Maternal prepregnancy body mass index and offspring white matter microstructure: results from three birth cohorts

1 Ma e nal p ep egnancy body mass index and o sp ing whi e ma e 1 mic os uc u e: esul s om h ee bi h coho s 2 3 Running i le: Ma e nal body mass index and child whi e ma e 4 5 Lis o au ho s and a ilia ions 6 Juan Ve dejo-Román1*, Lassi Bjö nholm2,3,4*, Ryan L. Mue zel5,6,7, F ancisco José To es-7 Espínola8,9, Johannes Liesleh o2,3,4, Vincen Jaddoe 6,10, Daniel Campos8,9, Juha Veijola2,3,4, 8 Tonya Whi e5, And és Ca ena1, Juha Nikkinen4,11, Vesa Ki iniemi12, Ma jo-Rii a Jä elin13, 9 Henning Tiemeie 5,14, C is ina Campoy8,9, Syl ain Sebe 13, Hanan El Ma oun5,6,10,15 10 11 * These au ho s con ibu ed equally o his wo k 12 13 1. Mind, B ain and Beha io Resea ch Cen e (CIMCYC), Uni e si y o G anada, Spain 14 2. The Depa men o Psychia y, Resea ch Uni o Clinical Neu oscience, Uni e si y o Oulu, Oulu, 15 Finland 16 3. Depa men o Psychia y, Oulu Uni e si y Hospi al, Oulu, Finland 17 4. Medical Resea ch Cen e Oulu, Oulu Uni e si y Hospi al and Uni e si y o Oulu, Finland 18 5. The Depa men o Child and Adolescen Psychia y, E asmus MC, Sophia Child en’s 19 Hospi al, Ro e dam, 3000 CB, The Ne he lands 20 6. The Gene a ion R S udy G oup, E asmus MC, Ro e dam, 3000 CA, The Ne he lands 21 7. The Depa men o Epidemiology, E asmus MC, 3000 CA, The Ne he lands 22 8. EURISTIKOS, Excellence Cen e o Pedia ic Resea ch, Uni e si y o G anada, Spain 23 9. The Depa men o Pedia ics, School o Medicine. Uni e si y o G anada, Spain 24 2 10. The Depa men o Pedia ics, E asmus MC, Sophia Child en’s Hospi al, Ro e dam, 3000 CB, The 1 Ne he lands 2 11. Depa men o Oncology and Radio he apy, Oulu Uni e si y Hospi al, Finland 3 12. Ins i u e o Diagnos ics, Depa men o Diagnos ic Radiology, Oulu Uni e si y Hospi al, Oulu, 4 Finland 5 13. Cen e o Li e Cou se Heal h Resea ch, Uni e si y o Oulu, Oulu, Finland 6 14. The Depa men o Social and Beha io al Science, Ha a d TH Chan School o Public Heal h, 7 Bos on, USA 8 15. Depa men o Psychology, Educa ion & Child S udies, E asmus Uni e si y Ro e dam, The 9 Ne he lands 10 11 Co esponding Au ho : D . Hanan El Ma oun, Depa men o Child and Adolescen Psychia y, 12 Depa men o Pedia ics, E asmus MC- Sophia Child en’s Hospi al, PO.Box 2060, 3000 CB, 13 Ro e dam, The Ne he lands. E-mail: h.ma ounel@e asmusmc.nl 14 15 Con lic o in e es : 16 The au ho s epo no biomedical inancial in e es s o po en ial con lic s o in e es s. 17 This wo k was suppo ed by he Eu opean Union's Ho izon 2020 esea ch and inno a ion 18 p og am [g an ag eemen No.633595 DynaHEALTH] and No.733206 Li eCycle], he 19 Ne he lands O ganiza ion o Heal h Resea ch and De elopmen [ZONMW Vici p ojec 20 016.VICI.170.200]. The PREOBE coho was unded by Spanish Minis y o Inno a ion and 21 Science. Jun a de Andalucía: Excellence P ojec s (P06-CTS-02341) and Spanish Minis y o 22 Economy and Compe i i eness (BFU2012-40254-C03-01). The i s phase o he Gene a ion R 23 S udy is made possible by inancial suppo om he E asmus Medical Cen e, he E asmus 24 3 Uni e si y, and he Ne he lands O ganiza ion o Heal h Resea ch and De elopmen (ZonMW, 1 g an ZonMW Gees k ach 10.000.1003). 2 4 Abs ac 1 Backg ound and Aims: P ep egnancy ma e nal obesi y is a global heal h p oblem and has been 2 associa ed wi h o sp ing me abolic and men al ill-heal h. Howe e , he e is a knowledge gap in 3 unde s anding po en ial neu obiological ac o s. This s udy explo ed he ela ion be ween 4 ma e nal p ep egnancy body mass index (BMI) and o sp ing b ain whi e ma e mic os uc u e 5 a he age o 6, 10 and 26 yea s in h ee independen coho s. 6 Subjec s and Me hods: The s udy used da a om h ee Eu opean bi h coho s (n=116 child en 7 aged 6 yea s, n=2466 child en aged 10 yea s, and n=437 young adul s aged 26 yea s). 8 In o ma ion on ma e nal p ep egnancy BMI was measu ed be o e o du ing p egnancy and 9 o sp ing b ain whi e ma e mic os uc u e was measu ed a age 6, 10 o 26 yea s. Magne ic 10 esonance imaging de i ed ac ional aniso opy (FA) and mean di usi i y (MD) we e used as 11 measu es o whi e ma e mic os uc u e in he b ains em, callosal, limbic, associa ion and 12 p ojec ion ac s. Linea eg essions we e i ed o examine he associa ion o ma e nal BMI and 13 o sp ing whi e ma e mic os uc u e, adjus ing o se e al socioeconomic and li es yle- ela ed 14 con ounde s, including educa ion, smoking and alcohol use. 15 Resul s: Ma e nal BMI was associa ed wi h highe FA and lowe MD in mul iple b ain ac s, o 16 example associa ion and p ojec ion ibe s, in o sp ing aged 10 and 26 yea s, bu no a 6 yea s. 17 In each coho ma e nal BMI was ela ed o di e en whi e ma e ac and hus no common 18 associa ions ac oss coho s we e ound. 19 Conclusions: Ma e nal BMI was associa ed wi h highe FA and lowe MD in mul iple b ain 20 ac s in o sp ing aged 10 and 26 yea s, bu no a 6 yea s o age. Fu u e longi udinal s udies 21 should examine whe he hese associa ions pe sis in la e s ages o de elopmen and explo e he 22 causal na u e o he indings. 23 1 In oduc ion 1 Ma e nal obesi y is a wo ldwide public heal h p oblem ha has been linked o mul iple heal h 2 consequences a ec ing he mo he and he o sp ing. S udies ha e in es iga ed he associa ion 3 be ween p ep egnancy ma e nal obesi y and subsequen inc eased isk o child obesi y (1), 4 diabe es (2) and ca dio ascula e en s in adul li e (3). In addi ion, ma e nal obesi y has been 5 associa ed wi h ad e se neu ode elopmen al ou comes in o sp ing including lowe in elligence 6 and cogni i e unc ioning (4-9). Ma e nal body mass index (BMI) has also been ela ed o o he 7 neu ode elopmen al ou comes, including lowe pe o mance in ine mo o skills (10), execu i e 8 unc ioning (11), a en ion p oblems, nega i e emo ionali y (12), and ex e nalizing p oblems 9 (13). This is also suppo ed by a ecen sys ema ic e iew epo ing e idence o an associa ion 10 be ween p ep egnancy ma e nal obesi y and se e al neu ode elopmen al ac o s including 11 cogni i e and mo o abili ies in child en (14). 12 Toge he , hese indings sugges ha e al exposu e o ma e nal obesi y may in luence 13 o sp ing neu ode elopmen wi h long- e m me abolic and men al consequences, hough he 14 unde lying mechanisms ha e ye o be elucida ed. Fo his pu pose, neu oimaging echniques can 15 be used o be e unde s and he possible associa ions be ween ma e nal obesi y on o sp ing 16 b ain s uc u e and unc ion. Recen ly, i has been shown ha ma e nal obesi y was nega i ely 17 associa ed o s uc u al and unc ional b ain connec i i y in neona es (15, 16). In addi ion, 18 newbo ns o mo he s wi h obesi y had lowe ac ional aniso opy (FA) in se e al whi e ma e 19 ac s, including p ojec ion, associa ion, callosal, halamic and limbic sys em ibe s when 20 compa ed o con ols (16). Fu he mo e, exposu e o ma e nal obesi y was ela ed o di e ences 21 in es ing-s a e unc ional connec i i y in he do sal an e io cingula e co ex (i.e. a b ain egion 22 ha is connec ed wi h he p e on al and pa ie al co ex) in newbo ns (15). These wo s udies 23 2 we e pe o med in a small g oup o newbo ns (n<40), and hus he long- e m consequences o 1 ma e nal obesi y on b ain de elopmen in childhood and adul hood emain unanswe ed. 2 The cu en s udy aimed o in es iga e he associa ion o ma e nal p e-p egnancy BMI 3 and o sp ing whi e ma e mic os uc u e a he age o 6, 10 and 26 yea s using h ee p ospec i e 4 bi h coho s. In he absence o longi udinal da a, we used h ee coho s wi h pa icipan s o 5 di e en ages anging om childhood o young adul hood o add ess he esea ch ques ion. 6 Based on he p io wo k in neona es (16), we hypo hesized ha ma e nal p ep egnancy BMI is 7 associa ed wi h widesp ead di e ences in whi e ma e mic os uc u e. Gi en he spa seness o 8 he li e a u e, an explo a o y app oach co e ing a se o 13 majo whi e ma e ac s was chosen 9 o s udy he associa ion be ween p ep egnancy BMI and o sp ing whi e ma e mic os uc u e. 10 11 Me hods 12 The p esen s udy consis s o pa icipan s d awn om h ee bi h coho s, including he PREOBE 13 S udy om G anada, Spain, he Gene a ion R S udy om Ro e dam, Ne he lands, and he 14 No he n Finland Bi h Coho 1986 (NFBC 1986), om he No he n Finland. De ailed 15 in o ma ion abou inclusion and exclusion c i e ia o each coho is included in he 16 supplemen a y ma e ial. All s udies we e app o ed by hei local Medical E hics Commi ee. 17 18 Se ing & pa icipan s 19 The PREOBE S udy 20 The PREOBE s udy (17) was designed as a p ospec i e obse a ional coho s udy explo ing 21 pe i- and pos na al in luences o ma e nal weigh s a us on he o sp ing. O he 331 mo he s 22 included in he s udy, 135 ga e consen o neu oimaging o he o sp ing a 6 yea s old. 19 o 23 3 he 135 pa icipan s we e disca ded due o mo ion a i ac s du ing acquisi ion, o o he scanne -1 ela ed a i ac s. A inal sample o 116 was included in he analysis. 2 3 The Gene a ion R S udy 4 The Gene a ion R S udy (www.gene a ion .nl) is an ongoing popula ion-based p ospec i e 5 coho s udy in Ro e dam ( he Ne he lands) designed o iden i y ea ly en i onmen al and gene ic 6 de e minan s o heal h and disease om e al li e onwa ds (18, 19). A app oxima ely 10 yea s o 7 age, 3992 child en isi ed he esea ch cen e o he neu oimaging session. O hese child en, 8 3063 child en had usable DTI da a, bu in 587 child en in o ma ion on ma e nal p ep egnancy 9 BMI was missing. 10 child en we e excluded om he analyses as hey had adiological 10 inciden al indings which could po en ially in luence he whi e ma e ac s and hei quali y. 11 Thus, he s udy popula ion o analyses included 2466 child en wi h in o ma ion on ma e nal 12 BMI and da a o whi e ma e mic os uc u e. 13 14 The NFBC 1986 S udy 15 The No he n Finland Bi h Coho 1986 S udy (NFBC 1986; h p://www.oulu. i/n bc/) is a 16 p ospec i e popula ion-based da a collec ion e o o heal h- ela ed in o ma ion on indi iduals 17 wi h an expec ed da e o bi h be ween he 1s o July 1985 and he 30 h o June 1986 in he wo 18 no he nmos p o inces o Finland. A o al o 9 362 deli e ies, i.e. 99% o all deli e ies in he 19 a ge pe iod, we e eco ded in he coho egis e (20). The 26-yea subsample, used in he 20 p esen s udy, was collec ed based on he pa icipan s o a 16-yea ollow-up. Owing o he 21 o iginal s udy ques ion, almos 50% o he pa icipan s we e exposed o ma e nal smoking du ing 22 p egnancy. O he in i ed 1396 eligible pa icipan s, a o al o 471 (34 %) pa icipa ed in he 23 4 s udy. Scanning was comple ed success ully in 451 pa icipan s (21). Common con aindica ions 1 o he MRI acquisi ion included p egnancy, pa icipan ’s me al o elec onic implan s and se e e 2 claus ophobia. O he 451 pa icipan s wi h neu oimaging da a, one was excluded due o la ge 3 en icles p e en ing image p ocessing e o s and h ee due o a ailed MRI p o ocol. Also, 10 4 indi iduals had missing ma e nal BMI da a, lea ing al oge he 437 indi iduals o he analysis. 5 6 Ma e nal BMI 7 In he PREOBE s udy, ma e nal heigh we e measu ed a he ec ui ing session be ween week 12 8 and 20 o ges a ion. P ep egnancy ma e nal weigh was sel - epo ed a he same session. In he 9 Gene a ion R S udy, in o ma ion abou weigh jus be o e p egnancy was ob ained by 10 ques ionnai e. A en ollmen , we measu ed heigh (cm) and weigh (kg) wi hou shoes and hea y 11 clo hing. The co ela ion o p ep egnancy weigh ob ained by ques ionnai e and weigh measu ed 12 a en ollmen was 0.95 (p <.001). In he NFBC 1986 s udy, p ep egnancy weigh was epo ed by 13 he mo he s a isi s o ma e ni y heal h cen e s in he se en h o eigh h mon h o p egnancy. 14 Ma e nal heigh was measu ed in 52% o mo he ’s du ing he same isi and sel - epo ed by he 15 es (22). In o ma ion o ma e nal weigh and heigh was used o calcula e ma e nal 16 p ep egnancy BMI in kg/m2. 17 18 Neu oimaging 19 Image acquisi ion 20 Scanne cha ac e is ics and echnical acquisi ion pa ame e s om each coho a e epo ed in 21 Table 1. Child en in he PREOBE and Gene a ion R coho unde wen a mock scanning session 22 p io o he ac ual MRI scan session. 23 5 1 P ep ocessing 2 All h ee coho s used he same p ocessing pipeline using he same so wa e (23); DTI images 3 we e p ocessed using he unc ional MRI o he B ain’s so wa e lib a y (FMRIB, FSL, 24). 4 Image p ocessing included adjus men o mino head mo ion ( ansla ions and o a ions) and 5 eddy-cu en induced a i ac s (25), o a ion o he g adien di ec ion able in he same way han 6 he images in he p e ious s ep, and non-b ain issue emo al using he FSL B ain Ex ac ion 7 Tool (26) and inally calcula ion o FA and MD maps by i ing he di usion enso using d i i 8 unc ion (PREOBE and NFBC1986) o he RESTORE me hod implemen ed in Camino 9 (Gene a ion R). The quali y o aw di usion-weigh ed images was assessed using he DTIP ep 10 ool (h ps://www.ni c.o g/p ojec s/d ip ep/) ha au oma ically examined he da a o slice-wise 11 a ia ion, a cha ac e is ic o a i ac , in each di usion-weigh ed olume. The sum-o -squa es 12 e o (SSE) maps om he di usion enso calcula ions we e examined o s uc u ed signal ha 13 was indica i e o a i ac . Each SSE map was a ed om 0 o 3 (0: “None”, 1: “Mild”, 2: 14 “Mode a e”, 3: “Se e e”). Any cases no excluded by he au oma ed DTIP ep ool ha had a 15 “Se e e” sco e om he SSE a ing we e also excluded om analyses. 16 17 P obabilis ic ibe ac og aphy 18 The au oma ed Au oP x (27) pipeline was used o un p obabilis ic ac og aphy o b ains em, 19 p ojec ion, associa ion, callosal, halamic and limbic sys em ibe s in each indi idual 20 (h ps:// sl. m ib.ox.ac.uk/ sl/ slwiki/Au oP x). As pa o he pipeline, na i e DTI da a we e 21 egis e ed o FMRIB-58 1-mm s anda d space and he alignmen was isually inspec ed. T ac s 22 we e de ined using seed, a ge , e mina ion, and exclusion masks ha we e wa ped o na i e 23 12 by ma e nal obesi y. This hypo hesis is also suppo ed by he inding o ea lie mena che in 1 emale o sp ing o mo he s wi h obesi y (47). 2 I is essen ial o s ess ha many o he discussed mechanisms we e only s udied in 3 animal models and hus we mus be cau ious in e p e ing he esul s o he cu en s udy. 4 Fu he mo e, we canno exclude he possibili y o esidual con ounding, e en hough we 5 con olled o a ious con ounde s. Fo example, we did no adjus o ma e nal die du ing 6 p egnancy, which has been shown o al e mesolimbic ewa d pa hway in o sp ing b ain (48) 7 and al e b ain cellula de elopmen (49, 50). Finally, i is also possible ha ou s udy su e s 8 om insu icien powe in demons a ing associa ions be ween ma e nal BMI and o sp ing 9 whi e ma e a 6 yea s in he PREOBE coho . 10 11 S eng hs and Limi a ions 12 The cu en s udy has se e al s eng hs. We used h ee di e en bi h coho s wi h neu oimaging 13 da a a di e en age anges, and we e able o use exac ly he same p ocessing pipeline. 14 None heless, ou indings mus be in e p e ed in he con ex o ele an limi a ions. 15 Fi s , he coho s only had a single neu oimaging measu emen , so i was no possible o 16 d aw conclusions abou he longi udinal associa ions o ma e nal p ep egnancy BMI and whi e 17 ma e de elopmen . Fu u e s udies should ocus on epea ed neu oimaging in o de o do so. 18 Second, i could be possible ha he associa ions obse ed e lec scanne di e ences, e en 19 hough we used he same p ocessing and analyses me hodology. Fu he , each coho had e y 20 di e en sample size which esul ed in powe di e ences and may ha e in luenced he indings. 21 In addi ion, inclusion and exclusion c i e ia we e di e en ac oss coho s and could po en ially 22 13 in luence he indings. Finally, he h ee coho s di e ed in e ms o socioeconomic and li es yle 1 ac o s and his may also ha e in luenced he indings. 2 3 Conclusions 4 O e all, we ound ha in h ee independen bi h coho s, ma e nal BMI was associa ed wi h 5 highe FA and lowe MD in mul iple b ain ac s in o sp ing aged 10 and 26 yea s, bu no a 6 6 yea s. Fu u e longi udinal s udies should examine whe he hese associa ions pe sis in la e ages 7 and explo e he causal na u e o he indings. 8 9 Acknowledgemen s 10 This wo k was suppo ed by he Eu opean Union's Ho izon 2020 esea ch and inno a ion 11 p og am [g an ag eemen No.633595 DynaHEALTH] and No.733206 Li eCycle], he 12 Ne he lands O ganiza ion o Heal h Resea ch and De elopmen [ZONMW Vici p ojec 13 016.VICI.170.200]. The PREOBE coho was unded by Spanish Minis y o Inno a ion and 14 Science. Jun a de Andalucía: Excellence P ojec s (P06-CTS-02341) and Spanish Minis y o 15 Economy and Compe i i eness (BFU2012-40254-C03-01). 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