{"paper_id":"f1a0d5f0-2891-46de-9430-e263e211c2e4","body_text":"1 \n \nCoho rt p r of ile:  The B ris t o l IVF Stu d y- A  longit udinal s tudy of w o men, their part ne r s and \ntr ea tmen t  out comes f ollowin g  assist ed  r epr od uc t ive t echnologie s  \nAmy E.  T a ylor 1,2,3 , T aemi Kawahar a 2,3 , Jennif er  Pr ovis 2,3 , Kar ema Al Ras hid 4 , Sophie  \nFitz gibb on 2 , Alix Gr oom 1 , 2,3 , A manda Je ff ery s 5,6 , Paul W il son 5 , Sc ot t M N elson 4 , V alentine  \nAk ande 5,7 , Debor ah A Lawlor 1,2,3 \n1. MRC I nt egr ative Epidemio logy U nit , U niv er sity of Br is t ol, Brist ol, UK. \n2. Population Health Scienc es, Bris t ol Medic al Sc hool, Univ er sity of Bris t ol, Br ist ol, UK. \n3. Nat ional I nstit ut e f or Health Resear ch Bris t ol B iomedic al Centr e, Un iv er sit y Hospit als  \nBr is t ol NHS F ounda tion T r ust  and Univ er sity of Bris t ol, B r ist ol, UK \n4. S c hool of Medicine, U niv er sity of Glasgow , U K.  \n5. Bris t ol Centr e f or Repr oductiv e M e dicine, Br is t ol, UK \n6.  U niv er sity Hos pit a ls Bris t ol and W e s t on NHS  F oundat ion T r ust , Bris t ol, U K  \n7. North Brist ol N HS T r ust, Brist ol, U K \n  \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \nNOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.\n\n2 \n \nAb str ac t  \nBackgr ound : The Bris t ol IVF  S t udy  (BRIST-IV F )  is a longitudinal c linic al coh ort, es t ablished t o  \ndet er min e f act or s  r e lat ed t o s u cce s s f ul liv e  birth and  other ou t c omes f ollowing c onception \nby a s s is t ed r epr oductiv e t echnologie s (AR T) . This  cohor t pr ofile d esc r ibes recruitment, data  \ncollec t ion and planned r esear ch.  \nMet hod s: The st udy g a ther ed comprehensiv e s o c iodemogr aphic , lif est yle, an thr o po metr ic , \nand c linic al da t a fr om wo men a n d th eir  par tner s bef ore an d dur ing tr eatmen t, as  well as  \ndur ing  pr egnanc y  and af t er birth. Bio logic al s amples , including b lood, urine, and saliva, wer e \nc ollec t ed a t  initia l r ecruit me nt and  at pr egnancy clinics, with c or d blood a nd placent al tiss ue \nobt ained a t birth. P art icipan ts consen t ed t o N HS r ec or d  link ag e, a llowing ac c e s s t o  \npr egnanc y and birt h out c omes f r om o bs t et ric n ot es.  \nR esults: B e t ween 3r d  Sept ember  2019 and 30t h June 20 23,  502 co uples or single women \nwer e r ecr uit ed (967 individuals in t ot a l) . O f these, 490 women unde r went  1,055 AR T \ntr eatment cy cle s  dur ing the s tudy f ollow-up  (up t o 31 st Mar ch 2024). R ecr uit ed  women  had  \na mea n  ag e of  35.8 y ear s  (SD = 4 .4) and a mea n  BMI of 25.1 (SD =  4.4).  A t the time o f \nr ecruit ment, 251 women (5 0% )  had nev er been pr egnan t, and 374 (75%) had not had a  \npr evious liv e birt h. W omen and  t heir  par tner s with a con firmed v iab le pregnanc y  a t a sc an  \nperf ormed  a t 7 weeks of  g est a tion  wer e in v ited t o participa te in  the  pregnanc y f ollow-up \ns tudy , with 305 women (f or 324 pr e gnancie s )  in vit ed. Dat a we r e c ollect e d fr om  p r egnancy \nques tionnair es (n =246, 76 %), p r egna nc y  c linic da t a (n=119, 3 7%) , and  bir th qu estion nair es  \n(n=223, 69%). Collection of  obst etric da t a fr om health r ec or ds is ongoing.  \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\n3 \n \nConclusion: The BRI ST-IV F  c ohor t enables nov el r es ear c h in t o  the pr edict or s  and \nc ons eq uen c es of AR T c once p tion, with comparison t o a  na t ur ally c onceiv ed cohor t, the  \nsecond g ener a tion of the A von L ongitudinal S t udy of Par ent s  and Childr en ( ALSP AC-G2).  \n \nList  of Abb r evia tions: ART : as s is t ed r epr oductiv e t echnology , IVF: in vitr o f e rtiliz ation, ICSI: \nintr a cyt oplasmic s per m injection, BCRM: Bris t ol Centr e f o r Repr oductive M edicine, EDT A:  \nE thylenediaminet et r aacetic acid, ACD : ac id citr at e de x t r ose, BMI: Body  ma s s inde x   \nKey wo rds :  in v itr o f er tiliz a tion, as si st ed r epr oduc t iv e t ec hnolog ies, longitudinal s tudy , \npr egnanc y out c omes   \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\n4 \n \nBackgr ound  \nInf er tility ,  as de fined by t he W orld  Health Or g aniza tion  (WHO), is  the inabilit y t o achieve \npr egnanc y a f t er 12 months or  mor e  of r egula r , unpr otect ed se xual int erc our s e. It af f ec t s  \nr ough ly one in s ix c ouples globally , w it h lif etime pr ev alence es tima t es r anging fr om 4% t o \n40%, d e p ending on r egional and me tho dological v ar iat ions  (1). Althou g h mos t pr ev alenc e \nda t a come s from h igh inc ome co u n tries, es tima t es fr o m low- t o mid dle -inc ome c oun tries \nsug ge s t t hat  r a tes ar e c ompar able (1). Be y ond it s  biologic al implica tions , inf er tility has  \npr of ound ps y chologic al and s ocial e ff ects , oft en leading t o emo tional dis tr ess, ment al health  \nchallenges, and r educed pr oductivity (2). \nAss i s t ed r epr od uc t ive t echnologies  (AR T)  ar e eff ectiv e  m edic al int erve n tions f or  tr eat ment \nof inf e r tility . AR T r e f e r s t o all int erv e n tions tha t in c lude t he in vitr o  handling of bot h human  \noocyt es and sper m or  embry os f or  the purp ose of r eprodu c t ion (3) . The  most  c ommonly  \nused f orms of  AR T ar e in -vit ro f ertiliza t ion (IVF) an d IVF with In t r ac y t oplas mic sperm \ninjection (ICSI) . Pla ns  f or  dev elopin g the BRIST-IVF c ohor t beg an pr ior  t o  int ern a tiona l \ngl os s ar i es  clar i f yi ng t er ms  f or  i nf er t ilit y an d i t s  t r ea t m en t .  WE ha ve r et ai ned t he s t udy name \n(BRI S T- IVF) and us e ART as  a g ener al t erm f or IVF and ICSI in this paper . \nGlo bally , AR T h a s r e sult ed in  the b ir th of o ver  8 million individua ls, wit h the number  of A R T \ncy cle s c on tinuing t o rise in high inc o me c oun tr ies , wit h incr easin g u se in  low- a n d middle- \ninc ome c oun tries  (4) . Iden tifying modifiable risk  f a c t or s tha t inf lu enc e live birt h succes s  and  \nof f spring a n d pa r ent al hea lth p os t concept io n is  es sen tial f or  impr o v ing tr ea tment e ff ic acy . \nHis t orically , r es ear c h  o n f a c t or s as so c i a t ed wit h AR T out c omes has f o c u s ed on clinic a l f act or s \ntha t  ar e r outinely collect ed dur ing IVF  tr eat me n t including ma t er na l ag e, r epr od uc t ive  \nhis t ory a n d type of IVF tr ea tmen t  (5, 6). However, incr ea sing evidence s ugge st s  that ART  \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\n5 \n \noutcome s ar e als o in fluenced by mater nal and pa t ernal h ealth and lifestyle chara cteristic s .  \nFor example, s t udies  have demonstr a t ed that bot h ma tern a l and paternal s mo k ing are \nasso ciated with r educed liv e birth rates following A R T (7, 8) and that o v erweigh t or o b es it y  \nin bot h th e fe ma le and ma le par tners  is a sso ciated with r educed lik elihood of succes s  in IV F  \ntr eatmen t  ( 9, 10). \nHigher  body mass  in dex  ( BMI) ma y influence s uc ce ss of I VF treat me nt via met abolic  \nalterations  t hat affect b oth oocyte and sperm q ualit y . In  w o men, metabolic pro files  in blood  \nhave been shown to ass o ciate w it h the c o mposit ion o f  the  follic ular  fluid ( FF ) , the  \nmicroenviro nm ent surr ounding th e  matur in g  ooc yt e (11). Stud ies in bot h animals  and \nhumans have s ho w n  that FF meta bo lit es  ar e assoc iat ed wit h oocyte quality and with  \npregnanc y ou tcome following ART (12,  13). Similarly, in  males , metabolit e  prof iles in both  \nserum and s emin al fluid have been s hown to  r elate to male in fertility (14, 15).  \nAdvancements in h igh t hroughput  n uc lear  magnet ic  resonance (N MR)  spec t ros c o p y  now \nallow prof iling o f over 200 c ir c ulat in g  metabolites in blood s er um or  pla sma ( 16). As s e s sin g \npre- tr eat men t and/ or  in treat m ent metabolite prof iles may  help ide nt ify biomar k er s  \npred ictive of IVF s u c ce ss and un cover  pot ential pathways for int ervention. A recent study  of \n400 w o men and their male par tners undergoing IV F tr eatment  in Glasgo w, UK, identified  \nsev er al novel associations between s erum metabo lites and markers of ova r ian reserve and \nsperm parameter s  (17, 18) . Thes e f indings highlight the need for f urther r eplic at ion and  \npros pective studies t o es t ablish met ab olic pr edic t ors of s ucce ss.  \nAs liv e-birth suc ce ss r at es f ollowing AR T c on tinue t o impr ov e, gr eat er at t ention  has been \nplaced on pot en tial per inat al and lo ng-t er m health  ou t comes  of AR T-c o nceived off spring. \nMan y s tudies e xamining t hes e out comes  ha v e been  desc r iptiv e, f ocus ing e x clu s iv ely on A R T-\nc onceiv ed individuals  without  c o mpar is on gr ou p s  or u sing select ive pee r- bas ed \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\n6 \n \nc omparisons. R e cen t r esults fr om a  lar g e c ollabor at ion of b irth  c ohor ts , wher e A R T and  \nna tur ally-c onceiv ed individuals wer e f ollowed -up  ide n t ic ally f r om p regnanc y t o ear ly  \nadultho od f o und  lit tle  evidence tha t AR T c onc ep tion a f f ec t ed bo d y c omposition or \nc ar diomet abo l ic health u p t o early adulth ood (19). These findings  wer e further  s uppo rt ed in  \na lar g e U K elec t r onic  health r ec or d s tu dy in whi ch bo th c on v en tional po pula tion a n aly ses ,  \nand w it hin sibling analy s es, w hich c on tr ols f or  f amily  level c onf ounding , s uc h a s  par ent a l \ninf ertility , f ound no a ssocia tion bet ween A R T concept ion and h o s pit al a d mis sion s f or  \ncir cula t ory dis ease s  (20). Elec t r onic health  r ec or d  s tudies ha v e also be en  used t o e xplor e  \ne ff ects of AR T c onception on perina t al ou t comes . R ec en t  analyse s i nco rpor a t in g both  \nc on v en tio nal po pu la tion a n d with in siblin g  c omparison s, support  a caus al ef f ec t  of fr esh-\nembr yo  A R T t r ans f er c ompa r ed t o  na t ur al con c ept ion on an incr ea sed  risk  of  small f or \ng est at ional ag e, while fr o z en embry o tr ansf er  incr eas ed  the r i s k  of la r g e f or ges t a tion a l a g e  \nc ompar ed t o natur al c onception. Bo th fr esh and fr o zen embry o tr a n sf er  in c r ea sed th e risk of  \npr et erm  birth (21) . W h ile bir th c oho rt and electr on ic health rec or d st udie s  p r ovide v a luable  \ninsight s  int o tr ea tm ent-r e la ted dif f er ences (e.g ., IVF vs. ICSI, f r esh v s . f r oz en embr yo \ntr ansf er ), t hey c annot  ev alua t e m or e det ailed tr e a tmen t v ariables , su c h  a s ov arian \ns timula tion pr ot oc ols . Furt hermo r e , elec t r onic healt h r ec or d st udies  c annot e xplore  \npot en tial molecular mechanisms  un der lying AR T-r e la t ed out c omes . The BRIST-IVF co hort,  \nwith its det ailed me t abolic and clinica l da t a, is  well-positioned t o addr ess  t hes e g a ps .  \nThe Br is t ol IVF Stu d y  ( BRIS T-IVF)  wa s d es igned t o es t ablish a clinic al AR T co hort t o under t ak e \nr esear ch o n th e pr ed ict io n and cau s es of live birt h succ e s s, pr egnan c y c omplic a tions and \nperinat al out c omes. The initial r ec r uitmen t  t ar g et wa s 1,20 0 coup le s or  single women. This \nwas  amende d as a r e sult of the COVID pandemic (det ails below )  \n \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\n7 \n \nThe initial objectiv es  (pr oposed in 2019) wer e t o :  \n1.  Impr ove t he ac cur acy of pr edic t ion of  live bi r th suc c es s  with ART;  \n2.  Identif y  modifiable risk fa c t ors and mechanis m s  that might be t ar gets for dev eloping  \ninter v entions (lif es t yle or  c linical) that  could improve rates of liv e bir th suc c es s;  \n3.  Det ermin e the as so ciat ions  of ART and  different ART tr eat men t proto c ols o n fet al \nepigenetic s ignal s ( s pecifically  cor d-blood DN A Methylation and potentially his t one marks);  \n4.  Det ermin e th e impac t  o f ART and different A R T  t reatment prot ocols  on cardio-\nmetabo lic risk  factor s  (and their tr a jec t ories) in mot he rs, and part ners dur ing t he f i r s t  5 \nyears after t reatmen t;  \n5.  Det ermin e the impac t  of  ART and different  AR T tr eatment  p r otocols on maternal, \npart ner and o ff s pr ing mental health. \n \nDu e t o  t he  Covid-19 p ande mic, BRIST-IVF  was clos ed  f or a  period  o f 13 mon ths. It became  \nclear f ollowing the closur e, and t he e f f ect of  the fir st clinic vis it s f or  tr ea tment being online, \nr a ther than in per s on onc e the A RT clinic  r eopened, tha t it wa s unlik ely tha t  t he initia l \nr ecruit ment t ar g et would be met. As a r esult, t he st udy wa s  c losed earlier  than p lann ed as  \npart  of the NIHR  r esear ch and r ec over y r eset pr ogr amme (22). The spe c i fic imp a ct s of  the \npandemic on s tudy oper a t io ns  ar e su mmar ised in Bo x 1.  \nThe objec t ives h av e been r ev ised  t o r e flec t  t he numb er of par ticipan ts r ecru it ed and the  \ndur a t ion o f f ollow-up and we will no w f oc u s  on two br oad objectiv es :  \n1.  To investigate deter minan ts of live  bir th ra t es  f ollowing ART. This will includ e  \ntr eatmen t  f ac t ors (e.g.  p rotocols) a nd biologic al measure s (e. g. N MR  metabolite  \nmeasures).   \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\n8 \n \n2.  To compar e pregnanc y and p e r inatal out c omes  between ART pregnancies a n d non-\nART pr egnancies  usin g the Avon Longitudinal Stud y  of  Parents and Childr en (ALSPAC) \nG2 c oh ort ( 23) a s  a  comp aris o n group, and e xplor e the extent  to which any of t hes e  \ndifferences  ar e mediated by N MR met a b olites , plac ent al tis s ue D NA methy lat ion or \ntr ans cript omic data.  \n \n \n  \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\n9 \n \nMetho ds  \nStud y R ec r uitme nt  \nW omen and their p a r tner s  wer e r e cr uit ed fr om the Br ist ol C en tr e f or  R eprodu c t ive Medic ine  \n(BCR M), wit h r ecruit men t occurr in g in two phase s  due t o t he C O VID- 19 p andemic. The fir st  \nphase of r ec r uitment  a t BCR M r an from 3 rd  Sept embe r 2019 t o 27 th  Mar ch 2020. The stud y \nr eopen ed on 1 April 2021 and c onclu ded on 30 th June 2023.  \nT o be el igible t o t ak e part in t he s tu dy , par ticip a n t s  had t o  be a g ed  18 o r  ov er and t o  be  \nunder g o in g or planning t o und e r go IVF  or ICSI t r ea tment . T r ea tmen t cou ld in volv e use of \nown or  dono r g amet es ( eg gs or  sper m) . Wher e t rea tm en t was  undert ak en wit h a p a r tn er , \nboth  the  woma n  and th eir part ne r wer e requir ed  to enr o ll t oget her  t o  pr ov ide con s en t f or  \nac c es s  t o BCRM medical no t es . Only pa tie n ts who had c onsen t ed t o r es ear ch c on t act via th e  \nHu man Fer tiliza t ion and Embry ology Aut hority (HFE A) c onsen t t o disclo s ur e f orm wer e  \neligible f or pa rt ic ipation ( cd-f orm-v10-16-oct ober-2019.pd f (hf ea.gov .uk )\n) .  \nP art ic ipan t s  wer e r ecruit ed prior t o e gg c ollection or  fr o z en embry o tr an sf er  as  part of AR T \nt r eat ment  or  f ol l owi ng a sc an  a t  7 w e eks g est at i on c onf i rmi ng a vi abl e pr egnanc y .  B ef or e t he \nC OVID- 19 pandemic, r ecruit men t f ollowed a f ace-t o-f ace model, wher e  pat ients r eceiv ed an  \ninvit ation let t er and par t ic ipant  inf or mat ion  s heet  by post bef or e their clinic v isit and pr ior t o  \nc ommencing dr ug pr ot oco ls. A  r e s ear ch midwif e or  nur s e obt ained wr it t en inf o rme d  \nc ons ent  in per son.    \nP os t-pandemic, due t o r educed in -per son c linic v i sits , t he r ec r uitment  pr oc es s shift ed t o  \nr emot e c onsen t. P a tients wer e con t act ed v ia email and t eleph one t o d iscuss stud y \npart ic ipa t io n, and up  t o two f ollow-up c alls wer e  made by the r es ear ch t eam. P ar tic ipan t s  \nc ompl et ed onl i ne c onsen t  f or ms i n con sul t a t io n wit h a r esear ch mi dwi f e or  nu r se.  A s par t of \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\n10 \n \nenr ollme n t, pa r ticipants als o pr ovide d c onsent f or  N HS medic al r ec or d link age t o f a cilita te  \nda t a c ollec t ion on pr egnancy and birth  o ut c omes .  \nQuest ionnair e \nP art ic ipan t s  c omplet ed  a bas eline ques tionnair e on pape r (pr e -C ov id)  or o n line (post -Covid ) \na t th e  poin t o f  recruitment. The ques tionnair e  a sk ed about employmen t, e duc a tion, cur r ent \nuse of medication s , own and f amily his t ory of c ar diov as cular dis ease , smokin g , alcoho l us e \nand phy s ic al ac t iv it y . A c opy of the quest ionnair e is  pr ovided in t he Supple ment a r y  mat e rial.  \nBaseline st udy m easur em en ts  \nBetween Sept ember 2019 a n d Mar ch  2020 , s tud y measur es wer e c omplet ed a t the p oint of \nr ecruit ment. F ollowing t he Apr il 20 21 r eopening , an appoin tment wa s made during the \nc ons en t  call f or  the r esear ch  t eam t o collect s tudy  measur e s. A t th es e vis it s ,  par tic ipan t s  had  \nheigh t, weigh t and bloo d pr es sur e measur ed and blood and u rine s amples t ak en .  Saliv a \nsamples  wer e sough t wher e part ic ip an t s  wer e not able t o or d id  no t wan t t o  give a bloo d  \nsample.  Wher e it was  not  p o ssible t o con duc t  a s tud y vi s it, heigh t , weigh t and blood  \npr essur e wer e obt ained fr om BCRM n ot es or self-r eported by t he participant.  \nDat a c o l lect i o n fr om  BC RM medical not es  \nF or each f e male und er going tr eatmen t, inf o rma tion on r epr oductiv e  his t o r y  inc luding \npr evious pr egnancie s and birt hs, p r evious f ertilit y  tr e a tme n ts, dur a t ion and c aus e s of  \ninf ertility , antr al f ollicle c ount and ant i mulle rian hormone (AMH) lev el wa s  pr ovided by the  \npart ic ipan t s  and/o r ext r act ed f r o m their  BC RM med ic al not es  by t he r es ear c h midwiv es .  \nInf or ma tion o n IVF or  ICSI t r eatmen ts was e xtr ac t ed fr o m BCR M medic al r e c or ds , cov ering \nboth  ongoing and  prior  tr eatmen t c y cles (f or those r ec r uit ed aft er t heir 7 - wee k sc an). Th e  \ne xtr act ed dat a  in c luded  tr e a tmen t type, dr ug r egimens, tr ea t me n t pr otoc ols, f ollic ulogr ams, \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\n11 \n \nnumber  of eg g s  c ollect ed, sperm par amet er s , embry ologic al da t a and tr e a tment out co mes  \n(pr eg n ancy and bir th). T r ea t me n t infor ma tion was co llect ed f or part ic ipant s  u p un til the 31 st  \nMar c h 2024. Collection of inf orma tion on birt h ou t c omes f r om these tr ea t m en ts is st ill \nongoing.  \nPr egn ancy f o l lo w u p  \nIf participan ts became pr egnan t  f ollowing AR T and h a d  a v iable pr egnanc y c onfir med by \nultr as ound  a t 7  week s g est a tion, t hey and t heir  par tner s we r e in v it ed t o participa t e  in th e  \npr egnanc y f o llow up s tud y . In vit a tio ns wer e initia lly sen t by p ost  but tr ansitioned t o email \nf ollowing the C OVID-19 pandemic . Pr eg n a n t women wer e ask ed t o c omplet e an ear ly  \npr egnanc y ques tionnair e (be f o r e 18 weeks g e st a tion), a lat e p r egnanc y q uest ionnair e (aft e r  \n28 week s  g es t a tion) and a bir th ques tionnair e ( a r ound 2 week s  aft er the b i r th of  t he ir baby). \nP art ner s wer e sen t one q uest io nnaire dur ing their partne r ’ s  pr egnanc y a nd a ques tionnair e  \naft er  t h e bir th o f th e ir  baby . Quest io nnair es c ollec t ed in f orma tion on p r egnanc y  health, \nsubst a n c e u s e, f eelings  and emotion s, pla n s and e xpect a tions f o r lab o ur  a n d par e n thood  \nand birt h e x pe r iences . All pr e gna nc y and birt h quest ionna ir es ar e a vailab le  in supplement a r y  \nma t e r ial.  \nPr egnan t  women and their p a r tner s  wer e  als o in vit ed t o at t end a clinic  at  the U niv er sity of \nBr is t ol du ring pr egnancy . A t th es e  clinics, participan ts had a n thr opometry and blood  \npr essur e mea sur ed a n d under t ook ph y sic al c apability and  c ognitiv e t es ts.  P art ic ipan t s wer e \na s k e d  t o  c o m pl e t e a n  o nl i n e d i e t  d i ary  f o r  5  d a y s  f o l l o w i n g  t h e  c l i n i c  a n d t o  w e a r  an  a ct i v i t y \nmonit or . At the clinic, participan ts ha d blood  samples  t ak en and pr egnan t women pr o v ided  a  \nurine s amp le. Sa liv a samples  wer e r eq uest ed wher e it wa s no t pos sible t o pr ovide a b lood  \nsample. Due t o  C OVID-19 r estr ic t io ns, v ir tual vis its wer e imp leme n t ed  f or a subset of \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\n12 \n \npart ic ipan t s , during which an equip men t pack wa s  p r ovided which enabled collection  of a  \nsubs et  of the measur es fr om t he f ac e- t o -f ace clinic .  \nA t birth, cor d blood and  plac en t a s amples, and measur emen ts of th e ba bies  wer e co llect ed \nwher e women d eliv er ed  at  pa r tic ipat ing hospit als  (Univer s ity Hospit als Bris t ol and  Wes t on  \nNHS F ounda tion T rus t (St  Michael’ s), North Brist ol N HS  T rust ( S outhmead Hos pit al)  a nd Roy al \nUnit ed Hos pit a ls  B at h NHS Fou nda tion T ru st. W her e pos s ible, v ir tual pos t birth visits wer e  \nc onduct ed 7- 15 da y s  aft er  the  birth of the  baby t o c ollect ant hr opome tric inf o rma tion  f or  \nboth t he m other and baby .  \nAll pr egnancy clinics , birth sample c ollec t ions  and pos t bir th  f ollow-up  visit s wer e car ried out  \nby  A von Longitudinal Study of Par ents and Childr en (ALSP AC) fieldwork er s us ing  identic a l \npr ot oc ols  as the ALSP AC second  g ener a tion pregnanc y clin ics (2 3). Thi s harmoniz a tion allows \nf or  dir ec t  comparis o ns between pr egnan c ie s c onceiv ed v ia AR T and n a tur ally c onceived \npr egnancies in f utur e analy se s .  \nBiological s am ples  \nBiologic al samples we r e co llect ed a t  thr ee k ey ph as e s:  baseline, d uring pr e gnanc y and a t the  \ntime of  bir th  (Figur e  3) . At baseline ,  no n-f ast ing blood, u rine and  saliva samples  wer e  \nc ollec t ed f rom particip a n t s . Blood samples wer e c ollect ed in  E th ylenediaminet et r aac et ic  \nacid (EDT A)  tubes, cen trif ug ed with in  24 hour s t o s epar at e plas ma and whit e blo od cells (a \nsour ce of DN A) and st ored at  -80\no C wit hin 2  hour s of pr ocessing. Pla s ma  w as st or ed in200µl \nand 500µl aliquot s ,  while whit e bloo d  c ells wer e st or ed in 1ml aliquot s . In it ial p r oces sin g f or \nmos t s amples t ook place a t  th e  BC R M o r Univer sity of  Br ist ol labor at ories  a t Southmead  \nHos pit al. All samples hav e sinc e been t r ans f erred f or  long t er m  st or ag e at Bris t ol Bio r es our c e \nLabor a t ories  (BB L ) .  \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\n13 \n \nF or an initial set of par ticipants, we also c ollec t ed a blood sample in acid c itr a t e de xtr os e \n(ACD) t ubes f or the cr ea t ion o f immort a liz ed cell lines . Howev er , t his c ollec t ion was \ndiscon t inued in  Nov ember 2 021 due t o  uncert a in ties r eg ar ding pr oces s ing  f easibili t y during  \nthe C OVID-19 pandemic.  \nA t th e pr egnanc y  clinic , non-f a s ting blo od and ur ine sa mples  wer e collect ed fr o m pr egnan t \nwomen, while pa rt ner s wer e  as k ed t o pr ov ide f asting blo od s amp les w h e r e possible. F or \nthese pr egnan cy  clinic samples , cho les t er ol and gluc os e lev els wer e obt ained using P TS \npanels® on a C ar dioChek® P A, and ha emoglobin le v els  mea sur ed  u s ing a H emo Cue® Hb 201+  \ns y s t em, within 90 min u t es of  obt aining t he sample. Following th ese t e st s, EDT A plas ma ,  \nheparin plas ma, s er um and w h it e blood c ell samples wer e aliquo t ed out aft er  ce n tr ifuging  \nand s t or ed a t - 80\no C.  \nCor d blood EDT A b lo od  samples  and placen t as wer e collect ed a t particip a ting ho s pit als a t \nthe birt h o f the babies  and wer e  cou rier ed  to t he  Univer sit y of Br is t ol f or pr oces sin g and \ns t or ag e. Be f o r e p la cen t a s wer e pr oc e s s ed  p hot ogr aphs and measur em en t s  wer e  t ak en. \nPlacen t as  wer e p r ocessed t o ma xim ise futur e us e by s t or in g  small pieces  i n a v ariety of wa y s  \nincluding , snap  f r ee z ing , fixing in  f ormalin and  in R N A la t er s o lu tion. Placen t al membr ane  \nand c or d slice s wer e  also st o r ed. Cor d blood  was c en t rifug ed and s epar a t ed in to EDT A \nplasma (aliq uot ed int o 200u l and 500u l)  a n d w h it e blood cells, which wer e st or ed a t -80\nO C \nUs e of  b iologic al samples  \nA t o t al o f  823 plasma samples wer e c ollect ed, co mprising 372  woman  a t baselin e, 307 \npart ner s a t  baseline, 57 woman dur ing pr egnan cy ,  28 p artner s  dur ing p r e gn a n cy and 59  \nof f spring co r d bloo d. T o dat e, N MR met abolit e q uantific a tion  h a s b ee n  c omplet ed on 200 \nsamples  t a k en at  bas eline in the women and  167 t ak en a t b aseline fr om part ner s. Wit h the \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\n14 \n \nc ompletion o f  bio -sample collectio n ( s ee Figur e 1 f o r final numb er s ) , N MR met abolit e  \nquan tifica tion f o r all baseline sample s fr om wo man and part ner is schedul ed f o r c ompletion  \nin lat e 2025. Thes e da t a will be used t o in v est iga t e  r es ear c h ques tions outlined in the  \nPlanned Analy ses  se ction, with comparis o ns  ma d e t o the AL SP AC -G 2 c oho r t, which includes \nequiv alent NMR met abo lit e a ssessme n ts during pr egnancy and in c or d blood. \nThe pr ot oc ol used in this  s tud y f or  pr eparing a n d st oring pla cen t al tiss u e i s  iden t ical t o  that \nuse in ALSP AC-G2 . We ar e curr en tly (Apr il 2025) pr ep a ring all 70 BRIST-IVF  placen t a samples  \nand 70 ag e m a t ched ALSP A C-G2 placen t al s amp les f or of tr ans crip t omic  and  DNA  \nmeth yla tion  analyse s t o e xplor e diff e r en c es in t he s e biologic al mea sur es bet ween AR T and \nna tur al c onception s .  \nWit h fu tur e  funding , additiona l analy se s  a r e planned, inc lud in g  s er um p r ot eomic  analy se s \non baseline woman and part ner seru m s amples and mas s  spe ctr ometry met abolit e pr o f iling \nof baseline a nd pr egnancy urine sa m ples  in women and the ir  partner . \nDat a manag emen t  \nDat a have been collected and stor ed using the Res ear c h Ele ctr onic Dat a Captur e (REDCAP) \nsoftware a nd wor kflow technolog y hosted at the U niversity  of Bristol (24) . Res ear c h data i s \nstored in  a  s epar ate filestore from  p ersonal data and o nly  t hree  r es ear c her s  hav e acce ss to \npersonal identifier s .  \nP a tien t  in volvemen t \nA pa tien t advis or y  gr oup of people w ho h a d  o r were under going IVF tr ea tmen t was  set up in \nearly 2019 t o advise on the r elev ance , ac cept ability of s tudy pr oc e s s e s and document a t ion.  \nE thical appr oval \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\n15 \n \nE thics  a p pr ov al f or t he st ud y wa s  obt ained f r om th e U K Na tional Healt h Ser vic e Sou th We s t- \nFr encha y R es ear ch E th ic s Commit t ee (IRAS pr o jec t  ID 236773, Initial appr o val 10/7/ 201 9)  . \n \n  \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\n16 \n \nR esults \nChar ac t erist ic s of t he r ecrui t ed s am ple \nFigur e 2 shows the f lo w  of p articipan ts fr om initial s cr eening thr ough in vit a tion  t o  \nre c r u i tm e n t .  \nPrior  t o th e C OVID-19 pandemic , 2 1 3 cou ples  or  sin gle wo men wer e scr eened, while 2,225 \nwer e scr eened f ollowing r e sumpt ion of AR T s erv ice s. O f  these  2,3 38 c oupl es / s in gle women, \n1,214 met the s tudy ’ s  eligibilit y crit eria, w it h 5 02 (4 1% )  suc c es sf ully  r ecr uit ed. The f ina l \nc ohort  co mprises  5 02  women and 4 6 5 p a r tner s  (4 45  women with a male p artner  (89%), 20 \nwomen with  a f emale par tne r (4%) and 37  women under going  tr ea t ment wit hout a  \npart ner(7%)) . S ince r ecru it me n t one s ingle woman has  with dr awn her c ons en t. \nChar a ct er istics of  t he r ec r uit ed  wo men and t heir part ner s ar e  shown in T ables  1 and 2. \nWher e same-se x  co uple s  wer e unde r g o in g r ecipr oc al IVF /IC SI, f or  da t a c ollection p urposes \nwe c onsid er ed t he woman who wo uld c arry t he embr y o as the woma n  under going \ntr eatment. W omen under g o in g  t r e atmen t had a mean ag e  of 35.8 y ear s (SD = 4.4) a t \nr ecruit ment and a  mean  BMI  of 25.1 (SD = 4.4). The majority (92%)  wer e of whit e  et hnicity .  \nA t the  time of r ecruit me n t, 251 women (50%) had ne v er been p r egnan t, a n d 374 (75%) had  \nnot had a pr ev ious liv e birt h. Their p artner s  had a mean ag e of  37.6  y ear s (SD = 5.8) and a \nmean BMI of 26.8 (SD = 4.3), with 94% ident ifying as whit e.  \nT r ea tm en t cy c les and pr eg n an c y ou t c o mes \nAmo ng the 501 c ouples and s ingle w omen who wer e s ucce s s fully r e cruit ed and r emained in  \nthe s tudy , 12 (2%) wer e  enr o lled following a c onfir m ed viable p r egnanc y a t  a  7 - wee k  \ngest at ional s c an.  \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\n17 \n \nF or this s tudy , we de f ined  a tr ea tmen t cy cle as an eg g co llection  with or w it hout a fr es h \nembr yo  tr ansf er or  a fr o z en embry o  tr ans f er . Be t ween r ec r uitme n t  and Mar ch 2024 , 490  \nwomen unde r went  a t o t al o f 1,05 5 ART c y cle s . F ollow up time in the s tudy f or the 11 wome n  \nwho wer e r ecruit ed but did  n ot und er go an y r elev an t cy c les r ang ed fr om 1 1-23 mon t hs . Of \nthe 1,0 55 AR T cy cles, 1 25 wer e IVF (in 69 o f these the  woman had a  fresh embry o t r ans f er), \n429 wer e ICSI (in 273 of these the  wo man had a fr es h embry o tr ansf er ) an d 501 wer e fr o zen \nembr yo t r ans f er s (s ee Figur e 3).  \nOf the 843 embry o tr ansf er s , 458 ( 54 %) r esult ed in a p ositiv e p r egnancy t es t, 378 (45%) in a \nneg a tiv e pr egnancy  t est and 7  out c omes wer e unkno wn. O f  the 45 8 pr egnancie s,  96 wer e  \nbiochemic al or end ed  in  a m is c arr iage pr ior  t o the 7 -week s c an. T r ea tmen t inf or m a tio n  \nr eport ed in t his paper  is t ak en fr om a  da t a download on  15  Augus t 2024.  R epor t ed numbe r s \nma y c h a n ge wher e t her e ar e up d at es  t o  clinic r ec or ds.  \nPr egn ancy que s tio nnair es and cl in ic    \nF ollowing a pos it ive 7-week sc an c o nfirming a v iable p r egnancy , 305 wo men and , wher e \nappr o priat e, t heir par tner s wer e in vit ed to par ticipat e in t he p r egnancy f ollow up st udy . O f \nthese 305 , 1 9 had t wo  pr egnan cies r e sulting in a  t o t al of 324 pr egnancie s o ver  the c our se of \nthe st udy (see Figur e 4). In vit at ions  wer e not iss u ed f or  38 p r egnancies  due to  clos ur e of \nclinics f or t he Covid-19 pandem ic, lack of c onsent f or  pr egnancy f ollow  up, or the s tudy t eam  \nnot be ing not ified o f the pr egnanc y .   \nAmo ng the 324 pr egnan c ies,  part ic ipa t io n in pr egnancy f ollow-up wa s a s f ollows: 246  (76%)  \npr egnancies r eturned a t least  one  pr egnanc y quest io nnair e, 23 3 pr eg n a n c ie s ha s a \nc omplet ed bir t h quest io nnair e, 117 wome n  (f or 119 pr egnan cies ) and 39 partn e r s \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\n18 \n \npart ic ipa t ed in pr egnancy  c linics a t the Univ er sit y of Bris tol and  70 placen t as and 58 c or d \nblood samples  wer e  d onat ed.  \nPr egn ancy and b i r th ou t come s  \nDa t a  collection on p r egnancy out c omes f ollowing tr e a tme n ts is ongoing. We ar e co llecting \nda t a f or  all pr egnancies of st udy par tic ipan t s  fr om BCR M me dical no t es. This inf o rma tion  \nincludes  pr egnancy out c ome (miscar riag e, st illbir th, ter min a tion of pr egna ncy , liv ebirt h ), se x \nand birt h we ight  of the baby .    \nAdditionally , pr egnancy and b ir th ou t c omes ar e being r etriev ed  fr o m o bst et ric r ec or ds  f or  \nwomen who ha v e c onsen t ed  t o  ac ces s  t o  their NHS  medical r ecor ds  and  ha ve giv en bir th at \nloc al participa t ing hospit als. The s e NHS  r ecor ds inc lude a nt ena t a l measures (height, weight, \nblood pr es sur e, haemoglo bin), ho spit al admis sion s,  diagno s es  during p r eg nancy ( ges t a tional \nhypert ens ion, pr e- ec lampsia , g e s t a tional diabet es), det ails  of labour (how labour st art ed, \nmode of d eliv e r y ) , child measur emen ts , APGAR s c or e and an y con g enit al ano malies  \ndiagnosed a t bir th. W e an ticipa t e  that  we will have NHS  c linic al dat a f or a ppr o xima tely 200 \npr egnancies , a nd tha t these da t a will be av ailable f o r r es ear ch use b y the end of 2025.  \n \n \n \n  \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\n19 \n \nD i sc u s si o n  \nStr ength s and Limit a tion s   \nBRIST-IVF i s a la r g e c linic al c ohor t of women and t h eir partner s under going ART , with \ne xt ensiv e d e mogr aphic, lif es tyle, biologic a l s amp les and tr ea t m en t-r e la t ed inf or mation  \na v a ilab le. W e h av e als o  be en  a ble t o  f ollow u p the pr egnancies and  bir ths via \nques tionnair es, c linic s  and medical r ec or d link age. Impor t antly , pr egnancy da t a collection  \nf ollowed the  same pr ot oc ols   as the ALSP AC G2 (2 3), allowing f or d ir ec t  comparisons \nbetween A R T p r egnancies  and na tur a lly c onceived  p r egnancies .  \nOur s tudy c ohort  c losely mirr o r s t he U K  popula tion unde r going IVF tr ea t m en t, bo t h in  t er ms  \nof a v er ag e ag e and f a mily t ype.  In 2 0 21, t he a ver age a g e o f I VF pa tien t s  in the UK wa s  36.0  \ny ear s , and 89% of women under going IVF had a male part n er , 4% had a  f e male partner , an d  \n6% had no part ner(25) . The BRIST-IVF  c ohort  ha s a higher pr oportion of pa r t icipant s  of whit e  \nethnicity (92 % )  compar ed t o the  UK a ver ag e f or IVF  t r eatme n t in 2 020-2 1 (77%)(26).  \nHo wev er , t his  pr oport ion aligns  wit h the et hnic  compos it ion of t he South W e st  r egion (9 3% \nof r esidents ar e o f whit e e t hnicit y)(27). \nDespit e these s tr eng t h s , limit a tion s in clude t he modes t r espon s e, with o nly  41 % of \nwomen/ cou ples  scr eened agr eeing t o p articipa t e. One imp ort ant  r eas on  f or the limit ed  \nr esear ch part ic ipa t io n wa s t he  high p r op ortion of patient s  ( 38% )  who did not  co ns en t  t o be  \nc on t act ed f or  r esear ch when c ompleting t he HFE A f orm prior t o beginning tr eatme n t a t  the  \nBCRM. This pr oport io n is  s imilar  t o findings fr om a s tudy  c onduct ed  a t a f ertility c en t r e in \nnor thern  England bet ween  2010 and 2019, wher e 47% of pa tien t s  de clined t o  pr ovid e  \nc ons ent  f or c ont act r es ear ch (28) .  \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\n20 \n \nWhils t we ha ve  near c omp let e  dat a fr om baselin e qu es tionnair es and t r e a tmen t d a t a f r o m  \nBCRM medic al r ec or ds, only 76% of  women in v it ed  c on tribu t ed t o  t he pregnanc y f ollow up \ns tudy b y answering a quest ionnair e  or a tt ending c linic. Howev e r , obst etric da t a  will be  \na v a ilable f or all wom en who consen t ed t o NHS medical r ec or d abst r action and deliv ered  \nwithin loc al partic ipa ting h os pit a ls. Add it ionally , bloo d and urine samples wer e f or  the mos t \npart  t ak en aft er women  had st art ed tr ea tment pr o t oc ols meaning th at biologic al meas ur es  \ne.g. met abolit es may be influenced by dru g s t ak en a s par t of t he I VF p r oc es s. However , \ndet ailed inf or mation on t rea tm en t  and drug pr o t oc ols  ha s  been collec t ed, allowing f or \nappr o priat e adjus tment  in analy ses .  \nPlanned  a n alyses  \nThe BRIST-IV F  s tudy will lev er age its ext ens iv e dat aset t o inv es tigat e s ev er al k ey r es ear c h \nques tions r ela t ed t o ART , met abo lic  pr ofiling , and perina t al ou t come s. Spec ifically , we aim t o \naddr ess the f ollowing:  \n1.\n D o  d i f f e r e n t  A R T  p r o t o c o l s  i n f l u e n c e  m e t a bo l i c  p r o f i l e s ?  T r e a t m e n t  c o m p a r i s o n s  t o  \ninclude: \na.  Us e of IVF  v s ICSI  \nb.  Transfer  o f frozen vs  Fresh embr yo  \n2.  Do  metabo lic pr ofiles  in fluence liv e birth  s ucce ss and perinatal ou tcome s (small for  \nges t ational age, la r ge for gestational age, pret erm bir t h)?  \n3.  Do  metabolic pr ofiles  influence pregnanc y complications (mis carriage, h y per tensiv e  \ndisorder s  of pr egnancy, ge stational diabetes)? \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\n21 \n \n4.  Dep e n ding on the results fr om 1  to 3 a bov e we will explor e whe th e r  v ar iat ion in  \nmetabo lic pr ofiles in th os e  u ndergoing ART mediate as soc iat ions between diff erent \nART appr oaches  and pr egnan cy or  p erinatal ou tcomes  \n5.  Do  metabo lic profiles differ be twe en p regnancies  con ceived by ART and t hos e \nconceiv ed nat urally?  \n6.  Ar e the re differences in plac ent al t is sue DNA met hyla t ion and gene express ion \nbetween AR T a n d natura lly conceived pr egnanc ies ?  \n7.  Ar e t here  differen c es in placental pa t hology bet ween bet w een AR T an d natur ally  \nconceiv ed pr egnan c ies?  \nT o addr ess que st ions  5  t o 7, we will use da t a f r om the ALSP AC G 2 c ohort  (23)  as a \nc omparison gr o up of n at ur ally c once i v ed pr egnancies.  Given tha t B RIST-IVF par ticip a n t s  \nwer e f o llowed  up  us ing id en tic a l clinic p r ot oc ols, labor at ory pr ocedur es, and pla cen t a l \ntiss u e analy se s , this  w ill allow f o r  direct and meaningful c ompar is ons bet ween A R T and  \nnon-AR T pr egnancies .  \nConclusions  \nThe BRIST-IVF s tudy , with its c ompr ehens iv e me t abolic, clinical, and b iologic al dat a, is  \nuniquely positioned t o addr ess  s ome o f the lim it a t ions  of birt h c ohor t  and elec t r onic health  \nr ec or d s tudies in AR T r esear ch. B y in t egr at ing det ailed  t rea tmen t inf o rma tion with  \nbiospecimen analy s i s and pr egnancy f ollow-up, t he B RIST-IVF st udy off er s  a  valuable  \nr esour ce f or  adv an c ing our  under s t anding of  the pr e d ict o r s a n d co n sequences  of AR T \nc onception, wit h impor t an t implic a tions f or optimizing f e r tility trea t m ents and impr ov ing  \nAR T pr egnanc y out comes .  \n \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\n22 \n \n \nDe c lar a t ions \nE thics appr oval and con sen t t o  participa t e  \nAll part ic ipant s  pr ovided inf ormed c o nsent t o part icipa t e  in the s tudy . E thic s  appr ov al f or the  \ns tudy wa s obt ain ed fr o m the  UK N a tion al Healt h Service Sout h W est - Fr enc h ay R e s ear c h  \nE thics Commit t e e ( IRAS pr oject ID 236773, Initial appr ov al 10/ 7/20 19) .  \nConsen t  f or pub li ca tio n \nNot applicable  \nA vailabil ity of  da t a and ma t e rials  \nWe ar e k een t o work w it h c ollabor a tor s  and welco me enquir ie s f r om resea r c h er s who ar e  \nin t e r est ed in the m easur es we ha ve c ollect ed and h av e ideas f or r es ear c h q uest io ns  be y ond  \nthose list ed abov e. In fut ure, r esear cher s will be able t o app ly t o use anon ymised s u b s et s of \nthe da t a f or appr ov ed  r es ear ch ques tions.  \nComp eting in t er est s   \nThe author s  declar e that  they ha v e  no competing inter es ts.  \nFunding  \nThis s tud y was f unded by the Eur op e an  R esear ch Council under  t h e  Eur opean Union’ s  \nHo rizon  2020 r esear ch and  innov a tion pr ogr am ( gr an t agr eemen ts No 10 102156 6) and the \nNIHR Biomedic a l R es ear c h Cen tr e a t Univ er sity Hos pit als Br ist ol N HS F ounda tion  T rus t and \nthe Unive r s ity of Bris t ol. The W ellc o me T rus t and UK Medic al R esear ch Co uncil fund the  \nALSP AC G 2 co hort and the c lin ic f ac ilities that we r e us ed in participan t f ollow-up  \n(02215/2 / 13 /2). A. T a n d D .A.L ar e suppor t ed by t he UK Medic al R esear ch C ouncil \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\n23 \n \n(MC_U U_00032 /05). The views  e xpr e s sed in this public a tion ar e  those of the auth o r(s) and  \nnot n ec es s ar ily t hos e of  an y of  the funder s , t he N HS,  o r the Departmen t of Healt h and Socia l \nCar e. None of t he funder s influenced the s tudy desi g n or analyse s.  \nAu thor s ’ con tr ibutio ns  \nDAL , V A, A T , SN, KAR designed the s t udy . A T , TK and J P manag ed da t a c ollection. SP and AG  \ndesig ned a nd manag ed the biologic a l sample pr oces s ing . A J  and PW  pr ovided s cientific input  \ndur in g  da t a co llection. A T a n a ly sed t he da t a  and A T and DAL  dr aft ed the ma n us cript . All \nautho r s  c ommen t ed on a dr aft  o f the manus cript.  \nAcknowledg em en ts  \nWe a r e v ery gr a t e ful t o the f ollowin g  people f or their  help w it h d a t a c olle c t ion: the t eam  of \nr esear ch midwiv es  and nu r s es (Alis on Kirby , Naomi Mallinson, Annie Deacon, Mic h elle  \nMagg s, Ashleigh Pr omnitz , S o phie W ic kham, Vict or ia Car ey) a t  N or th  B rist ol NHS T rus t who  \nr ecruit ed par ticipan ts f or  this  s tud y , t he s t af f a t  the Bris t ol Cen tr e f or  Reprodu c t ive Medic ine  \nwho f a cilit a t ed th is r esear ch , t he r esear ch midwiv es a t N o rth Bris t ol NHS T r ust ,  Univer s it y \nHo s pit als Bris t ol NHS F ounda t io n T r us t  and The R o y al U nit ed  Hospit als  B at h NHS  F ounda tion  \nT rus t who collect ed bir th samples and t he Children of t he 90s fieldwork ers who c ondu ct ed \nthe pregnanc y c linic s . We would a lso lik e t o thank the member s of t he  p at ien t adv isory  \ngr oup  who pr ovided valuable adv ice a n d f eedbac k on s tudy pr o c es ses and documen t a tion.  \n \n \n \n \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\n24 \n \n  \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\nFigure 1. Biological samples collected for BRIST-IVF \n \n \nIcon made by  Freepik/DinosoftLabs from www.flaticon.com\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\n \nFigure 2. Flowchart of study recruitment  \n \n26 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\nFigure 4. Overview of treatment cycles in IVF/ICSI \nOvarian s tim ula t ion ai m s  to s t i m ula te f o lli cles t o pr oduce mul t ip le ma ture oocy tes  to be \nr etrie ved v ia fol lic u l ar  aspiration. Matu re oo c y tes  ar e fer tilis ed in vitr o via IVF or I CSI and  \nsu c c es sful fert il isation r es ult s  in t he f orm ation of embry os.  Embry o s  of sufficient quality  can  \nbe tr a n s fer red into th e u terus wit hout freezing (f resh embr y o tr ansfer) or may  be frozen \nand stored for  fut u re use. Frozen embry os can then be t haw ed  and tr ansfer red into th e \n \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\n28 \n \nuter us  (fr oz en embr y o  tr ans f e r ). F or  each o v ar ia n  stimulation c y cle, t here may be b oth a \nfr es h embryo t ransfer and  multiple f rozen embr y o  transfer s .  C ouple s /individuals  ma y  \nunder go multip le ovarian  stimulation  c ycle s .  Icon made \nby  Freepik/cube29/Ba c k wood s /Sma shicons from www.flaticon. com .  \n \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\n \nFigure 4. Flowchart of the pregnancy follow up to date \n \n29 \n \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\n30  \n \nT able 1. Char act er ist ic s of th e wo me n r ecruit ed t o t he st udy ( N=501)*  \n  Mea n \n( SD ) /N (% )/ M e d i a n (IQ R)  \nAg e  Y ea r s 35.8 (4. 4)  \nE thnicity  Whit e \nOther et hnic it y  \n461 (92 % )  \n38 (8%)  \nBM I  Kg /m 2  (N=477)  25.1 (4. 4)  \nSmoking  Never  s mo k er \nFo r m e r s m oke r \n371 (74 % )  \n129 (26 % )  \nAlc ohol use be f o r e \ntr yi n g  t o conceiv e  \nNever  \nMon t hly or les s  \n2-4 times a mon th \n>once a week  \n46 (9%)  \n135 (27 % )  \n156 (3 1% )  \n161 (32 % )  \nNumber of  t imes  per  \nw eek doing \nmoder a te t o  vigor ous \nex e r c i s e \n0 \n1-2 \n3-4 \n5+ \n100 (20 % )  \n249 (5 0% )  \n122 (24 % )  \n29 (6%)  \nHas a degr ee \n \nYe s  \nNo  \n376 (7 5% )  \n125 (25 % )  \nPr evious pr egnan cies 0 \n1 \n2 \n3 or mo r e  \n251 (5 0% )  \n135 (27 % )  \n54 (11%)  \n61 (12%)  \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\n31  \n \nPr evious live births 0 \n1 or mo r e  \n374 (7 5% )  \n127 (25 % )  \nAn ti M ulle rian \nHo rmon e (A M H )  \npmol/L  ( N =479) 14.1 (7. 1 , 26 .0)  \n*1/502 w om a n  withd r ew f r o m the s tud y . Mis s ing da t a f or eth n ic it y  (N =2), BM I (N=24), \nSmoking ( N=1), Alc ohol (N= 3 ), Ex er c i s e (N =2) , AMH  (N =22 ) \n \nT able 2. Char act er ist ic s of th e partn e r s ( N =465)  \n  M ea n  ( SD ) / N(% )/ M ed i an (IQR)  \nAg e  Y ea r s 37.6 (5.8)  \nSe x  Male \nFe m a l e  \n 445 (96%)  \n20 (4%)  \nE thnicity  Whit e \nOther et hnic it y  \n433 (94%)  \n30 (6%)  \nBM I  Kg /m 2 (N=422)  26.8 (4.3)  \nSmoking  Never   \nFo r m e r  \nC u rre nt  \n293 (63%)  \n164 (35%)  \n7 (2%) \nAlc ohol use be f o r e \ntr yi n g  t o conceiv e  \nNever  \nMon t hly or les s  \n2-4 times a mon th \n>once a week  \n44 (10%)  \n91 (20%)  \n145 (32%)  \n181 (39%)  \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\n32  \n \nNumber of  t imes  per  \nw eek doing \nmoder a te t o  vigor ous \nex e r c i s e \n0 \n1-2 \n3-4 \n5+ \n68 (15%)  \n158 (34%)  \n135 (29%)  \n102 (22%)  \nHas a degr ee \n \nYe s  \nNo  \n284 (61%)  \n180 (39%)  \nMis s ing da t a  f o r ethnicity (N=2), BM I ( N =43),  Smo king ( N=1), Alc ohol (N=4), Ex er ci s e (N=2)  \n  \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\n33  \n \n \n \n \n \n \n \n \n \n \n  \nBox 1. The impact of the Covid-19 pandemic on the BRIST-IVF Study \nBRIS T-I VF wa s s u spend ed f o r  13 mon th s betw e e n Mar ch 2020 an d A pr il 2021  due  t o Cov i d 19 \nr e str ic tio ns and s t a ff redeploy me n t . A s a r e sult , the st u dy wa s  unabl e t o me et it s  the  initial  \nr ec r uit me nt  t a r ge t and wa s clo sed e arli er  than pl ann ed a s  pa rt of the  NIHR R e sea r c h and R ec ove ry \nRe s e t  P ro g ra m m e .  \nPla nne d da t a  col lection w a s aff ec t ed i n t he f ollowing wa y s :  \n• During th e clos ure p eriod i t  was no t po s sibl e to t r a ck  t h e tr e atmen t outcom e s of a ll \nrec r ui ted  par ticipa n ts in r ea l time a nd in vi t e  particip a nt s  t o preg na ncy  follow  up.  \nHowe ver, we  have  s till  b een a bl e to c olle c t  informa tion on p r eg nanc y outco m e s  fr om \nBCRM me dica l  not es  a nd fr om ob ste tr ic  note s wher e par t i cipan ts h av e co n s ent e d t o \nac ces s t o N HS  medic al r ec or d s .  \n• Redu ction in t he  numbe r of fac e - to -fac e consul tati on s at t he B CRM during  and a ft er the \npan demic  mean t tha t the c on s ent pr oce s s  moved f rom fa c e- to -f ace t o  t e le phone \napp ointme nt s  a nd that s t ud y mea s ure s v isit s  we re no longe r c arr i e d out on the d a te o f \nrec r uit m e nt. Thi s me ant th at :  \n - Bi ologic al sample s  w er e mo st l y c ollec te d af ter tr e a t m en t pro t oc ol s had b e en in itia te d.  \n - F ewer stu dy me asure s vis it s were com pleted , and mo re study mea sure s  w ere se lf - \nrepor ted o r info rmati on was col l ected f r om fe rtili t y  cen tre no te s .  \n• Pregn a ncy  clini cs move d from face - t o- fa c e to vir tual  visi t s  for seve ra l month s a ft er t h e \nstu dy reope ne d mean i ng that a mor e  lim ited se t of me asure s we re  coll ect ed f or s ome \npartic ipan t s.  \n• Coll ec tion o f  blood sample s for the purp os e of ma king  immortal c ell li ne s  wa s sto ppe d a s it \nw as  uncle a r  wheth er th e se c ould be p r oc es sed f o ll owin g Covi d.  \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint \n\n34  \n \nR ef er ence s \n1. Inf er til ity pr ev alenc e es timat es, 1990- 2021. Genev a: W orld H ealth Or g aniza tion , \n2023.  \n2. Cousineau TM , D omar AD . P sy chologi cal impact of inf e r til ity . Best  Pr a ct R es  C l in \nOb st et G ynaec ol. 200 7;21(2):2 93- 308 . \n3. F aus er  BC. T o war ds  t he glob a l c ov er a g e of a unif ied r egis try of IV F  ou t co m es . R epr od \nBiomed Online. 2019;38(2) :133-7.  \n4. V a y ena E, P et er son HB , Ad a m s on D , Ny gr en K G. Assist ed r epr o duc t ive t ec hn ologi es in \ndev eloping cou n tr ies: ar e w e car ing y et ?  F ert ili ty and st er ili ty . 20 0 9;92(2):4 13- 6. \n5. Nel son SM, La wlor D A . Pr edicting li v e  b i r th ou t com es  aft er in vi t r o  f e r ti lis a ti o n. 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CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 25, 2025. ; https://doi.org/10.1101/2025.04.24.25326332doi: medRxiv preprint","source_license":"CC-BY-4.0","license_restricted":false}