In e na ional Jou nal o
En i onmen al Resea ch
and Public Heal h
A icle
Ma e nal Fe i in Le els du ing P egnancy and
ADHD Symp oms in 4-Yea -Old Child en: Resul s
om he INMA–IN ancia y Medio Ambien e
(En i onmen and Childhood) P ospec i e Bi h
Coho S udy
Lo e o San a-Ma ina 1,2,3, Ne ea Le xundi 2,4, Aina a Andia ena 2,4, Amaia I iza 1,2,5,*,
Jo di Sunye 1,6,7, Amaia Molinue o 1, Sab ina Llop 1,8, Jo di Jul ez 1,7,9 , And ea Benei o 8,
Jesús Iba luzea 1,2,3,4 , Lihe Imaz 3,10 and Mai e Fe in 11,12
1Spanish Conso ium o Resea ch on Epidemiology and Public Heal h (CIBERESP),
Ins i u o de Salud Ca los III, C/Mon o e de Lemos 3–5, 28029 Mad id, Spain;
[email p o ec ed] (L.S.-M.); [email p o ec ed]g (J.S.); [email p o ec ed] (A.M.);
[email p o ec ed] (S.L.); [email p o ec ed]g (J.J.); [email p o ec ed] (J.I.)
2
Biodonos ia, Epidemiology and Public Heal h A ea, En i onmen al Epidemiology and Child De elopmen
G oup, 20014 San Sebas ian, Spain; ne [email p o ec ed] (N.L.); aina a.andia [email p o ec ed] (A.A.)
3Public Heal h Di ision o Gipuzkoa, Basque Go e nmen , 20013 San Sebas ian, Spain;
[email p o ec ed]
4Facul y o Psychology, Uni e si y o he Basque Coun y (UPV/EHU), A enida Tolosa 70,
20018 San Sebas ian, Spain
5Facul y o Medicine and Nu sing, Uni e si y o he Basque Coun y (UPV/EHU), Ba io Sa iena s/n,
48940 Leioa, Spain
6Hospi al del Ma Resea ch Ins i u e, 08003 Ba celona, Spain
7ISGlobal—Ins i u o de Salud Global de Ba celona–Campus MAR, PRBB, 08003 Ba celona, Spain
8
Epidemiology and En i onmen al Heal h Join Resea ch Uni , FISABIO–Uni e si a Jaume I–Uni e si a de
València, 08003 València, Spain; [email p o ec ed]
9Ins i u d0In es igacióSani à ia Pe e Vi gili (IISPV), Hospi al Uni e si a i San Joan de Reus,
43204 Reus, Spain
10
Biodonos ia, Epidemiology and Public Heal h A ea, Epidemiology o Ch onic and Communicable Diseases
G oup, 20014 San Sebas ian, Spain
11 Ha ingey Child and Adolescen Men al Heal h Se ice, Ba ne , En ield and Ha ingey NHS Men al Heal h
T us , London N15 3TH, UK; [email p o ec ed]
12 Recogni ion Heal h, London W1G 9RU, UK
*Co espondence: [email p o ec ed]
Recei ed: 2 Oc obe 2020; Accep ed: 19 Oc obe 2020; Published: 22 Oc obe 2020
Abs ac :
Fe i in s a us du ing p ena al b ain de elopmen may in luence he isk o a en ion de ici
and hype ac i i y diso de (ADHD) symp oms in childhood. We in es iga ed he associa ion o
ma e nal e i in in p egnancy and ADHD-like symp oms in o sp ing. A o al o 1095 mo he -child
pai s om h ee bi h coho s o he INMA P ojec (Spain) we e s udied. Ma e nal plasma e i in
in p egnancy was measu ed a 11.57 weeks o ges a ion. Child en
0
s ADHD-like symp oms a ages
4–5 yea s we e assessed using he ADHD Ra ing Scale-IV. The coun model o he ze o-in la ed Poisson
eg ession model showed a signi ican in e se associa ion be ween e i in (con inuous a iable)
and ina en ion,
β
=
−
0.19 (
−
0.32,
−
0.07), o boys. Compa ing e i in le el by e iles, signi ican
di e ences we e obse ed be ween he i s e ile ([1.98, 20.92]) and he second ([20.92, 38.79]) and
hi d e iles ([38.79, 216.5]) (mg/L).The numbe o symp oms was lowe o hose in he hi d e ile,
β
=
−
0.3 (
−
0.55,
−
0.5), and o hose in he second one,
β
=
−
0.37 (
−
0.6,
−
0.14). The model s a i ica ion
by sex also showed his in e se associa ion o boys only,
β
=
−
0.21 (
−
0.34,
−
0.08). No associa ions
In . J. En i on. Res. Public Heal h 2020,17, 7704; doi:10.3390/ije ph17217704 www.mdpi.com/jou nal/ije ph
In . J. En i on. Res. Public Heal h 2020,17, 7704 2 o 17
we e ound be ween e i in le el and hype ac i i y o o al ADHD symp oms. High e i in le els
du ing p egnancy show a p o ec i e associa ion wi h child ina en i e- ype ADHD symp oms.
Keywo ds: e i in s a us; p egnancy; ADHD symp oms; childhood
1. In oduc ion
A en ion de ici /hype ac i i y diso de (ADHD) is he mos equen childhood-onse
neu opsychia ic condi ion, wi h an es ima ed wo ldwide p e alence o app oxima ely 5% in school-aged
child en [1]. ADHD symp oms end o pe sis in o adul hood in as many as 65% o cases [2].
Despi e ADHD being he mos s udied neu opsychia ic condi ion in child psychia y
wo ldwide [
3
], he e iological ac o s [
4
] a e no well unde s ood [
5
]. No speci ic e iology has been
iden i ied o ADHD, and indings a e consis en wi h a mul i ac o ial model [
6
]. Indeed, he diso de
is likely o be due o a complex combina ion o en i onmen al, gene ic and biological ac o s. The ange
o e iologies ela ed o p ena al and pe ina al isk ac o s, gene ics and neu obiological de ici s ha
ha e been p oposed may all be in ol ed in he pa hophysiology o ADHD [7].
The human b ain is highly sensi i e o en i onmen al exposu e occu ing du ing pa icula
pe iods o ulne abili y [
8
,
9
]. In ea ly li e, biological b ain de elopmen is highly ac i e and any ac o s
enhancing o dis u bing his p ocess could ha e pe manen e ec s on b ain unc ion [
10
]. I is also
es ablished ha bo h gene ic and a wide ange o en i onmen al ac o s, including physical, biological,
psychological and social ac o s, a e able o modula e b ain s uc u e and i s unc ion by in e ac ing
wi h genes and exp ession mechanisms (i.e., epigene ic de e minan s) [11].
In ecen yea s, i has been sugges ed ha i on de iciency (ID) may con ibu e o beha io al
and cogni i e dys unc ions [
12
]. I on is an essen ial ace me al, which plays a cen al ole in many
essen ial b ain unc ions [
13
]. Animal models show ha ea ly i on de iciency may lead o s uc u al
and unc ional b ain abno mali ies including al e a ions in dopamine me abolism, ene gy me abolism
and myelina ion [
14
]. Se e al case-con ol s udies ha e epo ed a signi ican associa ion be ween i on
de iciency and low sco es in es s assessing men al, social and mo o de elopmen in in an s, as well
as a lowe in elligence quo ien [
15
], poo lea ning pe o mance and impai ed neu opsychological
unc ions (e.g., poo spa ial memo y) [13].
Fu he e idence suppo s he hypo hesis ha a lack o b ain i on migh con ibu e o he
pa hophysiology o ADHD [
16
,
17
]. Fi s ly, i on is a co ac o o enzymes necessa y o he syn hesis and
ca abolism o he monoamine gic neu o ansmi e s including dopamine [
18
], which has been linked
o ADHD [
7
,
19
]. Secondly, ID is associa ed wi h a dec ease in dopamine anspo e exp ession [
20
],
and he co esponding gene is linked o a gene ic ulne abili y o ADHD [
21
]. Thi dly, ID may lead
o dys unc ion in he basal ganglia [
22
], which again a e belie ed o play a signi ican ole in he
pa hophysiology and exp ession o ADHD [5].
The ole o se um e i in le els as a eliable measu e o i on s o es in body issues, including he
b ain, in child en wi h ADHD has been s udied in ecen yea s. A me a-analysis [
23
] and a sys ema ic
e iew [
24
] ha e ound con adic o y indings o he ela ionship be ween e i in le els and ADHD,
and he e o e he ex en o which se um e i in co ela es wi h b ain i on le els emains unclea [
25
,
26
].
In addi ion, ma e nal e i in le els and hei e ec s on child neu opsychological de elopmen ha e
been less s udied. A p ospec i e popula ion-based s udy in a u al p o ince in Vie nam, which en olled
497 p egnan women a 12–20 weeks o ges a ion and ollowed hem up wi h hei in an s un il six
mon hs pos pa um, ound ha lowe e i in le els we e associa ed wi h a poo e cogni i e unc ion
and wo se social and emo ional de elopmen in he child en [
27
]. Simila ly, a ecen s udy based on
heal h and popula ion egis e da a om he S ockholm You h Coho e alua ed 532,232 women wi h
ID diagnosed du ing he i s 30 weeks o p egnancy and ound ha anemia diagnosed up o his poin
In . J. En i on. Res. Public Heal h 2020,17, 7704 3 o 17
in p egnancy was associa ed wi h an inc eased isk o au ism spec um diso de (ASD), ADHD and
in ellec ual disabili y in o sp ing [12].
The e o e, he objec i e o he p esen s udy was o e alua e he ela ionship be ween p ena al
e i in le els wi h in an ADHD symp oms. Fo ha , he associa ion be ween ID du ing p egnancy
measu ed by e i in le els in ma e nal se um and ADHD symp oms in child en aged 4–5 yea s
was assessed. Findings migh ha e impo an implica ions o clinical p ac ice, ega ding p ena al
i on supplemen a ion.
2. Ma e ials and Me hods
2.1. Subjec s
The INMA (IN ancia y Medio Ambien e, Childhood and En i onmen ) P ojec [
28
], a mul icen e
bi h coho s udy, was es ablished be ween 2003 and 2008 in 3 egions o Spain, namely: Gipuzkoa
(Basque Coun y), Sabadell (Ca alonia) and Valencia. Pa icipan ec ui men and ollow-up p ocedu es
ha e been epo ed in de ail elsewhe e (Guxens e al., 2012). A o al o 2644 eligible women we e
ec ui ed du ing p ena al isi s in he i s imes e o p egnancy. Inclusion c i e ia we e:
≥
16 yea s
o age, single on p egnancy and in en ion o deli e a he e e ence hospi al; and exclusion c i e ia
we e: women ha ing any communica ion p oblems ha migh hinde hei pa icipa ion in he
s udy, e uses ha ing mal o ma ions and p egnancies ha ing been achie ed by assis ed concep ion.
Women we e ollowed up du ing p egnancy, and hei child en we e en olled a bi h and ollowed up
un il 4–5 yea s o age. The popula ion inally s udied was composed o 1095 p egnan women om he
gene al popula ion esiden in Sabadell (N =443), Valencia (N =339) o Gipuzkoa (N =313) and hei
child en a 4 yea s o age (Figu e 1).
In . J. En i on. Res. Public Heal h 2020, 17, x FOR PEER REVIEW 4 o 22
Figu e 1. Ma e nal e i in le els (mg/L) we e assessed du ing he i s imes e o p egnancy. The
s udy was app o ed by he e hics commi ees o he cen e s in ol ed in he s udy, and w i en
in o med consen was ob ained om he pa en s o all child en.
2.2. Fe i in Measu emen
Ma e nal whole blood samples we e collec ed du ing p egnancy (mean [SD] 13.3 [1.5] weeks o
ges a ion) by enipunc u e unde as ing condi ions and s o ed be ween −70 and −80 °C un il
analysis. Ma e nal plasma e i in concen a ions we e quan i ied in samples om Gipuzkoa and
Sabadell coho s by ime- esol ed luo escence immunoassay (DELFIA Fe i in ki A069−101), a he
Gipuzkoa Public Heal h Labo a o y, and in samples om he Valencia coho by
immuno u bidime y (Beckman Coul e AU analyse s) a La Fe hospi al.
Flow cha
Exclusion o 859
wi hou ADHD
symp oms da a
Exclusion o 196
wi hou e i in
le el.
Eligible women wi h e i in da a
in he i s imes e o p egnancy:
n = 1954
632 Gipuzkoa
651 Sabadell
669 Valencia
Women en olled in he i s imes e o
p egnancy: n = 2150
638 Gipuzkoa
657 Sabadell
855 Valencia
Eligible child en wi h ADHD
symp oms da a a 4 yea s old:
n = 1095
313 Gipuzkoa
443 Sabadell
339 Valencia
Figu e 1.
Ma e nal e i in le els (mg/L) we e assessed du ing he i s imes e o p egnancy. The s udy
was app o ed by he e hics commi ees o he cen e s in ol ed in he s udy, and w i en in o med
consen was ob ained om he pa en s o all child en.
In . J. En i on. Res. Public Heal h 2020,17, 7704 4 o 17
2.2. Fe i in Measu emen
Ma e nal whole blood samples we e collec ed du ing p egnancy (mean [SD] 13.3 [1.5] weeks o
ges a ion) by enipunc u e unde as ing condi ions and s o ed be ween
−
70 and
−
80
◦
C un il analysis.
Ma e nal plasma e i in concen a ions we e quan i ied in samples om Gipuzkoa and Sabadell
coho s by ime- esol ed luo escence immunoassay (DELFIA Fe i in ki A069–101), a he Gipuzkoa
Public Heal h Labo a o y, and in samples om he Valencia coho by immuno u bidime y (Beckman
Coul e AU analyse s) a La Fe hospi al.
2.3. Child and Family Cha ac e is ics
Da a on ma e nal and child cha ac e is ics we e collec ed h ough wo ques ionnai es adminis e ed
du ing ace- o- ace in e iews a di e en poin s in he i s and hi d imes e o p egnancy, a bi h,
a 14 mon hs a e bi h and when child en eached 4–5 yea s o age. We used da a on ma e nal coun y
o o igin (Spain/o he ), ma e nal social class (manual o lowe class [IV and V] and non-manual/skilled
o highe class [I–III]), ma e nal educa ion (p ima y o lowe , seconda y and uni e si y), ma e nal
age, ma e nal men al heal h (men al p oblems, yes/no), ma e nal in elligence quo ien , pa i y, smoking
du ing p egnancy (yes/no), alcohol in ake du ing p egnancy (yes/no), p e-p egnancy body mass
index (BMI) (unde weigh =BMI <18.5; no mal weigh =BMI 18.5–25; o e weigh =BMI 25–30;
and obesi y =BMI >30 kg/m
2
) and b eas eeding (weeks o any b eas eeding). An h opome ic
measu es a bi h and he sex o he in an we e ob ained om he child’s medical eco ds. Deli e ies
be o e 37 weeks o ges a ion we e de ined as p e e m bi hs. Ges a ional age was calcula ed om he
da e o he las mens ual pe iod epo ed a ec ui men and con i med using ul asound examina ion
a week 12 o ges a ion. Whole blood samples we e collec ed by enipunc u e o co d essels be o e
he placen a was deli e ed o he measu emen o me cu y in he newbo n. A 14 mon hs o age,
a ious ypes o da a ela ed o he child en we e collec ed including dayca e a endance, bi h o de
among siblings ( i s /no i s ), whe he hey we e li ing wi h hei pa en s (bo h/only one) and he
numbe o people in he household. The exac age o he child was also eco ded a he ime o he
assessmen o ADHD-like symp oms.
2.4. ADHD Symp oms
Child ADHD symp oms a 4 yea s o age we e assessed in he pe iod 2008–2013 using he
ADHD Ra ing Scale-IV de eloped by DuPaul, Powe and Anas opoulos [
29
] comple ed by he child’s
class oom eache , which e lec s he Diagnos ic and S a is ical Manual o Men al Diso de s 4 h edi ion
C i e ia o ADHD (ADHD-DSM-IV; [
30
]). The scale comp ises 18 ADHD symp oms and is designed
o e alua e ina en ion (9 symp oms) and hype ac i i y/impulsi i y (9 symp oms). Each symp om is
a ed using a 4-poin scale: 0 =“no a all”, 1 =“jus a li le”, 2 =“p e y much” and 3 =“ e y much”.
Sco es we e summed o p o ide con inuous measu es o ina en ion, hype ac i i y/impulsi i y and
o al ADHD symp oms. The p esence o symp oms in he clinical ange was es ima ed by coding a ings
o 0 and 1 as “symp om absen ” and a ings o 2 and 3 as “symp om p esen ”. The good psychome ic
cha ac e is ics o his measu emen in he INMA p ojec ha e been epo ed p e iously [31].
2.5. S a is ical Analysis
Fi s , we compa ed socio-demog aphic cha ac e is ics o mo he s and child en ac oss he h ee
coho s s udied (Gipuzkoa, Sabadell and Valencia). The di e ence in he mean numbe o symp oms
was analyzed using he S uden ’s - es ( o wo samples) and one-way analysis o a iance (mo e han
wo samples).
Due o he excess o ze os in symp om a ings, he associa ion be ween e i in le el and symp oms
was analyzed using ze o-in la ed Poisson eg ession models. This ype o model has wo pa s,
a Poisson coun model and a logi model o p edic ing excess ze os. The le el o e i in was en e ed
in he models in wo ways: as a con inuous a iable and ca ego ized in e iles (Te ile 1: [1.98, 20.92];
In . J. En i on. Res. Public Heal h 2020,17, 7704 5 o 17
Te ile 2: (20.92, 38.79]; and Te ile 3: (38.79, 216.5] (mg/L)) o s udy he end ac oss he e iles. Ini ially,
a iables wi h a p- alue
≤
0.20 in he bi a ia e analysis we e added o he base models ( e i in le el
and ADHD symp oms). These a iables we e main ained in he models i hey changed he magni ude
o he main e ec s by mo e han 10% o we e signi ican . The inal model was adjus ed o : coho
(Gipuzkoa, Sabadell o Valencia), ma e nal smoking du ing p egnancy (yes/no), alcohol in ake du ing
p egnancy (g/day), p e-p egnancy BMI and social class (manual/non-manual), he child’s sex, age a
he ime o he es and whe he hey we e li ing wi h pa en s (bo h/only one) and he week o sample
collec ion o e i in analysis. Fo he coun model o he associa ion o ina en ion symp oms wi h
e i in le els, he in e ac ion be ween e i in and sex was signi ican , and hence esul s a e shown
sepa a ely o boys and gi ls. The inal model was also s a i ied by coho and sex o he child.
S a is ical analyses we e conduc ed using R e sion 3.6.1.
3. Resul s
O e all, 1095 eligible mo he -child pai s we e included in his s udy (Figu e 1).
The socio-demog aphic cha ac e is ics o mo he s and child en ac oss he h ee coho s (Gipuzkoa,
Sabadell and Valencia) a e summa ized in Table 1. The Valencian coho had highe le els o e i in
and an ea lie week o blood sample collec ion han he Gipuzkoa and Sabadell coho s. Mo he s
ec ui ed in Gipuzkoa we e he oldes , b eas ed o he longes and had he highes le el o educa ion
and social class, lowes BMI and lowes pe cen age o o eign mo he s. Rega ding li es yle du ing
p egnancy, Valencia had he highes a es o smoking and alcohol consump ion among he mo he s.
In addi ion, child en om Valencia had he highes le els o Hg in umbilical co d blood. The mean
ages o mo he s and child en a assessmen o ADHD-like symp oms we e 30.9 yea s and 4.9 yea s,
espec i ely. Compa ed wi h women excluded, hose included in he analysis we e olde , had highe
le els o educa ion and social class, b eas ed o longe and ended o smoke less du ing p egnancy
(Supplemen a y Table S1).
The mean ma e nal e i in le el was 35.9 mg/L (s anda d de ia ion: 26.81 mg/L). In he uni a ia e
analyses, he o al ADHD symp om sco e was highe in boys han gi ls. Fu he , o al ADHD symp om
sco es we e highe in child en o mo he s wi h highe BMI, lowe alcohol in ake, wo se men al heal h
and lowe educa ion and social class, who smoked and did no b eas eed (Table 2).
Conside ing e i in le els as a con inuous a iable, he coun model o he ze o-in la ed Poisson
eg ession model showed a signi ican in e se associa ion be ween e i in le els and ina en ion
symp oms,
β
=
−
0.19 (
−
0.32,
−
0.07), in boys. In addi ion, compa ing e i in le els by e iles o
boys, he e we e signi ican di e ences be ween he i s and second e ile,
β
=
−
0.3 (
−
0.55,
−
0.05),
and he i s and hi d e ile,
β
=
−
0.37 (
−
0.6,
−
0.14), wi h a signi ican end (p=0.002). In con as ,
no signi ican associa ion was ound be ween e i in le el and hype ac i i y/impulsi i y o o al
ADHD symp om sco es (Table 3).
The s a i ica ion o he coun model by he sex o he child also showed an in e se associa ion
be ween e i in le el and ina en ion symp oms o boys, bo h when aking e i in le els con inuously,
β
=
−
0.21 (
−
0.34,
−
0.08), and also when compa ing he indi iduals by e iles: he expec ed change
in he numbe o symp oms was lowe o hose in he second e ile,
β
=
−
0.32 (
−
0.57,
−
0.06),
and o hose in he hi d one,
β
=
−
0.4 (
−
0.63,
−
0.16) (p o end 0.001). In con as , he coun
model o ina en ion showed a posi i e associa ion o he gi ls in he hi d e ile o e i in le els,
β
=0.58 (0.02, 1.13), compa ed wi h hose in he i s one (p o end 0.012). Simila ly, when conside ing
he o al numbe o ADHD symp oms, a nega i e associa ion was obse ed o he boys in he hi d
e ile,
β
=
−
0.22 (
−
0.39,
−
0.06). The ze o-in la ion model o ADHD symp oms showed a posi i e
associa ion,
β
=0.6 (0.05, 1.16), o gi ls in he second e ile and a posi i e associa ion was also
obse ed when aking e i in le el as a con inuous a iable, β=0.39 (0.08, 0.69) (Table 4).
In . J. En i on. Res. Public Heal h 2020,17, 7704 6 o 17
Table 1. Desc ip i e cha ac e is ics o he s udy sample.
GIPUZKOA SABADELL VALENCIA p-Value * TOTAL
N=313 N =443 N =339 N =1095
Va iables N (%) Mean (SD) N (%) Mean (SD) N (%) Mean (SD) N (%) Mean (SD)
Child cha ac e is ics
Sex Female 157 (50.16) 217 (48.98) 166 (48.97) 0.939 540 (49.32)
Male 156 (49.84) 226 (51.02) 173 (51.03) 555 (50.68)
Missing 0 (0) 0 (0) 0 (0) 0 (0)
P e e m No 301 (96.17) 425 (95.94) 320 (94.4) 0.168 1046 (95.53)
Yes 11 (3.51) 12 (2.71) 18 (5.31) 41 (3.74)
Missing 1 (0.32) 6 (1.35) 1 (0.29) 8 (0.73)
Sibling o de No i s 143 (45.69) 188 (42.44) 147 (43.36) 0.669 478 (43.65)
Fi s 170 (54.31) 255 (57.56) 192 (56.64) 617 (56.35)
Missing 0 (0) 0 (0) 0 (0) 0 (0)
Li es wi h mo he / a he Bo h 295 (94.25) 426 (96.16) 332 (97.94) 0.488 1053 (96.16)
Only one 3 (0.96) 5 (1.13) 7 (2.06) 15 (1.37)
Missing 15 (4.79) 12 (2.71) 0 (0) 27 (2.47)
Numbe o people who hey li e wi h Missing 15 (4.79) 2.58 (0.72) 12 (2.71) 2.57 (0.79) 0 (0) 2.58 (0.76) 0.997 27 (2.47) 2.57 (0.76)
Child’s age a he ime o he es Missing 119 (1.74) 4.41 (0.22) 1 (0.09) 4.44 (0.26) 0 (0) 5.92 (0.32) <0.001 20 (1.83) 4.90 (0.75)
B eas eeding Missing 13 (4.15) 29.33 (20.14) 1 (0.23) 27.48 (19.64) 0 (0) 23.04 (19.3) <0.001 14 (1.28) 26.6 (19.82)
Hg (µg/l) in umbilical co d Missing 35 (11.18) 9.6 (5.83) 117 (26.41) 8.35 (6.53) 95 (28.02) 15.34 (11.6) <0.001 247 (22.56) 10.77 (8.65)
Ma e nal cha ac e is ics
Fe i in le el (log scale) Missing 0 (0) 3.28 (0.74) 0 (0) 3.25 (0.79) 0 (0) 3.45 (0.68) <0.001 0 (0) 3.32 (0.75)
Ma e nal blood collec ion week Missing 0 (0) 13.33 (1.31) 2 (0.45) 13 (1.8) 0 (0) 8.09 (4.23) <0.001 2 (0.18) 11.57 (3.58)
Alcohol in ake du ing p egnancy Missing 0 (0) 0.19 (0.47) 0 (0) 0.37 (1.07) 0 (0) 0.41 (1.19) 0.009 0 (0) 0.33 (0.98)
P e-p egnancy BMI Missing 0 (0) 22.9 (3.35) 0 (0) 23.87 (4.71) 0 (0) 23.8 (4.43) 0.004 0 (0) 23.57 (4.29)
Age Missing 0 (0) 31.58 (3.48) 1 (0.23) 30.66 (4.1) 0 (0) 30.64 (4.06) 0.002 1 (0.09) 30.92 (3.94)
Men al heal h (14 mon hs a e bi h) Missing 39 (12.46) 9.23 (3.33) 27 (6.09) 9.9 (3.95) 339 (100) −0.021 405 (36.99) 9.64 (3.72)
Pa i y Missing 0 (0) 0.53 (0.64) 2 (0.45) 0.49 (0.65) 0 (0) 0.5 (0.64) 0.705 2 (0.18) 0.51 (0.64)
Smoking du ing p egnancy No 269 (85.94) 379 (85.55) 264 (77.88) <0.001 912 (83.29)
Yes 34 (10.86) 58 (13.09) 75 (22.12) 167 (15.25)
Missing 10 (3.19) 6 (1.35) 0 (0) 16 (1.46)
Coun y o bi h Spain 305 (97.44) 402 (90.74) 318 (93.81) 0.001 1025 (93.61)
O he 8 (2.56) 39 (8.8) 21 (6.19) 68 (6.21)
Missing 0 (0) 2 (0.45) 0 (0) 2 (0.18)
Social class No manual 190 (60.7) 247 (55.76) 157 (46.31) <0.001 594 (54.25)
Manual 123 (39.3) 196 (44.24) 182 (53.69) 501 (45.75)
Missing 0 (0) 0 (0) 0 (0) 0 (0)
Educa ion le el P ima y 34 (10.86) 104 (3.48) 90 (26.55) <0.001 228 (20.82)
Seconda y 116 (37.06) 190 (42.89) 155 (45.72) 461 (42.1)
Uni e si y 162 (51.76) 146 (32.96) 94 (27.73) 402 (36.71)
Missing 1 (0.32) 3 (0.68) 0 (0) 4 (0.37)
* One-way ANOVA o mean di e ences and chi-squa ed es o ca ego ical a iables.
In . J. En i on. Res. Public Heal h 2020,17, 7704 7 o 17
Table 2. Pe cen iles 75–90–95, mean and s anda d de ia ion o ina en ion, hype ac i i y and ADHD symp oms.
Ina en ion Hype ac i i y ADHD
Pe cen iles Mean sd p* Pe cen iles Mean sd p* Pe cen iles Mean sd p*
Va iables
Child cha ac e is ics
Sex Female 0 1 2 0.33 1.13 <0.001 0 1 3 0.43 1.23 <0.001 0 2.1 5 0.76 1.97 <0.001
Male 1 4 6 0.89 1.98 1 3 5 0.76 1.76 2 6 9 1.65 3.3
P e e m No 0 2 5 0.61 1.63 0.768 0 2 4 0.6 1.54 0.362 1 4 8 1.21 2.76 0.848
Yes 1 2 3 0.68 1.54 1 2 2 0.46 0.87 2 3 5 1.15 1.89
Sibling o de No i s 0 2 4.15 0.63 1.61 0.884 0 2 4 0.59 1.48 0.871 1 4 7 1.21 2.66 0.997
Fi s 0 2 5 0.61 1.67 0 2 4 0.6 1.57 1 5 8 1.21 2.84
Li es wi h mo he / a he Bo h 0 2 5 0.61 1.63 0.760 0 2 4 0.59 1.53 0.020 1 4 7.4 1.2 2.75 0.342
Only one 0 0 2.1 0.47 1.81 0 0.6 1.3 0.2 0.56 0 1.2 3.8 0.67 2.09
Numbe o people who hey li e
wi h ≤2 0 2 4 0.56 1.55 0.318 0 2 3.15 0.57 1.49 0.693 1 4 7.15 1.13 2.63 0.415
>2 0 2 5 0.67 1.73 0 2 4 0.61 1.55 1 4 7.55 1.27 2.87
Child´s age a he ime o he es ≤4.50 0 1 3 0.46 1.4 0.001 0 2 3 0.49 1.7 0.018 1 3 5 0.95 2.39 0.001
>4.50 0 3 5.65 0.79 1.87 0 3 4.65 0.72 1.37 1 5 9 1.51 3.11
B eas eeding (weeks) No 1 4.7 6 1.02 2.17 0.010 0 3 5 0.78 1.83 0.028 2 8 10 1.8 3.54 0.007
0–16 0 2 5 0.67 1.67 1 3 5 0.79 1.91 1 5 8.35 1.47 3.13
16–24 0 2.5 5 0.66 1.79 0 2 4 0.57 1.4 1 5 6.5 1.24 2.92
>24 0 2 3.7 0.49 1.39 0 2 3 0.48 1.28 1 4 6 0.97 2.24
Hg (µg/l) in umbilical co d ≤8,2 0 2 5 0.64 1.690 0.608 0 2 3 0.58 1.58 0.791 1 4 7.75 1.22 2.87 0.653
>8.2 0 2 4 0.59 1.590 0 2 4 0.55 1.46 1 4 7 1.14 2.68
Ma e nal cha ac e is ics
Coho Gipuzkoa 0 1 3 0.42 1.29 0.012 0 1 2 0.35 1.18 0.004 0 3 5 0.77 2.22 0.002
Sabadell 0 2 5 0.62 1.62 1 2 4 0.69 1.6 1 4.8 7.9 1.31 2.8
Valencia 0 3 6 0.8 1.92 0 3 4.1 0.7 1.69 1 5 9 1.5 3.1
Fe i in le el (log scale) ≤3.37 0 2 5 0.61 1.67 0.955 0 2 4 0.62 1.49 0.636 1 4 8 1.23 2.75 0.819
>3.37 0 2 4.8 0.62 1.61 0 2 4 0.57 1.57 1 4.6 7 1.19 2.77
Ma e nal blood collec ion week ≤12 0 2 5 0.67 1.72 0.300 0 2 4 0.61 1.53 0.824 1 5 8 1.27 2.82 0.462
>12 0 2 4 0.56 1.55 0 2 4 0.59 1.53 1 4 7 1.15 2.7
Alcohol in ake du ing p egnancy ≤0.0201 0 3 5.8 0.71 1.850 0.019 0 2 4 0.67 1.65 0.052 1 5 9 1.39 3.12 0.013
>0.0201 0 2 4 0.49 1.300 0 2 3 0.5 1.34 1 4 6 0.99 2.18
P e-p egnancy BMI
Unde weigh
0 2 2.9 0.51 1.1 <0.001 0 1 2.9 0.49 1.39 0.073 0.5 4 4.9 1 2.01 <0.001
No mal
weigh 0 2 4 0.49 1.44 0 2 4 0.54 1.42 1 4 6 1.03 2.46
O e weigh
0 3 6 0.78 1.92 1 2 3.4 0.69 1.68 1 5 9.4 1.47 3.31
Obese 2 6 7.2 1.42 2.44 1 4 5.6 0.96 2.04 4 8.2 10.6 2.37 3.76
Age ≤31 0 2 5 0.64 1.64 0.664 0 2 4 0.64 1.56 0.295 1 5 7 1.27 2.77 0.404
>31 0 2 5 0.59 1.64 0 2 4 0.54 1.49 1 4 8 1.13 2.76
Men al heal h (14 mon hs a e bi h)
≤9 0 1 3 0.39 1.15 0.015 0 2 3 0.46 1.2 0.265 1 3 5 0.85 2 0.040
>9 0 2 5 0.68 1.8 0 2 3 0.58 1.55 1 4 8 1.26 2.98
In . J. En i on. Res. Public Heal h 2020,17, 7704 8 o 17
Table 2. Con .
Ina en ion Hype ac i i y ADHD
Pe cen iles Mean sd p* Pe cen iles Mean sd p* Pe cen iles Mean sd p*
Pa i y 0 0 2 5 0.61 1.67 0.921 0 2 4 0.6 1.57 0.833 1 5 8 1.22 2.84 0.954
≥1 0 2 4.05 0.62 1.6 0 2 4 0.59 1.48 1 4 7 1.21 2.65
Smoking in p egnancy No 0 2 4 0.54 1.54 0.003 0 2 3.45 0.53 1.45 0.006 1 4 6 1.08 2.6 0.001
Yes 1 4.4 6 1.06 2.11 1 4 5 0.97 1.93 2 7 10 2.03 3.51
Coun y o bi h Spain 0 2 5 0.6 1.61 0.305 0 2 4 0.59 1.51 0.430 1 4 7.8 1.19 2.72 0.292
O he 1 2.3 6.3 0.87 2.08 1 2 5 0.76 1.81 2 5 7.3 1.63 3.38
Social class
Non-manual
0 1 3 0.44 1.31 <0.001 0 2 3 0.54 1.38 0.158 1 3 6 0.98 2.36 0.002
Manual 0 3 6 0.83 1.94 0 2 4 0.67 1.69 1 5 9 1.5 3.15
Educa ion le el P ima y 0.25 5 7 1.03 2.25 <0.001 0.25 2 4 0.7 1.68 0.283 2 6.3 10 1.73 3.41 0.001
Seconda y 0 2 4 0.61 1.52 0 2 4 0.62 1.54 1 5 6 1.23 2.64
Uni e si y 0 1 3 0.39 1.28 0 2 3 0.51 1.41 0 3 5 0.9 2.41
* - es o mean compa ison (2 samples) o ANOVA (mo e han wo samples).
Table 3.
Ze o-in la ed Poisson eg ession models o he associa ion be ween ina en ion, hype ac i i y and ADHD symp oms wi h e i in le els (mg/L log scale) in
con inuous scale and in e iles.
Te ile 1
[1.98, 20.92] (mg/L)
Te ile 2
(20.92, 38.79] (mg/L)
Te ile 3
(38.79, 216.5] (mg/L) p o T end ** Con inuous
Be a CI (95%) Be a CI (95%) Be a CI (95%) Be a CI (95%)
Ina en ion
Coun model *1
Male *** 1 (Re .) −0.3 (−0.55, −0.05) −0.37 (−0.6, −0.14) 0.002 −0.19 (−0.32, −0.07)
Female *** 1 (Re .) −0.11 (−0.64, 0.42) 0.35 (−0.07, 0.77) 0.066 0.09 (−0.13, 0.31)
Ze o-in la ion model *21 (Re .) 0.19 (−0.24, 0.63) 0.19 (−0.24, 0.63) 0.488 −0.04 (−0.26, 0.19)
Hype ac i i y
Coun model *11 (Re .) −0.07 (−0.29, 0.16) −0.11 (−0.33, 0.11) 0.327 −0.03 (−0.15, 0.09)
Ze o-in la ion model *21 (Re .) 0.24 (−0.16, 0.64) 0.17 (−0.23, 0.56) 0.411 0.11 (−0.11, 0.32)
ADHD
Coun model *11 (Re .) −0.09 (−0.24, 0.06) −0.09 (−0.23, 0.05) 0.239 −0.02 (−0.1, 0.05)
Ze o-in la ion model *21 (Re .) 0.36 (0, 0.71) 0.12 (−0.22, 0.47) 0.515 0.13 (−0.06, 0.33)
Models adjus ed by coho , smoking du ing p egnancy, alcohol in ake du ing p egnancy, p e-p egnancy BMI, social class, sex and age o he child, li ing wi h mo he / a he and weeks
( e i in ex ac ion). *
1
Coun model coe icien s (Poisson wi h log link). *
2
Ze o
−
in la ion model coe icien s (binomial wi h logi link). ** p o he end be ween e iles. *** Model wi h
in e ac ion e m be ween sex and e i in.
In . J. En i on. Res. Public Heal h 2020,17, 7704 9 o 17
Table 4. Ze o-in la ed Poisson eg ession models o he associa ion be ween ina en ion, hype ac i i y and ADHD symp oms wi h e i in le els (log scale).
Te ile 1 Te ile 2 Te ile 3 p T end ** Con inuous
[1.98, 20.92] (mg/L) (20.92, 38.79] (mg/L) (38.79, 216.5] (mg/L)
Be a CI (95%) Be a CI (95%) Be a CI (95%) Be a CI (95%)
S a i ied by sex
Ina en ion
Boys Coun model *11 (Re .) −0.32 (−0.57, −0.06) −0.4 (−0.63, −0.16) 0.001 −0.21 (−0.34, −0.08)
Ze o-in la ion model *21 (Re .) 0.09 (−0.46, 0.63) −0.27 (−0.8, 0.25) 0.27 −0.14 (−0.43, 0.15)
Gi ls Coun model*11 (Re .) 0.04 (−0.61, 0.69) 0.58 (0.02, 1.13) 0.012 0.15 (−0.09, 0.39)
Ze o-in la ion model *21 (Re .) 0.37 (−0.36, 1.09) −0.32 (−1.13, 0.49) 0.311 −0.38 (−1.17, 0.42)
Hype ac i i y
Boys Coun model *11 (Re .) −0.09 (−0.37, 0.19) −0.16 (−0.44, 0.11) 0.244 −0.03 (−0.18, 0.12)
Ze o-in la ion model *21 (Re .) 0.16 (−0.37, 0.68) 0 (−0.52, 0.51) 0.981 −0.03 (−0.32, 0.25)
Gi ls Coun model *11 (Re .) −0.02 (−0.44, 0.39) −0.07 (−0.49, 0.35) 0.727 −0.1 (−0.33, 0.13)
Ze o-in la ion model *21 (Re .) 0.41 (−0.22, 1.04) 0.48 (−0.16, 1.12) 0.143 0.34 (−0.02, 0.7)
ADHD
Boys Coun model *11 (Re .) −0.14 (−0.32, 0.03) −0.22 (−0.39, −0.06) 0.008 −0.07 (−0.16, 0.02)
Ze o-in la ion model *21 (Re .) 0.25 (−0.23, 0.73) −0.05 (−0.52, 0.41) 0.778 −0.02 (−0.27, 0.24)
Gi ls Coun model *11 (Re .) 0.02 (−0.31, 0.34) 0.17 (−0.13, 0.47) 0.237 0.02 (−0.14, 0.19)
Ze o-in la ion model *21 (Re .) 0.6 (0.05, 1.16) 0.49 (−0.05, 1.04) 0.077 0.39 (0.08, 0.69)
S a i ied by coho
Ina en ion
Gipuzkoa Coun model *11 (Re .) −0.18 (−0.82, 0.47) 0.18 (−0.35, 0.71) 0.41 0.22 (−0.04, 0.48)
Ze o-in la ion model *21 (Re .) 0.8 (−0.15, 1.75) 0.05 (−0.82, 0.91) 0.873 0.16 (−0.31, 0.63)
Sabadell Coun model *11 (Re .) −0.35 (−0.72, 0.03) −0.22 (−0.55, 0.1) 0.116 −0.16 (−0.31, 0)
Ze o-in la ion model *21 (Re .) 0.38 (−0.29, 1.05) 0.03 (−0.6, 0.66) 0.887 −0.03 (−0.36, 0.3)
Valencia Coun model *11 (Re .) −0.24 (−0.64, 0.15) −0.39 (−0.76, −0.02) 0.043 −0.29 (−0.51, −0.06)
Ze o-in la ion model *21 (Re .) −0.44 (−1.22, 0.35) −0.6 (−1.35, 0.14) 0.123 −0.27 (−0.71, 0.18)
Hype ac i i y
Gipuzkoa Coun model *11 (Re .) −0.07 (−0.77, 0.62) 0.06 (−0.67, 0.78) 0.932 0.23 (−0.11, 0.57)
Ze o-in la ion model *21 (Re .) 0.65 (−0.3, 1.6) −0.1 (−1, 0.8) 0.838 0.1 (−0.4, 0.59)
Sabadell Coun model *11 (Re .) −0.25 (−0.6, 0.11) −0.31 (−0.64, 0.02) 0.053 −0.12 (−0.28, 0.03)
Ze o-in la ion model *21 (Re .) 0.24 (−0.36, 0.85) −0.09 (−0.69, 0.51) 0.814 −0.04 (−0.35, 0.27)
Valencia Coun model *11 (Re .) 0.06 (−0.36, 0.48) 0.06 (−0.36, 0.48) 0.904 0.01 (−0.25, 0.27)
Ze o-in la ion model *21 (Re .) −0.02 (−0.87, 0.82) 0.59 (−0.17, 1.36) 0.07 0.4 (−0.03, 0.82)
ADHD
Gipuzkoa Coun model *11 (Re .) −0.06 (−0.48, 0.36) 0.37 (−0.01, 0.74) 0.045 0.33 (0.14, 0.53)
Ze o-in la ion model *21 (Re .) 0.85 (0.06, 1.63) 0.27 (−0.48, 1.02) 0.412 0.28 (−0.13, 0.69)
Sabadell Coun model *11 (Re .) −0.29 (−0.53, −0.06) −0.28 (−0.5, −0.07) 0.005 −0.1 (−0.21, 0)
Ze o-in la ion model *21 (Re .) 0.39 (−0.14, 0.92) 0.03 (−0.49, 0.55) 0.857 0.08 (−0.19, 0.35)
Valencia Coun model *11 (Re .) 0.09 (−0.16, 0.35) −0.11 (−0.35, 0.14) 0.244 −0.07 (−0.21, 0.08)
Ze o-in la ion model *21 (Re .) −0.04 (−0.68, 0.6) 0.07 (−0.55, 0.69) 0.788 0.12 (−0.24, 0.49)
Models adjus ed by coho , smoking du ing p egnancy, alcohol in ake du ing p egnancy, p e-p egnancy BMI, social class, sex and age o he child, li ing wi h mo he / a he and weeks
( e i in ex ac ion). Gipuzkoa and Sabadell models do no include he a iable “li es wi h mo he / a he ”. *
1
Coun model coe icien s (Poisson wi h log link). *
2
Ze o-in la ion model
coe icien s (binomial wi h logi link). ** p o he end be ween e iles.
In . J. En i on. Res. Public Heal h 2020,17, 7704 16 o 17
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a ilia ions.
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