o e P egnancy, Yes 80 13 (16.3%)
Dep essi e Symp oms
T imes e -Weigh ed Mean Sco e o Cen e o Epidemiological S udies 86 10.3 (6.0)
Dep ession Scale Dep essi e Symp oms du ing P egnancy
T imes e -Weigh ed Mean Sco e o Cen e o Epidemiological S udies 86 14 (16.3%)
Dep ession Scale Dep essi e Symp oms du ing P egnancy ≥ 16
1s P egnancy T imes e Cen e o Epidemiological S udies Dep ession 81 10.2 (6.7)
Scale Dep essi e Symp om Sco e
Mean o 2nd P egnancy T imes e Cen e o Epidemiological S udies 86 10.4 (6.5)
Dep ession Scale Dep essi e Symp om Sco es
Mean o 3 d P egnancy T imes e Cen e o Epidemiological S udies 86 10.3 (6.6)
Dep ession Scale Dep essi e Symp om Sco es
Numbe o P egnancy T imes e s wi h Cen e o Epidemiological S udies 81
0 53 (65.4%)
1 16 (19.8%)
2–3 12 (14.8%)
Beck Dep ession In en o y-II Sco e Concu en ly o Ra ing he Child 60 5.9 (5.5)
Placen al Mo phology
Volume o SMAb-Posi i e Villi pe Placen a (ml) 88 95.1 (50.9)
Volume o Capilla ies pe SMA-Posi i e Villi pe Placen a (ml) 88 56.0 (35.6)
Volume o SMAb-Nega i e Villi pe Placen a (ml) 88 182.7 (63.9)
Volume o Capilla ies pe SMAb-Nega i e Villi pe Placen a (ml) 88 157.5 (51.8)
Ra io o he Dis ibu ion o SMAb-Posi i e Villi o SMA-Nega i e Villi (%) 88 63.7 (56.8)
Villous Ba ie Thickness o SMAb-Posi i e Villi (µm) 88 7.5 (1.7)
S anda d De ia ion o Villous Ba ie Thickness o SMAb-Posi i e Villi (Va iabili y in Thickness) (µm) 88 6.3 (2.3)
Villous Ba ie Thickness o SMAb-Nega i e Villi (µm) 88 11.9 (4.6)
S anda d De ia ion o Villous Ba ie Thickness o SMAb-Nega i e Villi (µm) 88 10.2 (5.5)
Placen al Weigh (g ams) 88 589.7 (107.4)
Toddle Cha ac e is ics
Ges a ion Leng h (weeks) 88 40.3 (1.0)
Sex 88
Boys 41 (46.6%)
Gi ls 47 (53.4%)
Age a Follow-up (mon hs) 60 25.5 (2.9)
Child Beha io Checklis /1½-5 Psychia ic P oblems
To al P oblems 60 46.8 (9.2)
In e nalizing P oblems 60 45.4 (8.5)
Ex e nalizing P oblems 60 48.6 (9.4)
Table 1. Cha ac e is ics o he S udy Sample. aSMA = γ-smoo h muscle ac in. bSD = s anda d de ia ion.
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SCIENTIFIC RePoRTS | (2018) 8:791 | DOI:10.1038/s41598-017-19133-9
hinning, syncy io ophoblas ic o ganelles accumula e in hicke a eas ou wi h he VSMs, called syncy ial kno s33.
Thus, an i egula i y in illous ba ie hickness de elops and i s appea ance indica es op imal placen al ma u a-
ion. Acco ding o p e ious indings he de elopmen o VSMs and syncy ial kno s dec ease di usion esis ance
by 26%, compa ed wi h ha o a ba ie wi h uni o m hickness34 and he e is an in e se ela ionship be ween
he numbe o VSMs and e al hypoxia26. Analysis o uncomplica ed ull- e m placen as showed ha al hough
absolu e illous ba ie hickness measu emen s a ied be ween di e en placen as, he uni o mi y index (a a io
be ween he hick and hin illous ba ie a eas) was ela i ely cons an om one placen a o ano he 34. This indi-
ca es ha he e is likely an op imal i egula i y o he illous ba ie o maximally and op imally se e he g owing
e us. Ou da a showing ha less he e ogenei y in placen al illous ba ie hickness is associa ed wi h ma e nal
dep essi e symp oms could poin o a mechanism whe eby ma e nal dep ession- ela ed changes cause sub le
al e a ions in placen al ma u a ion, especially in he dynamic illous ophoblas laye s. This may comp omise
he e iciency and obus ness o ma e no- e al exchange (di usion con olled anspo in hinned memb ane
a eas and ac i ely suppo ed anspo in hicke a eas), which hen a ec s e al neu ode elopmen , leading o
psychia ic p oblems in oddle s. Among illous ophoblas laye s, he mos impo an o his inding could
be he syncy io ophoblas , which is he epi helium a he ma e no- e al bo de and can be conside ed a s eady
s a e s uc u e in a ulne able sandwich posi ion be ween cy o ophoblas p oli e a ion and syncy ial shedding35.
While ma e nal diabe es o hype ension in p egnancy did no explain he associa ions o placen al mo -
phology wi h ma e nal o oddle psychopa hology, placen as om diabe ic o hype ensi e p egnancies had
smalle essel olumes in SMA-posi i e illi. The essels wi hin he SMA-posi i e illi a e he undamen al con-
dui s o blood supply om e us o he SMA-nega i e pe iphe al pa o he illous ee, which a e he p ima y
si es o ma e no- e al exchange15. Any educ ion in essel olume wi hin he mo e cen ally loca ed and la ge
SMA-posi i e illi would esul in subop imal blood supply o pe iphe al illi and hence comp omised e al nu i-
en and oxygen supply and was e emo al15. Al hough he illous ba ie hickness and hence he di using capac-
i y o he ba ie is unal e ed in p egnancies wi h diabe ic o hype ensi e diso de s36,37, i he ca ying capaci y o
s em illi capilla ies is comp omised due o hei sca ceness, a de icien exchange may ensue due o blood supply
om he e us being limi ed by he subop imal s em illi essel olume.
Figu e 1. (A) Ma e nal clinically signi ican an ena al dep essi e symp oms and placen al SMA-nega i e illi
illous ba ie hickness a iabili y. The igu e shows he unadjus ed mean alues and 95% Con idence In e als
o he s anda d de ia ion o placen al SMA-nega i e illi illous ba ie hickness (in s anda d de ia ion uni s)
o mo he s wi h imes e -weigh ed mean an ena al dep essi e symp oms below o abo e he clinical cu o
o ≥16 poin s. P- alues e e o g oup di e ence signi icances om unadjus ed linea eg ession models (model
1), models adjus ed o ma e nal age, educa ion, p e-p egnancy BMI, hype ensi e and diabe ic diso de s
in p egnancy and ges a ion leng h (model 2), and models adjus ed also o ma e nal his o y o physician-
diagnosed men al diso de s be o e p egnancy (model 3). (B) Ma e nal accumula i e dep essi e symp oms
du ing p egnancy and SMA-nega i e illi illous ba ie hickness a iabili y. The igu e shows he unadjus ed
mean alues and 95% Con idence In e als o he s anda d de ia ion o SMA-nega i e illi illous ba ie
hickness in s anda d de ia ion uni s, acco ding o he numbe o p egnancy imes e s [0, 1, 2–3] ma e nal
dep essi e symp om sco es du ing p egnancy we e abo e he clinical cu o o ≥16, when calcula ed om he
alue a he i s imes e and mean alues ac oss second and hi d imes e s. P- alues e e o he signi icances
o g oup di e ences and linea ends om unadjus ed linea eg ession models (model 1), models adjus ed o
ma e nal age, educa ion, p e-p egnancy BMI, hype ensi e and diabe ic diso de s in p egnancy and ges a ion
leng h (model 2), and models adjus ed also o ma e nal his o y o physician-diagnosed men al diso de s be o e
p egnancy (model 3).
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SCIENTIFIC RePoRTS | (2018) 8:791 | DOI:10.1038/s41598-017-19133-9
The limi a ions o ou s udy include he small sample size and use o only ma e nal epo s o ma e nal dep es-
si e symp oms and oddle psychia ic p oblems. The sample size was 86 o he analyses on ma e nal dep essi e
symp oms du ing p egnancy and placen al mo phology, and only 60 o he analyses on placen al mo phology
and oddle psychia ic p oblems. Hence, he e is a possibili y o chance indings, and ou indings need o be
eplica ed in la ge s udy samples.
Fu he mo e, a i ion analyses sugges ed ha some key cha ac e is ics o he s udy sample may be associa ed
wi h s udy a i ion, which may limi he gene alizabili y o ou indings. Since he women pa icipa ing in he
cu en s udy sco ed lowe on an ena al dep essi e symp oms han he o he women in he PREDO, and since
bi h egis e da a sugges s ha none o he pa icipa ing mo he s had been diagnosed wi h men al diso de s
du ing p egnancy, he gene alizabili y o he indings o mo e se e e le els o ma e nal dep ession is ques ion-
able. Howe e , we did de ec associa ions wi h he same indica o o placen al mo phology o bo h con inu-
ously assessed an ena al dep essi e symp oms and o an ena al dep essi e symp oms exceeding a cu o sco e
o clinically ele an symp oms. Also he oddle s in he cu en s udy sample we e younge han he o he
PREDO child en a he ime o comple ion o he CBCL, e lec ing ha sampling o placen as we e added la e o
he PREDO s udy p o ocol, and some psychia ic p oblems assessed in he CBCL may no ye ha e de eloped o
hei ull ange o a ia ion by 2–3 yea s o oddle age when psychia ic p oblems we e assessed. P e ious s udies
show ha he le el o in e nalizing p oblems inc eases be ween 1.5 and 5 yea s o age3,38. Howe e , he age ange
o he cu en s udy sample is wi hin he in ended age ange o he use o CBCL ques ionnai e (1.5–5 yea s), he
scale has been alida ed o his whole age ange38–40, and oddle age was no associa ed wi h oddle in e nal-
izing, ex e nalizing, o o al psychia ic p oblems in ou s udy sample ( = 0.00, = −0.12, = −0.07, espec i ely,
P- alues ≥ 0.37).Ye , ou indings need o be eplica ed also among olde child en.
Also, e en hough ou explo a i e s udy indica ed associa ions o he biological ma ke s o placen al mo -
phology wi h ma e nal an ena al dep essi e symp oms and oddle psychia ic p oblems, we do no know which
physiological ac o s unde lie hese associa ions. As s a ed, ma e nal dep ession du ing p egnancy is associa ed
wi h physiological changes in he unc ioning o he neu obiological s ess sys em, oxida i e s ess and ma e nal
nu i ion6,9–14. As such changes a e also associa ed wi h placen al mo phology41–45 and/o wi h psychia ic p ob-
lems in he o sp ing46,47, hese ac o s may ha e con ibu ed o he associa ions ound. Fu he mo e, we canno
ule ou o con i m gene ic explana ions o ou indings, wi h some gene ic ulne abili ies con ibu ing bo h
o ma e nal dep essi e symp oms, abe a ions in placen al de elopmen and inc eased psychia ic p oblems in
oddle s. Fu he s udies a e needed o elucida e he con ibu o y e ec s o gene ic and en i onmen al ac o s o
ou indings.
On he o he hand, we ci cum en ed he weakness o con en ional his ologic illous classi ica ions (di e -
en ia ion in s em, in e media e, and e minal illi) in he ecogni ion o pe iphe al illous a bo iza ions48–50
by de ec ing SMA as a c i e ion o mo e cen al (s em illus like, SMA-posi i e) o pe iphe al (SMA-nega i e)
illi. Howe e , ca e should be aken since many SMA-posi i e illi did no ha e a la ge calib e han many
SMA-nega i e illi, making hem his ologically indisce nible. The e m s em illus is hus no a synonym o
e m SMA-posi i e illus. By 2D sec ion his ology, ecognizing di e ences in a bo iza ion opology is impossible;
nodes canno be ecognized. The ecen ly in oduced 3D mic oscopy o pe iphe al illous ees48–50 can po en-
ially p o ide his in o ma ion in u he s udies. Ye , ou s udy has a no el ocus, and i s s eng hs include he
Placen al Mo phology C i e ia
Ma e nal Dep essi e Symp oms du ing P egnancy
Model 1aModel 2bModel 3c
B(95% CI) pB(95% CI) pB(95% CI) p
Volume o SMA-posi i e illi pe placen a 0.06(−0.15;0.28) 0.56 0.11(−0.11;0.33) 0.34 0.11(−0.13;0.34) 0.36
Volume o capilla ies pe SMA-posi i e illi pe
placen a 0.05(−0.17;0.27) 0.65 0.09(−0.13;0.31) 0.42 0.10(−0.14;0.34) 0.41
Volume o SMA-nega i e illi pe placen a −0.09(−0.33;0.14) 0.43 −0.08(−0.31;0.14) 0.47 −0.06(−0.30;0.18) 0.64
Volume o capilla ies pe SMA-nega i e illi pe
placen a −0.13(−0.35;0.09) 0.26 −0.12(−0.34;0.10) 0.28 −0.10(−0.33;0.13) 0.40
Ra io o he dis ibu ion o s em illi o SMA-
nega i e illi 0.13(−0.09;0.34) 0.26 0.16(−0.06;0.38) 0.15 0.16(−0.07;0.40) 0.18
Villous ba ie hickness o SMA-posi i e illi −0.10(−0.32;0.12) 0.36 −0.12(−0.35;0.11) 0.31 −0.06(−0.30;0.18) 0.60
S anda d de ia ion o illous ba ie hickness o
SMA-posi i e illi ( a iabili y in hickness) −0.10(−0.31;0.13) 0.42 −0.08(−0.31;0.15) 0.49 −0.07(−0.32;0.18) 0.57
Villous ba ie hickness o SMA-nega i e illi −0.17(−0.38;0.04) 0.12 −0.21(−0.43;0.01) 0.06 −0.14(−0.37;0.09) 0.22
S anda d de ia ion o illous ba ie hickness o
SMA-nega i e illi ( a iabili y in hickness) −0.24(−0.46;−0.03) 0.03 −0.27(−0.50;−0.05) 0.02 −0.20(−0.43;0.04) 0.096
Table 2. Ma e nal Dep essi e Symp oms ac oss P egnancy and Placen al Mo phology. Uns anda dized
eg ession coe icien s (B) and hei 95% Con idence In e als (CI) indica ing s anda d de ia ion uni inc ease
in placen al mo phology c i e ia pe one s anda d de ia ion inc ease in ma e nal dep essi e symp oms ac oss
p egnancy om linea eg ession models whe e ma e nal dep essi e symp oms du ing p egnancy we e used
as p edic o s o placen al mo phology c i e ia. SMA = γ-smoo h muscle ac in. aModel 1 e e s o unadjus ed
linea eg ession models. bModel 2 e e s o linea eg ession models adjus ed o ges a ion leng h, ma e nal age
a deli e y, educa ion, p e-p egnancy body mass index and diabe ic and hype ensi e diso de s in p egnancy.
cModel 3 e e s o linea eg ession models adjus ed o model 2 co a ia es and ma e nal his o y o men al
diso de s be o e p egnancy.

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SCIENTIFIC RePoRTS | (2018) 8:791 | DOI:10.1038/s41598-017-19133-9
longi udinal design, he use o alida ed ques ionnai es on ma e nal and oddle psychopa hology39,51–54, and he
epea ed, o nigh ly assessmen s o ma e nal an ena al dep essi e symp oms.
In summa y, ou no el, explo a i e, hypo hesis-gene a ing s udy showed ha ma e nal dep essi e symp oms
du ing p egnancy we e associa ed wi h lowe a iabili y in he hickness o he illous memb ane o he pe iph-
e al illi in e m placen as. This lowe a iabili y, indica ing a educ ion in he a iabili y in he illous ba ie
hickness o SMA-nega i e illi, was also associa ed wi h subsequen oddle psychia ic p oblems. We p opose
ha his lowe he e ogenei y in illous ba ie hickness may comp omise ma e no- e al exchange, sugges ing a
possible ole o al e ed placen al s uc u e in he e al p og amming o men al diso de s16.
Me hods
Pa icipan s we e om he p ospec i e PREDO coho 55, which comp ises 4777 p egnan women who ga e bi h
o single on li e-bo n child en in 2006–2010. These women we e ec ui ed o he s udy in ea ly p egnancy a
i s ul asound measu emen s a he an ena al clinics o en s udy hospi als in Finland. All pa icipa ing women
Dep essi e Symp oms du ing 1s P egnancy T imes e (n = 81) 2nd P egnancy T imes e (n = 86) 3 d P egnancy T imes e (n = 86)
Placen al C i e ia B(95% CI) pB(95% CI) pB(95% CI) p
Volume o SMA-posi i e illi pe placen a
Model 1 0.01(−0.22; 0.23) 0.97 0.05(−0.16; 0.26) 0.61 0.12(−0.09; 0.33) 0.27
Model 2 0.06(−0.18; 0.31) 0.61 0.10(−0.11; 0.32) 0.33 0.14(−0.07; 0.36) 0.19
Model 3 0.07(−0.18; 0.32) 0.59 0.10 (−0.12; 0.32) 0.37 0.15 (−0.08; 0.38) 0.21
Volume o capilla ies pe SMA-posi i e illi pe placen a
Model 1 0.00(−0.23; 0.23) 0.99 0.04(−0.17; 0.25) 0.68 0.11(−0.11; 0.32) 0.33
Model 2 0.07(−0.17; 0.32) 0.55 0.09(−0.13; 0.30) 0.43 0.12(−0.10; 0.34) 0.27
Model 3 0.09(−0.17; 0.34) 0.49 0.09(−0.14; 0.32) 0.43 0.14(−0.10; 0.37) 0.25
Volume o SMA-nega i e illi pe placen a
Model 1 0.05(−0.19; 0.29) 0.70 −0.07(−0.29; 0.14) 0.48 −0.16(−0.37; 0.06) 0.15
Model 2 −0.01(−0.26; 0.25) 0.97 −0.05(−0.27; 0.17) 0.66 −0.13(−0.35; 0.09) 0.23
Model 3 0.01(−0.26; 0.28) 0.94 0.02(−0.25; 0.21) 0.86 −0.11(−0.35; 0.13) 0.36
Volume o capilla ies pe SMA-nega i e illi pe placen a
Model 1 −0.02(−0.22; 0.26) 0.88 −0.12(−0.33; 0.09) 0.27 −0.18(−0.40; 0.03) 0.09
Model 2 −0.07(−0.32; 0.18) 0.59 −0.08(−0.29; 0.13) 0.46 −0.15(−0.36; 0.07) 0.17
Model 3 −0.06(−0.32; 0.20) 0.66 −0.06(−0.28; 0.17) 0.61 −0.13(−0.37; 0.10) 0.26
Ra io o he dis ibu ion o s em illi o SMA-nega i e illi
Model 1 0.01(−0.23; 0.25) 0.92 0.11(−0.10; 0.32) 0.30 0.20(−0.01; 0.41) 0.07
Model 2 0.09(−0.16; 0.35) 0.47 0.14(−0.07; 0.36) 0.19 0.21(−0.01; 0.42) 0.06
Model 3 0.09(−0.17; 0.36) 0.48 0.14(−0.09; 0.36) 0.23 0.22(−0.02; 0.45) 0.07
Villous ba ie hickness o SMA-posi i e illi
Model 1 −0.09(−0.33; 0.15) 0.45 −0.06(−0.27; 0.15) 0.58 −0.14(−0.35; 0.08) 0.20
Model 2 −0.13(−0.39; 0.13) 0.33 −0.07(−0.29; 0.15) 0.52 −0.15(−0.38; 0.07) 0.18
Model 3 −0.08(−0.34; 0.18) 0.55 −0.03(−0.25; 0.20) 0.82 −0.10(−0.34; 0.14) 0.40
S anda d de ia ion o illous ba ie hickness o SMA-posi i e illi ( a iabili y in hickness)
Model 1 −0.06(−0.30; 0.19) 0.65 −0.07(−0.28; 0.14) 0.49 −0.10(−0.32; 0.11) 0.34
Model 2 −0.06(−0.32; 0.21) 0.67 −0.07(−0.29; 0.16) 0.56 −0.10(−0.33; 0.13) 0.38
Model 3 −0.04(−0.32; 0.23) 0.76 −0.06(−0.29; 0.18) 0.63 −0.10(−0.34; 0.15) 0.45
Villous ba ie hickness o SMA-nega i e illi
Model 1 −0.16(−0.40; 0.08) 0.18 −0.16(−0.36; 0.04) 0.12 −0.17(−0.38; 0.04) 0.11
Model 2 −0.25(−0.50; 0.00) 0.052 −0.19(−0.40; 0.03) 0.08 −0.19(−0.40; 0.02) 0.08
Model 3 −0.19(−0.44; 0.06) 0.14 −0.12(−0.34; 0.09) 0.26 −0.11(−0.34; 0.12) 0.35
S anda d de ia ion o illous ba ie hickness o SMA-nega i e illi ( a iabili y in hickness)
Model 1 −0.24(−0.48; −0.01) 0.04 −0.20(−0.40; 0.01) 0.06 −0.22(−0.43; −0.01) 0.04
Model 2 −0.33(−0.58; −0.08) 0.01 −0.23(−0.44; −0.01) 0.05 −0.23(−0.45; −0.01) 0.04
Model 3 −0.27(−0.53; −0.02) 0.04 −0.15(−0.37; 0.07) 0.18 −0.14(−0.37; 0.10) 0.24
Table 3. Ma e nal T imes e -Speci ic P ena al Dep essi e Symp oms and Placen al Mo phology. SMA = γ-smoo h
muscle ac in. Uns anda dized eg ession coe icien s (B) and hei 95% Con idence In e als (CI) om linea
eg ession models, indica ing s anda d de ia ion uni inc ease in placen al mo phology c i e ia pe one s anda d
de ia ion inc ease in mean ma e nal dep essi e symp oms du ing each p egnancy imes e . Reg ession Model 1 is
unadjus ed. Model 2 is adjus ed o ma e nal age and educa ion le el, p e-p egnancy body mass index, hype ensi e
and diabe ic diso de s in p egnancy and ges a ion leng h. Model 3 is adjus ed o Model 2 co a ia es and ma e nal
his o y o men al diso de s be o e p egnancy.
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signed in o med consen s. The PREDO s udy p o ocol was app o ed by Helsinki and Uusimaa Hospi al Dis ic
e hical commi ees55. The PREDO s udy has been conduc ed in acco dance wi h he decla a ion o Helsinki.
Placen al biopsy collec ion was in oduced o he s udy p o ocol in 2009. Samples we e collec ed a wo ma e -
ni y clinics in Helsinki, Finland. Placen al mo phology da a we e a ailable om 96 mo he -child dyads wi h
in an s bo n a e m in 2009–2010. Eigh had nei he ma e nal no child psychia ic da a and we e excluded om
his s udy.
Ou inal s udy sample hus comp ises 88 pa icipan s. O hem, 86 had da a on ma e nal dep essi e symp oms
du ing p egnancy and 60 on oddle psychia ic p oblems. Compa ed o o he PREDO mo he s, he mo he s
pa icipa ing in his s udy had less dep essi e symp oms du ing he hi d p egnancy imes e (MD = −0.24 SD
uni s: 95% CI = −0.45; −0.02: P = 0.03). Compa ed o non-pa icipa ing PREDO child en, he pa icipa ing od-
dle s we e younge a childhood ollow-up (MD = −1.37 yea s: 95% CI = −1.30; −1.44: P < 0.001). The e we e
no di e ences be ween pa icipa ing and non-pa icipa ing mo he s o oddle s in o he assessed cha ac e is ics
(ma e nal age, educa ion le el, BMI, diabe es and hype ension in p egnancy, his o y o physician-diagnosed
men al diso de s be o e p egnancy, dep essi e symp oms a o he ime poin s, ges a ion leng h o oddle sex o
psychia ic p oblems; P- alues ≥ 0.08).
Placen al Mo phology. Two placen a samples wi h an edge leng h o ~1 cm and ull dep h o he placen a
we e aken om each placen a a e bi h wi hou a p e e ence o speci ic placen al si es om mac oscopically
unsuspicious a eas, hen ou inely ixed in o maldehyde. A e ixa ion las ing a leas 24 hou s, he samples we e
ou inely dehyd a ed in an alcohol s ep g adien and embedded in pa a in. Fo mo phome ic analysis, hese
pa a in blocks we e ans e ed o LMU Munich, Ge many.
Pa a in samples we e sec ioned as 4–6 mic ome es hick sec ions and placed on supe os objec slides
(Supe F os plus, The mo ishe , Munich, Ge many). All slides we e depa a inized h ough xylene and a s ep-
wise e hanol g adien . Immunohis ochemical double labelling was pe o med, comp ising an an ibody o CD34
(labelling o e al endo helium) and o SMA (labelling o pe i ascula myo ib oblas -like cells)19. Pe oxidase wi h
DAB as subs a e (an i-CD34, b own eac ion p oduc ) and β-galac osidase wi h X-Gal as subs a e (an i-SMA,
indigo-blue eac ion p oduc ) we e used o di e en ial isualiza ion in b igh ield mic oscopy. Nuclei we e coun-
e s ained wi h haema oxylin. The sequence o s eps was empi ically op imized such ha he an i-CD34 de ec ion
was always ca ied ou i s and comple ely. Bo h immunohis ochemical sequences used s ep a idin-enzyme
conjuga es. C oss eac i i y due o s ep a idin use in bo h sequences was excluded by con ols included in
he second immunohis ochemical sequence (an i-SMA). SMA-de ec ion was used o classi ica ion o illi
based on ecommenda ions in he li e a u e49. A e pe oxidase de ec ion, an i-SMA de ec ion was pe o med.
Supplemen a y TablesS3–S4 gi e ull de ails o he immunohis ochemical eac ion s eps. Finally, he nuclei
we e coun e s ained wi h haema oxylin and he slides moun ed wi h co e slips (Kaise ’s glyce ol jelly, Me ck,
Da ms ad , Ge many). All objec slides we e s o ed a 4 °C p io o mic oscopic e alua ions.
We examined nine placen al mo phology c i e ia: he olumes o SMA-posi i e and SMA-nega i e (pe iph-
e al) illi pe placen a, he olume o capilla ies pe SMA-posi i e and SMA-nega i e illi pe placen a, he
a io o olumes o SMA-posi i e o SMA-nega i e illi, he illous ba ie hicknesses (dis ance om he
ou e ophoblas o he endo helium o he e al essels inside he illous ee) and he SDs o illous ba ie
hicknesses s a i ied by SMA-posi i e and SMA-nega i e illi. The olume c i e ia a e exp essed in millili es
and we e calcula ed by di iding he assessed c i e ion by placen al weigh (g ams). Volume es ima es we e
pe o med acco ding o he Ca alie i p inciple on single hin (4–6 mic ome es) his ological sec ions using
a compu e ized s e eology wo ks a ion, which comp ised a modi ied ligh mic oscope (Axioskop;Zeiss) wi h
mo o ized specimen s age o au oma ic sampling [MBF Bioscience, Willis on, VT, Uni ed S a es o Ame ica
Figu e 2. Immunohis ochemical double labeling o pe i ascula shea h and e al illous endo helium. (A)
Shows an example o a γ-smoo h-muscle-ac in(SMA)-posi i e illus (indigo-blue in pe i ascula posi ion;
whi e a ows). The endo helium o e al essels is labelled (CD34: b own; black a ows), he illous s oma
ma ked by as e isks and he ophoblas (bluish nuclei; shaded a ows) isible. (B) Exempli ies a SMA-nega i e
illus (no SMA eac i i y in pe i ascula posi ion). The endo helium o e al essels is labelled (CD34: b own;
black a ows), illous s oma ma ked by as e isks and ophoblas (bluish nuclei; shaded a ows) isible. Red
a ow heads label asculo-syncy ial-memb ane spo s. (A) Scale ba is 25 µm and alid o (B).
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SCIENTIFIC RePoRTS | (2018) 8:791 | DOI:10.1038/s41598-017-19133-9
(USA)] and s age con olle [Type MAC 6000, Ludl Elec onics, Haw ho ne, New Yo k, USA], ocus encode
(Type MT 1271, Heidenhain, Ge many), CCD colou ideo came a (1600H 3 1200 V pixels, MBF Bioscience,
Willis on, VT, USA) and s e eology so wa e (S e eo In es iga o e sion 10;MBF Bioscience). This app oach
deli e s olume ac ions as aw da a, which we e s a i ied o he illous ee subs uc u es ( illous s oma,
essel lumen, endo helium, and syncy io ophoblas ), in e illous space and ib inoid. Then, absolu e olumes
we e calcula ed by mul iplying olume ac ions wi h o al placen al olume [placen al olume is de ined by
placen al weigh di ided by he densi y o placen al issue (1.03 g/millili e)]. To de e mine illous ba ie
hickness, we used he Nea es Neighbo op ion in he s e eology so wa e (S e eo In es iga o e sion 10, MBF
Bioscience). The illous ba ie hickness is exp essed in mic ome es. Figu es2 and 3 show illus a ions o he
placen al mo phology c i e ia measu emen s.
Ma e nal Dep essi e Symp oms. The women assessed hei dep essi e symp oms o nigh ly up o 14
imes du ing p egnancy om p egnancy weeks + days 12 + 0/13 + 6 un il deli e y o 38 + 0/39 + 6 p egnancy
weeks + days wi h he Cen e o Epidemiological S udies Dep ession Scale (CES-D)53, which comp ises 20
Toddle Psychia ic P oblem Scale To al P oblems In e nalizing P oblems Ex e nalizing P oblems
Placen al Mo phology S uc u e B(95% CI) pB(95% CI) pB(95% CI) p
Volume o SMA-posi i e illi pe placen a
Model 1 0.02(−0.23; 0.27) 0.88 −0.03(−0.27; 0.19) 0.77 −0.05(−0.31; 0.21) 0.70
Model 2 −0.00(−0.27; 0.27) 0.98 −0.05(−0.29; 0.19) 0.69 −0.08(−0.36; 0.20) 0.58
Model 3 −0.04(−0.20; 0.27) 0.76 −0.02(−0.23; 0.20) 0.88 −0.04(−0.29; 0.22) 0.78
Volume o capilla ies pe SMA-posi i e illi pe placen a
Model 1 0.02(−0.23; 0.27) 0.90 −0.03(−0.25; 0.20) 0.81 −0.05(−0.31; 0.21) 0.68
Model 2 −0.02(−0.29; 0.25) 0.87 −0.07(−0.30; 0.17) 0.59 −0.08(−0.36; 0.20) 0.58
Model 3 −0.01(−0.25; 0.23) 0.92 −0.05(−0.27; 0.16) 0.63 −0.08(−0.33; 0.17) 0.54
Volume o SMA-nega i e illi pe placen a
Model 1 −0.05(−0.32; 0.23) 0.72 0.04(−0.21; 0.29) 0.75 −0.11(−0.39; 0.18) 0.46
Model 2 −0.12(−0.44; 0.19) 0.44 −0.02(−0.30; 0.26) 0.88 −0.20(−0.52; 0.13) 0.22
Model 3 0.05(−0.22; 0.32) 0.71 0.13(−0.11; 0.37) 0.28 −0.03(−0.31; 0.26) 0.84
Volume o capilla ies pe SMA-nega i e illi pe placen a
Model 1 −0.09(−0.35; 0.18) 0.51 −0.00(−0.24; 0.24) 0.99 −0.12(−0.40; 0.15) 0.36
Model 2 −0.20(−0.51; 0.11) 0.21 −0.09(−0.37; 0.19) 0.51 −0.25(−0.57; 0.07) 0.13
Model 3 0.00(−0.26; 0.25) 0.98 0.08(−0.15; 0.31) 0.49 −0.06(−0.33; 0.21) 0.67
Ra io o he dis ibu ion o SMA-posi i e illi o SMA-nega i e illi
Model 1 0.02(−0.23; 0.27) 0.88 −0.07(−0.30; 0.16) 0.54 0.00(−0.26; 0.26) 0.99
Model 2 0.03(−0.25; 0.31) 0.82 −0.06(−0.30; 0.19) 0.64 0.01 (−0.27; 0.30) 0.92
Model 3 0.01(−0.23; 0.25) 0.92 −0.08(−0.29; 0.14) 0.48 −0.00(−0.26; 0.25) 0.97
Villous ba ie hickness o SMA-posi i e illi
Model 1 −0.08(−0.36; 0.21) 0.60 −0.12(−0.37; 0.14) 0.36 0.02(−0.27; 0.31) 0.89
Model 2 −0.11(−0.44; 0.21) 0.48 −0.19(−0.47; 0.09) 0.18 0.01(−0.33; 0.35) 0.95
Model 3 0.02(−0.26; 0.29) 0.91 −0.04(−0.29; 0.21) 0.75 0.10(−0.19; 0.39) 0.49
S anda d de ia ion o illous ba ie hickness o SMA posi i e illi ( a iabili y in hickness)
Model 1 −0.02(−0.28; 0.23) 0.86 0.02(−0.21; 0.25) 0.87 −0.05(−0.31; 0.21) 0.70
Model 2 −0.05(−0.32; 0.22) 0.71 −0.01(−0.25; 0.23) 0.93 −0.07(−0.35; 0.21) 0.62
Model 3 0.06(−0.19; 0.31) 0.63 0.09(−0.13; 0.31) 0.40 0.02(−0.24; 0.27) 0.91
Villous ba ie hickness o SMA-nega i e illi
Model 1 −0.14(−0.42; 0.13) 0.31 −0.18(−0.42; 0.07) 0.16 −0.00(−0.29; 0.28) 0.98
Model 2 −0.16(−0.45; 0.12) 0.26 −0.20(−0.45; 0.05) 0.12 −0.01(−0.31; 0.29) 0.93
Model 3 −0.08(−0.34; 0.19) 0.56 −0.12(−0.36; 0.12) 0.31 0.05(−0.23; 0.33) 0.71
S anda d de ia ion o illous ba ie hickness o SMA-nega i e illi ( a iabili y in hickness)
Model 1 −0.34(−0.60; −0.07) 0.01 −0.32(−0.56; −0.08) 0.01 −0.20(−0.48; 0.09) 0.17
Model 2 −0.35(−0.63; −0.07) 0.01 −0.34(−0.59; −0.10) 0.01 −0.21(−0.51; 0.09) 0.16
Model 3 −0.29(−0.54; −0.03) 0.03 −0.28(−0.51; −0.05) 0.02 −0.15(−0.43; 0.13) 0.28
Table 4. Placen al Mo phology and Toddle Psychia ic P oblems. Uns anda dized eg ession coe icien s (B) and
hei 95% Con idence In e als (CI) indica ing s anda d de ia ion uni inc ease in oddle psychia ic p oblems
pe s anda d de ia ion inc ease in placen al mo phology c i e ia om linea eg ession models whe e placen al
mo phology c i e ia we e used o p edic oddle psychia ic p oblems. SMA = γ-smoo h muscle ac in. Model 1
is unadjus ed. Model 2 is adjus ed o oddle ’s age and sex, ges a ion leng h, ma e nal age a childbi h, educa ion,
p e-p egnancy BMI and ma e nal diabe ic and hype ensi e diso de s in p egnancy. Model 3 is adjus ed o ma e nal
dep essi e symp oms concu en ly o assessing he child’s psychia ic p oblems.
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SCIENTIFIC RePoRTS | (2018) 8:791 | DOI:10.1038/s41598-017-19133-9
ques ions on he equency o dep essi e symp oms du ing he p eceding week. CES-D sum-sco es ange om
0 o 60. Highe sco es indica e mo e dep essi e symp oms. The CES-D cu o sco e o ≥16 indica es isk o clin-
ical dep ession53. The CES-D has excellen psychome ic p ope ies52–54,56,57, and i has been alida ed also among
p egnan women57,58. In ou sample, he CES-D had high in e nal consis ency (C onbach’s α a ying om =0.85
o =0.93).
Toddle Psychia ic P oblems. When he oddle s we e 1.9–3.1 yea s old, he mo he s comple ed he
Child Beha io Checklis o Ages 1½-5 (CBCL1½-5) which is a well- alida ed and e y widely used scale on
child psychia ic p oblems39,51. I comp ises 99 i ems, a ed om 0 o 2. Highe -sco es e lec mo e p oblems
on he CBCL1½-5 main scales o in e nalizing, ex e nalizing and o al p oblems51, on he se en CBCL1½-5
Synd ome Scales and on he i e CBCL1½-5 Diagnos ic and S a is ical Manual o Men al Diso de s-Fou h
Edi ion-o ien ed scales51.
Co a ia es. In o ma ion on ma e nal p e-p egnancy heigh and weigh , o which p e-p egnancy BMI (kilo-
g ams/me es2) was calcula ed, ma e nal diabe es and/o hype ension in p egnancy (ges a ional and ype 1 dia-
be es, p eeclampsia, ch onic and ges a ional hype ension; any s. none), ma e nal age a deli e y, oddle sex,
bi h da e and ges a ion leng h was ex ac ed om he Finnish Medical Bi h Regis e and pa ien case eco ds.
Ma e nal his o y o physician-diagnosed men al diso de s (dep ession, panic diso de , schizoph enia, o he psy-
chosis, o he men al diso de ) be o e p egnancy (no/yes; n = 80; 6 mo he s wi h missing da a we e dummy-coded
o an own ca ego y o eg ession analysis) and educa ion le el (p ima y/seconda y s. e ia y) was sel - epo ed
du ing p egnancy. Mo he s assessed hei dep essi e symp oms a oddle ollow-up wi h he Beck Dep ession
In en o y-II59. Toddle age a ollow-up was calcula ed by sub ac ing bi h da e om CBCL1½-5 comple ion da e.
Figu e 3. An illus a ion o he illous memb ane hickness measu emen p inciple. (A,B) Show examples
o SMA-nega i e illi wi h endo helium labelled by CD34- eac i i y (b own eac ion p oduc ). (C,D) Show
examples o SMA-posi i e illi (indigo-blue eac ion p oduc in pe i ascula posi ion) wi h endo helium
labelled by CD34- eac i i y (b own eac ion p oduc ). (A–D) We measu ed memb ane hickness wi h he
Nea es Neighbo analysis and he sho es dis ance ( ed line) om he ophoblas o he e al endo helium by
inc easing a ci cle ( ed) om he ophoblas su ace un il i s in e sec ion wi h he endo helium. Exempla y
measu emen posi ions a e ma ked wi h black a ows. Scale ba is 25 µm.