REVIEW ARTICLE
The role of prenatal and perinatal factors in eating disorders:
a systematic review
Enrica Marzola1&Fabio Cavallo1&Matteo Panero1&Alain Porliod1&Laura Amodeo1&Giovanni Abbate-Daga1
Received: 9 March 2020 / Accepted: 20 July 2020 # The Author(s) 2020
Abstract
Numerous studies showed that factors influencing fetal development and neonatal period could lead to lasting alterations in the brain of the offspring, in turn increasing the risk for eating disorders (EDs). This work aims to systematically and critically review the literature on the association of prenatal and perinatal factors with the onset of EDs in the offspring, updating previous findings and focusing on anorexia nervosa (AN) and bulimia nervosa (BN). A systematic literature search was performed on Pubmed, PsycINFO, and Scopus. The drafting of this systematic review was conducted following the PRISMA statement criteria and the methodological quality of each study was assessed by the MMAT 2018. A total of 37 studies were included in this review. The factors that showed a more robust association with AN were higher maternal age, preeclampsia and eclampsia, multiparity, hypoxic complications, prematurity, or being born preterm (< 32 weeks) and small for gestational age or lower birth size. BN was only associated with maternal stress during pregnancy. Many methodological flaws emerged in the considered studies, so further research is needed to clarify these inconsistencies. Altogether, data are suggestive of an association between prenatal and perinatal factors and the onset of EDs in the offspring. Nevertheless, given the methodological quality of the available literature, firm conclusions cannot be drawn and whether this vulnerability is specific to EDs or mental disorders remains to be defined. Also, a strong need for longitudinal and well-designed studies on this topic emerged.
Keywords Eating disorders . Anorexia nervosa . Bulimia nervosa . Pregnancy complications . Obstetric complications
Introduction
Eating disorders (EDs) are complex mental illnesses charac-terized by unknown etiology, with many putative risk factors (Fairburn and Harrison2003; Dalle Grave2011; Jacobi et al.
2011) facilitating the ED onset. Genetic risk factors are of great importance, with genes impacting on the development of both anorexia nervosa (AN) and bulimia nervosa (BN) as well as on their predisposing traits (Trace et al.2013; Baker et al.2017). An altered neurodevelopment has been implicat-ed in the pathogenesis of several mental disorders (Katzman et al.1997; Chowdhury et al.2003; King et al.2018) such as schizophrenia (Geddes and Lawrie1995; Verdoux et al.1997; Geddes et al.1999; Cannon et al.2000), attention deficit hy-peractivity disorder (Lindström et al. 2006), and autism (Gardener et al.2009). With more detail, hypoxic complica-tions and prematurity have been associated with schizophrenia risk (Geddes and Lawrie1995; Verdoux et al.1997; Geddes et al.1999; Cannon et al.2000), leading to the formulation of a “neurodevelopmental hypothesis for schizophrenia” (Rapoport et al.2012).
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00737-020-01057-5) contains supplementary material, which is available to authorized users.
* Giovanni Abbate-Daga giovanni.abbatedaga@unito.it Enrica Marzola enrica.marzola@unito.it Fabio Cavallo fabio.cavallo@unito.it Matteo Panero matteo.panero@unito.it Alain Porliod alain.porliod@unito.it Laura Amodeo laura.amodeo@unito.it
1 Department of Neuroscience“Rita Levi Montalcini”, University of Turin, via Cherasco 15, 10126 Turin, Italy
Several studies (Gillberg et al.1994; Connan et al.2003) linked prenatal and perinatal complications (Raevuori et al.
2014) to EDs, with the hypothesis that subtle neurological damages (Gillberg et al.1994), neuropsychological disabil-ities (Galderisi et al.2003), and nonreversible morphological brain changes could ease the disorder onset. Krug and co-workers (Krug et al.2013) systematically reviewed the litera-ture on obstetric complications (OCs) and EDs, selecting 14 articles, and performing a meta-analysis where possible. Conflicting results emerged, so their meta-analysis found a nonsignificant association between instrumental delivery and prematurity and ED risk. More recently, a descriptive review of 22 articles focusing on additional risk factors (e.g., the role of sex hormones, maternal status, and maternal EDs) found once more mixed results (Raevuori et al.2014). Another re-view of 13 studies (Jones et al.2017) focused instead on“fetal programming” as a model on how stimuli/insults occurring during critical or sensitive periods of fetal development could have physiological effects that unfold across the life span. The latter review introduced new risk factors, such as maternal stress during pregnancy, but finding again controversial re-sults. Therefore, the aim of this systematic review is twofold: (a) to critically review the updated literature on the association of prenatal and perinatal factors with the onset of EDs in the offspring and (b) to expand knowledge on the critical points that need to be addressed by future lines of research.
Methods
Search strategy and selection criteria
The drafting of this systematic review was conducted follow-ing the PRISMA statement criteria (Moher et al.2009), and the studies included in this systematic review have been eval-uated by the MMAT (Mixed Methods Appraisal Tool, 2018 version; Hong et al.2018).
A systematic literature search was done between March 1 and May 1, 2019, including online database searches, namely, Pubmed, PsycINFO, and Scopus, and journal hand searching to ensure a wide inclusion of eligible studies.
The search was designed to include those studies published since 1998; this is a reasoned choice as the purpose of this systematic review was to analyze the most recent studies on the topic. All full-text studies published were included if they met the following inclusion criteria:
& Study type criteria: cohort study and case-control study & Eating disorder assessment criteria (EDs): DSM (III, III-R,
IV, IV-TR, 5) diagnosis, ICD (8,9,10) diagnosis, clinical diagnosis or self-report diagnosis, or ED symptomatology obtained with questionnaire scores
& Risk assessment criteria: obstetric birth records, parents recall, and/or a combination of both
The following list of terms were included and combined together in different search lines:“eating disorders,” “anorexia nervosa,” “bulimia nervosa,” “pregnancy complications,” “obstetric complications,” “prenatal risk factors,” “perinatal risk factors,” “gestational diabetes,” “hypertensive disease in pregnancy,” “maternal anemia,” “preeclampsia,” “eclamp-sia,” “maternal viral infection,” “season of birth,” “vit. D levels during pregnancy,” “prenatal sex hormones,” “dysmaturity,” “preterm birth,” “mother weight,” “mother smoke habit,” “maternal stress,” “maternal anxiety,” “placenta previa,” “pregnancy bleeding,” “breech delivery,” “induced labor,” “inertia uteri,” “premature rupture of the membrane,” “forceps,” “cesarean section,” “vaginal instrumental deliv-ery,” “vacuum extraction,” “cephalohematoma,” “umbilical cord wrapped around the neck,” “placental infarction,” “cya-nosis,” “jaundice,” “need for resuscitation,” “need for oxy-gen,” “need for intubation,” “birth weight,” “prematurity,” “tremors,” “hypothermia,” “hypotonia,” and “neuromuscular disturbances.”
Two investigators (E.M., F.C.) screened the title and ab-stracts of 851 studies identified through the search using the inclusion criteria. Full-text articles were retrieved for all stud-ies that met the inclusion criteria or required more information than was provided in the abstract. The reasons for excluding the studies were documented and shown in Fig.1.
Data analysis
All database search results were imported into Zotero. Duplicate entries were removed before the screening. Data from the studies were extracted and summarized (see Table1and Supplementary Materials). Data extracted includ-ed authors, year, study type, sample size, psychiatric assess-ment, maternal factors, pregnancy complications, obstetric complications, neonatal factors, and main findings.
As reported in Table1, the methodological quality of each study was assessed by two investigators (F.C. and E.M.) using MMAT (Mixed Methods Appraisal Tool, 2018 version; Hong et al. 2018) that allows a quality assessment of qualitative, quantitative, and mixed methods studies (Pluye et al. 2009; Pace et al.2012) with a double evaluation and a high intraclass correlation. The overall agreement was 90% on the MMAT items; when discrepancies emerged, they were resolved through discussion. The quality score ranged from 0 (no criteria met) to 5 (all criteria met).
According to earlier literature (Whittemore and Knafl
2005), due to the extreme heterogeneity of the study results, it has not been possible to conduct a meta-analysis so it was preferred to proceed with a thematic meta-synthetic approach to critically synthesize literature on the role of prenatal and
perinatal factors on the onset of EDs. The findings of all the included studies were independently read and re-read, coded, and organized into categories, which were then com-pared across studies to identify relationships and themes (Whittemore and Knafl2005).
Results
Of the 815 studies screened, 96 full-text articles were assessed for eligibility, and 37 were finally included in the systematic review (please see Table1and Supplementary Materials for all details).
The outcomes assessed in the studies were highly variable and were divided as follows: (1) maternal factors, (2) preg-nancy complications, (3) obstetric complications, and (4) neo-natal factors. Study distribution has been outlined in Fig.2.
As shown in Fig.3, the methodological quality of studies ranged from low (2 points) to high (5 points). Overall, no studies were rated as showing very low methodological qual-ity (1 point) and only the category of pregnancy complications showed the majority of studies (56%) as scoring low and fair. In fact, all other categories (pregnancy complications,
obstetric complications, and neonatal factors) reported about 60% of studies with high (4 points) or very high (5 points) methodological quality scores (see Fig.3).
The most frequent limitations were participants’ poor rep-resentativeness of the target population (Shoebridge and Gowers 2000; Foley et al. 2001; Feingold et al. 2002; Klump et al. 2006; Culbert et al.2008,2013; Smith et al.
2010; Coombs et al.2011; Quinton et al.2011; Nosarti et al.
2012; St-Hilaire et al.2015), small sample size (Shoebridge and Gowers2000; Feingold et al.2002; Klump et al.2006; Culbert et al. 2008,2013; Smith et al.2010; Quinton et al.
2011), and unappropriate measurements (e.g., self-report di-agnosis, ED symptomatology investigated with question-naires on healthy participants, lack of a clear DSM or ICD diagnosis; Feingold et al. 2002; Montgomery et al.2005; Klump et al. 2006; Culbert et al.2008, 2013,2015; Baker et al. 2009; Nicholls and Viner 2009; Smith et al. 2010; Wehkalampi et al.2010; Coombs et al.2011; Quinton et al.
2011; Lydecker et al.2012; Nosarti et al.2012; Allen et al.
2013; Romero-Martínez and Moya-Albiol2014; St-Hilaire et al.2015; Lofrano-Prado et al.2015; Matinolli et al.2016; Sacks et al.2016), and uncontrolled confounders (Shoebridge and Gowers 2000; Foley et al. 2001; Feingold et al. 2002; through database
searching
indentified through other sources
815 records screened
96 full-text articles accessed for eligibility
37 studies included in systematic review
59 full-text articles excluded 56 not adress history of prenatal, perinatal or obstetrics complications in patients suffering from EDs
3 review articles 719 records excluded by title
and abstract 48 duplicates removed
Ta bl e 1 Ar tic le summa ry o f st udy res u lts inc lude d in this re v ie w Asse ssed conditi ons Authors S tudy ty pe S ample Maternal factors P regnancy complications O b ste tri c complic at ions Neona tal fac tor s Mai n fi ndi ngs Qua lity ra ting Cn att ingi us et al . 199 9 Case -c ontrol st udy w ith ra n dom ly se lecte d co ntr o l (S wed is h In pa tie n t Registe r— 1 973 –19 84) AN (n =7 8 1 ), H C s (n = 3 9 05) M at er n al ag e H ype rt en sive di sea se , d iab etes, b le ed ing du rin g pr eg na ncy , multiparity Inertia uteri, forceps , or va cu um d eli ver y , p re te rm ru ptur e o f the m em b ra ne s, ce sa re an se cti on, ce ph alo h em at oma , ot he r trauma Ge st ati ona l age, b ir th weight and b irt h weight for g es tat ional ag e, Apg ar sco re , jau ndi ce AN diag n o sis w as assoc iated with maternal age, very p reter m b irth (< o r = 3 2 w ee ks ), sm al l fo r ges tational age in very p reter m b irth , cephalohematoma 5 Mo rg an et al. 200 0 Case -c ontrol st u d y BN (n = 9 35), pat ients with AN hist ory an d BN dia gno sis (n =2 2 7 ) ge ner al pop ula tio n d at a –– – Month o f b irth BN di agnosi s is not ass o ci at ed wi th a spe ci fic month o f b irth AN his tor y an d B N dia g n o sis ar e asso cia te d with a p ea k se ason o f b irth in M ar ch 4 Sh oe br idg e & Gowers et al. 200 0 Case -c ontrol st u d y AN (n =4 0 ) an d H C s (n =4 0 ) – Ante pa rt um h em o rr ha ge To x em ia, pr ev io us o b stetric co mpl ica tio ns, for ce ps d eliv ery , ce sa re an sec tio n M ea n b irt h w ei ght , ges ta tion len gth (full-term, 3 6 w eeks, 32 weeks ) APGAR sc or e, th e b ab y loo k ed af ter in a sp ec ial ca re bab y un it No as soc ia tion w as fo u n d 2 Fo le y et al. 200 1 Twin co hor t st u d y (V ir g in ia Twin R egi stry, n = 2 352 ) AN (n = 7 ), br oa dly de fin ed A N (bd AN) (n =7 1 ), B N (n = 42) , b roa dly d ef in ed BN (bd B N) (n = 1 00) , twi n co ntr o l (n = 1 58 6) – High blo o d p re ssur e, va gin al b le edi ng, seizures or toxemia, Ge rm an m easles, an y o th er co mpl ica tio n, an y pr en ata l co mpl ica tio n Pr em atu re co n tr ac tio ns, lab or lasting m ore than 2 4 h , b re ec h d eliv er y, ce sar ean delivery, forceps d elivery, co rd wr appe d aro und th e neck, b lue at b irt h ,r equired an in cu b ator , an y p er in atal co mpl ica tio n Birth w eigh t, ge sta tio n al ag e, ja u n d ice , failur e to breathe at fi rst , co nv uls ion s, blo o d transfus ion AN: low g est ational age, # p ren atal m ate rn al complications bd AN: pr en ata l m ate rn al complications BN: # p ren atal m ater n al complications bd BN: # pr en ata l m ate rn al complications 3 Feingold et al. 200 2 His torical pros p ec tiv e co ho rt (T hom as Je ff er so n Univers ity Hospi tal 1 979 –19 81, n =8 6 ) In fa nts b o rn p re ter m (n =8 4 ) M o th er old er tha n 40 ye ar s, alc o h o l abus e P ree cla m p sia , ec la mps ia , ch or ioa m ni onit is, u rin ar y tr act inf ecti on, ce rvi cit is, as thm a, hy per te n si on, hy per emes is g ra v id ar um , ce rv ical ca n cer , v ag in al bleeding, multiparity Pr em atu re ru p tu re of th e me mbr an es , ce sa re an de live ry, br ee ch or trans v erse delivery, ab ru p tio p lac en tae, p lac en ta p rev ia, inc o m p et en t ce rv ix, the tot al n umber o f co mpl ica tio ns Small for gestational age No as sociation w ith ED symptomatology for any of the studied variables 4 Li ndb er g and Hjern 20 03 Population cohort st u d y (Sw ed is h AN (n = 1 1 22) , H Cs (n = 9 8 8 ,7 49) Ma te rn al ag e P ree cla mp si a P re ma tur e ru p tur e o f th e me mbr an es , pla ce n ta l Ge st ati ona l age, siz e for ges ta tion al age , AN diag n o sis w as assoc iated with maternal age 4
Tab le 1 (continued) Assess ed conditions Authors S tudy type Sample Maternal factors P regnancy complic at ions Obs tetric complications Neona tal factors M ain findings Quality rati Re gis te r Da ta 197 3– 1 982 n = 989 ,87 1 ) ab rupti on, br ee ch d eli ve ry, ce p h al ohe ma tom a, ne on ata l O2 n ec essit y pr em atu rit y, Ap ga r scor e, d istr ess (> 25 years), g estational ag e at b ir th (2 3– 32 we ek s) , pr ee cl am psia , p re mat u re ru ptu re o f the m em b ra ne s, low A pgar, O2 neces sity, an d d is tr ess , ce p h al oh em ato m a, br ee ch delivery Mo ntgo me ry et al . 20 05 Co hor t stu dy (Bri tish coh or t stud y 1 9 7 0 n = 404 6) BN (n = 1 0 0 ), HCs (39 46) Ma te rna l ag e at de liv er y, smoke h abit, oc cu pa tion , so cial cla ss, p syc hiatr ic morbi d ity, BM I –– – Se lf -r ep ort ed d ia gno sis o f B N is ass o ci ated wi th maternal smo k e dur ing p re gn an cy 3 Fa va ro et al . 20 06 Bir th coh ort study (Pad ua bir th co hor t 197 1– 1 979 ) AN (n = 1 14) , B N (n =7 3 ), HCs (n = 5 54) M ater n al ag e, so cial cla ss Ble ed ing, pr ee clam p sia , m ate rn al d ia b et es , th re at en ed misca rr iag es, an d an em ia Inertia uteri, breech delivery, pr em at ure ru p tu re of the me mb ra ne s, br ee ch delivery, placental infarction o r abruption, pl ac en ta pr evi a, m ec o n ium st ain ing of th e amn ioti c fl uid , fo rc ep s o r v ac u u m extraction, the u mbil ical co rd wra p p ed ar oun d the infant ’sn ec k , ce ph al o p elv ic ne ed fo r resuscitation O2 ,a n d intubati on, disproportion, # o f o bstetric complicati ons , ce p h al ohe ma tom a Sm al l fo r ge sta tio n age , bir th w ei ght , cya no sis, re spir ato ry and ca rd ia c pr obl em s, ja und ic e, ne ur omu scu la r dis tur ba nc es su ch as hy por ea ct ivit y, hy poto n ia , and tr em ors , hy poth er m ia AN dia g n o sis w as asso ci ate d with d iab ete s, ane mia , pr ee cl am psia , p la ce n ta l in fa rctio n, Po n d er al In de x < 25, ne ona ta l ca rd iac pr obl ems , ne on ata l hy por ea ct ivit y, # o f co mpl ica tio ns, the umb ilic al co rd wr appe d ar ou nd th e n ec k B N was assoc iated with ne ona ta l h y por ea ctivi ty, early feeding diffi culties, pla ce nt al in fa rc ti on, lo w bir th w ei gh t for ge sta tion al ag e, # o f co m pli ca tio ns 5 Klump et al. 2 006 Twin coho rt stud y (M ich iga n St ate T win St udy ) FS S (n =1 1 3 ) – Le ve ls of pr en ata l testosterone (ind ire ct ly st udi ed by 2D:4D ratio) –– ED sy mp to ma to lo gy was as so ciate d with lo wer le ve ls of pr en ata l te stos te ron e (hi ghe r 2 D:4D ratio) 2 Culbert et al. 20 08 Twin coho rt stud y (M ich iga n St ate T win St udy ) FS S (n =3 0 4 ), F O S (n =5 9 ), M O S (n =5 4 ), MS S (n =1 6 5 ), H C s (n =6 9 ) – Le ve ls of pr en ata l testosterone (ind ire ct ly st udi ed by OS and S S twin st udy ) –– High est lev el s o f d iso rd er ed ea tin g w er e obs er ve d fo r fSS twins , followed b y fOS twins, m OS twins, and mSS twins 3
Tab le 1 (continued) Assess ed conditions Authors S tudy type Sample Maternal factors P regnancy complic at ions Obs tetric complications Neona tal factors M ain findings Quality rati ng Fa va ro et al . 20 08 Bir th coh ort study (Pad ua bir th co hor t 197 1– 1 979 ) AN (n =6 6 ), B N (n = 44) , HCs (n = 2 57) M ater n al ag e V ag ina l ble ed in g , pr ee clam p sia , ma ter n al di ab ete s, thr ea ten ed misca rr iag es, an d an em ia Inertia uteri, breech delivery, pr em at ure ru p tu re of the me mb ra ne s, pl ac en ta l infarction o r abruption, pl ac en ta pr evi a, m ec o n ium st ain ing of th e amn ioti c fl uid , fo rc ep s o r v ac u u m extraction, the u mbil ical co rd wra p p ed ar oun d the infant ’sn ec k , ce p h al ohe ma tom a, n ee d for res uscitation O2 an d intubati on Sm al l for g es tat iona l ag e, bir th w ei ght , cya no sis, re spir ato ry and ca rd ia c pr obl em s, ja und ic e, ne ur omu scu la r dis tur ba nc es su ch as hy por ea ct ivit y, hy poto n ia , and tr em ors , hy poth er m ia Pr et er m b ir th an d n eona ta l dy sma tur ity we re as so ciate d with hig h h ar m av o ida nc e in the of fs p rin g af fe ct ed by EDs 4 Rae vuo ri et al. 20 08 Twin coho rt stud y (F in nTwin 1 6, 197 5– 1 979 sample n= 242 6) 2426 female twins w ith known zigosity (OS dizygotic n =7 9 3 , S S dizygotic n =7 6 5 , mo noz ygo tic n = 868 ), 1, 962 mal e twi n s (OS dizygotic n =7 1 7 , S S dizygotic n =7 0 5 , mo noz ygo tic n = 540 ) – Le ve ls of pr en ata l testosterone (ind ire ct ly st udi ed by OS and S S twin st udy ) –– Opposite-sex twin pai rs w ere no t sig nif ica ntl y di ff er en t fr om m ono zy got ic o r same-sex dizygot ic tw ins (f em al e) in th e asso cia tio n with AN or BN 4 Ba ker et al. 200 9 Swe d is h twin study o f child an d ad o le sc en t de vel opm en t (TCHAD) 198 5– 1 986 n = 4 3 9 id en ti ca l fe ma le s, n n = 2 1 3 fraternal females , n = 461 identic al m ales, n = 344 fraternal males , n = 371 o pposite-gender tw in p airs – Le ve ls of pr en ata l testosterone (ind ire ct ly st udi ed by twin study) –– ED sy mp to ma to lo gy was n ot as sociated with tw in types 3 Nic holl s an d Viner 2 009 Prospective b ir th cohort (Britis h co hor t stu dy, n = 16, 567 ) AN (n = 1 01) , H Cs (n = 1 1,2 61) Sm oke ha bit , et hni cit y Gestational d iabetes , ma ter n al an em ia Per ina ta l hyp oxi a B irth wei ght, g es ta tion al ag e, pre m at ur ity (< 3 7 wee k s) No sig n ifica nt d iff er en ces be twe en A N and HCs 3 Smith et al. 201 0 Cross -sectional obs er va tion al stud y Ma le col leg e stude nt s (n = 2 04) – Le ve ls of pr en ata l testosterone (ind ire ct ly st udi ed by 2D:4D ratio) –– High er tes tos ter o n e expo sur e (l ower 2D:4D ratio) w as as so ciate d with le ss ED sym p to ms, g re at er dr ive fo r m u sc u la rit y , dim inis h ed dr ive fo r leannes s 2 We hk al amp i et al . 20 10 Ca se -c ont ro l study (Hels inki St udy o f Ve ry Low B irt h W eight Adults Very low b irth weight adult s (n = 2 55) , te rm (n = 1 89) M ater n al ag e, smoke h abit, BM I, ed uc ati o n –– Ges tat ional age, v ery pr et er m b ir th (< 3 2 wee k s) , v er y low b irt h weight — VLBW (< 150 0 g ) In both se x es , E DI-2 sc or es were lo wer in V L B W in div idu als tha n in H Cs 3
Tab le 1 (continued) Assess ed conditions Authors S tudy type Sample Maternal factors P regnancy complic at ions Obs tetric complications Neona tal factors M ain findings Quality rati 197 8– 1 985 (n =2 5 5 ) Co o m bs et al. 20 11 Obse rv ati ona l stud y o n a M idla n d s High Sc ho ol (UK) stud en ts n = 1 32 pu p ils (a ge 1 1– 14) – Le ve ls of pr en ata l testosterone (ind ire ct ly st udi ed by 2D:4D ratio) –– No st ron g associatio n w as fo und 2 Fa va ro et al . 20 11 Bir th coh ort study (Pad ua Bi rth Co hor t 197 0– 1 984 , n = 27, 682 ) AN (n = 4 02) , H Cs (n = 2 6,9 50) Ma te rna l ed uc ati on, ma te rna l, and so cial cla ss Ma te rn al ex p o su re d u ri ng p re gna nc y to ch ic ke npo x, measles, rubella, o r inf lue nz a – M o n th o f b ir th AN d iag no sis w as assoc iated with the exposure to ru be lla and ch ick en pox at the 6 th of pre g n an cy. B ei n gb o rni nJ u n e w as as so ciate d with AN 4 Quinton et al . 20 11 Ca se -c ont ro l stud y AN (n =2 5 ), B N (n = 26) , HCs (n =9 9 ) – Le ve ls of pr en ata l testosterone (ind ire ct ly st udi ed by 2D:4D ratio) –– AN was associ ated wit h low 2D:4D ratio (hi gher pr en ata l te sto ste ro ne ) BN: h igh 2 D:4D ratio was as so ciate d with lo wer pr en ata l te sto ste ro ne 2 Nosarti et al. 20 12 Historical pop ula tio n-ba sed co hor t stud y (Swedish Bi rth R egis ter 197 3– 1 985 and H ospital Discharge Re gis te r n = 1 ,3 01,5 22) ED (n = 9 97 ), o the r ps ych ia tri c d is or de r and HCs M ater n al ag e, ma te rna l ed uc ati on, ma te rna l p syc hiatr ic fa mil y hi stor y Parity – Ges tat ional age, b ir th wei ght for g estational ag e, ne wbor n se x , Apgar scor e at 5 min ED: g estational w eek (<3 2 wee k s) 4 Ly d eck er et al. 20 13 Thre e twin coho rt stud y (MATR (US), N IPHTP (No rwa y), STAGE (Swe de n) ) US: O S (n = 481 ), SS (n = 1 022 ) Norway: O S (n = 345 ), SS (n = 1 430 ) S w ed en : O S (n = 2 433 ), SS (n = 700 0) – Le ve ls of pr en ata l testosterone (ind ire ct ly st udi ed by OS and S S twin st udy ) –– No assoc iation b etwee n co -t win sex an d E Ds 4 Allen et al. 2 013 Po pula tio n coho rt (Wes ter n Australian Preg na nc y Co hor t (Ra ine ) n = 290 0) ED (n =9 8 ), H C s (n = 4 28) M ater n al ag e, BMI, dr inki ng al co hol, smo k in g ci garettes, ed uc ati on, fa mil y in com e Se ru m 2 5 (OH) D lev el at 18 we ek s, k idn ey dis ea se o r d y sf unc tio n, u rin ar y trac t inf ec tio n , th yr oid d ysf u n cti on – Ges tat ion al age at b ir th, se as on o f bi rth , we ig h t, p re term b irth (< 3 7 wee k s) , ne wbor n sex EDs w er e asso ciated with lo w quartile serum 25(OH)D le ve l an d se as on o f bi rth (s pri ng) , k idne y d ise ase or dysfunction, sex (female) B N was assoc iated with lo w quartile serum 25(OH)D le ve l an d se as on o f bi rth (s pri ng) 3
Tab le 1 (continued) Assess ed conditions Authors S tudy type Sample Maternal factors P regnancy complic at ions Obs tetric complications Neona tal factors M ain findings Quality rati ng Culbert et al. 20 13 Twin coho rt stud y (M ich iga n St ate T win St udy ) FS S , fO S, m O S, mS S (n = 3 94) , H Cs (n =6 3 ) – Le ve ls of pr en ata l testosterone (ind ire ct ly st udi ed by OS and S S twin st udy ) –– No d iff er en ce s w er e o bse rv ed in th e lev els o f d iso rde re d eating attitudes in op posi te-se x and sa me -s ex twins in p re-e ar ly p ube rt y. Dur ing la te r p ha se s o f pu ber ty, fe ma les fr o m op posi te-se x twi n p ai rs ex hib ite d lowe r diso rd er ed eating attitudes than fe ma le s fr o m sam e-se x twin pai rs 3 Tab o re lli et al . 20 13 Ca se -c ont ro l stud y (Sis ter Pa ir Stu dy) AN (n =9 4 ), B N (n = 63) , HCs (n = 1 57) Anxi ety dur ing pr eg na ncy (q ue stio nna ir e) – Anxi ety dur ing p re gn an cy was as sociat ed w ith AN, bu t not BN 4 Ve llisca et al . 20 13 Ca se -c ont ro l stud y AN (n = 2 1 0 ), g en er al po pula tio n d at a –– – Mo nth o f b ir th AN dia g n o sis w as no t as sociated with th e m onth of bir th 4 Wi nj e et al . 20 13 Ca se -c ont ro l stud y AN (n = 4 045 ), HCs w it h the same y ear o f b irth, sex, and region o f b irth –– – M o n th o f b ir th No sig n ifica nt d iff er en ces be twe en A N and HCs 4 Good ma n et al. 20 14 Po pula tio n coho rt stud y (Swedish Re gis te r Da ta, 197 5– 1 998 , n = 2 ,1 35,2 79) AN (n = 7 351 ), BN (n = 2 804 ), o the r ea ting dis o rd er s (n = 10, 408 ), HCs (n = 2 015 ,86 2 ) M ater n al ag e, ma te rna l ed uc ati on, nu mbe r o f fu ll siblings, numbe r o f half-si b lings, ea tin g d is or de r in mother, multipl e smoke ha bit s Multiparity Premature rupt ure o f the me mb ra ne s, ce sa re an section, ins trumental de liv er y, cephal ohematoma, o ther bi rth tra um a Ges tat ional age, b ir th wei ght for g estational ag e, bir th le n g th for ge sta tio na l ag e, APGAR score AN was associ ated wit h m ater n al ag e, m u ltip arity , lower g es tat ional age (d ose -r es pon se ). We ak ev id en ce of ce sa re an an d ins tru me nta l de liv er y and bir th tra uma o th er tha n ce ph alo h em at oma AN wa s n eg ati v el y as soc ia ted with h igh er maternal weight and smo k in g B N was asso ciated with hig h er bi rth w eig h t for ge sta tio nal ag e (d ose -r es pon se ) 5 Rome ro -Ma rtíne z an d Moya-Albiol 20 14 Obse rv ati ona l stud y AN (n =3 4 ), H C s (n = 4 0) M ater n al ag e, ma te rna l BMI , ri ght 2 D :4D ratio, educ ati on, m ar ita l st atu s of children Le ve ls of pr en ata l testosterone (ind ire ct ly st udi ed by 2D:4D ratio) –– Low 2 D: 4D ra tio (hi ghe r pr en ata l te sto ste ro ne ) in AN. Sal ivary testos terone was negatively relat ed to the 2D:4D ratio 3
Tab le 1 (continued) Assess ed conditions Authors S tudy type Sample Maternal factors P regnancy complic at ions Obs tetric complications Neona tal factors M ain findings Quality rati Culbert et al. 20 15 M ich iga n State University Twin Registry St udy 1 (2D:4D rat ios): mo noz ygo tic (n = 2 29) an d d y zi goti c (n = 180 ) St udy 2 (OS-F stu dy) :1 538 ma le s an d fe ma le s and 1 3 1 n on -twin fem ale s as an ad diti ona l co mpa rison gr oup – Le ve ls of pr en ata l testosterone (ind ire ct ly st udi ed by 2D:4D ratio and by OS-F twin st udy) –– In both stu die s, h ighe r pr en ata l te sto ste ro ne ex pos ur e (lowe r 2 D:4D, females from o pposite-sex twin pai rs v s contr o ls ) pr ed ict ed lowe r di sor d er ed eating sympt oms in early ad ole sc en ce an d yo ung ad ult hoo d 3 Lof ra no-Pr ad o et al . 20 15 Cross -sectional obs er va tion al stud y College students (n = 408 ) M ot he r’ s ag e > 25 y ea rs Number of obs tetric co m p lica tio n s, cesar ea n delivery Low b ir th weight (< 2 500 g ), n o br ea stf ee d ing, not fi rs t in th e b irth order Mot h er ’sa g e lo w er th an 2 5 ye ar s o ld is as so ciate d with AN symptoms BN sy mp tom s ar e asso ci ate d with # o f obs tet ric co mpl ica tio ns 4 M icali et al. 20 15 Co hor t stu dy (v er y p re te rm co hor t n = 476 ) VPT, < 3 3 w eeks (n = 1 43) –– Ce sa re an sectio n, v ag ina l delivery Birthwei ght, g estational ag e, ve ntr icu la r dil atation, neonatal co mpl ica tio ns ED sy mp to ma to lo gy was n ot as so ciate d with an y o f th e facto rs. Ce sa re an de live ry was as sociat ed w ith co m p en sa tor y b eha vio rs . 2 St -Hil air e et al. 20 15 Co hor t stu dy (Pro jec t Ic e St orm co hor t, n = 54) Te en ag er s b o rn fro m coho rt m o the rs (n =5 4 ) M ater n al ag e, ma te rna l ed uc ati on, so cial cla ss, ma te rna l st re ss ex pos ur e, trimester o f str es s expo sur e (Sto rm 2 4 , IE S-R scale s) –– Birth w ei ght, len gth o f gestation High er EAT-26 sc ore s ar e as so ciate d with ma te rn al ex pos ur e to str ess in th e thi rd trimest er 3 Te nc on i et al. 20 15 Bir th coh ort study (Pad ua ne w Bi rth C o hor t 196 9– 1 997 an d p re v iou s 197 1– 1 979 ) New cohort: AN (n =1 5 0 ), BN (n =3 5 ), H C s (n =7 3 ) Whole coho rt: A N (n = 2 64) , B N (n = 1 08) , H Cs (n = 6 24) M ater n al ag e, so cial cla ss Ble ed ing, pr ee clam p sia , ma ter n al di ab ete s, thr ea ten ed misca rr iag es, an d an em ia Inertia uteri, breech delivery, pr em at ure ru p tu re of the me mb ra ne s, br ee ch delivery, placental infarction o r abruption, pl ac en ta pr evi a, m ec o n ium st ain ing of th e amn ioti c fl uid , fo rc ep s o r v ac u u m ex tr ac tio n, u m bil ica l cor d wr ap ped ar oun d th e infant ’s n ec k, an d ce p h al ope lvi c di spr opo rti on, # o f ob ste tr ic comp lic at ions , Sm al l fo r ge sta tio n age , bir th w ei ght , cya no sis, re spir ato ry and ca rd ia c pr obl em s, ja und ic e, ne ur omu scu la r dis tur ba nc es su ch as hy por ea ct ivit y, hy poto n ia , and tr em ors , hy poth er m ia AN maintains its associ ati ons as sh own in F av ar o ( 2 006 ), an d h ighe r m ate rn al age an d w eig h t g ain d ur ing pr eg na ncy . Ma te rn al d iab etes an d an em ia lo st their as sociat ion B N is as so ciate d with ne ona ta l h y por ea ctivi ty, early feeding diffi culties, sho rt and small for ge sta tio nal ag e 5
Tab le 1 (continued) Assess ed conditions Authors S tudy type Sample Maternal factors P regnancy complic at ions Obs tetric complications Neona tal factors M ain findings Quality rati ng need for res uscitation, O2 an d intub at ion, ce p h al ohe ma tom a Matinolli et al. 20 16 Po pula tio n coho rt study (ESTER 198 5– 1 989 e AYLS 198 5– 1 986 ) Ear ly p re te rm (n = 185 ), late preterm (n =3 4 8 ), te rm -bo rn con tro l (n = 6 37) Maternal weight, ma te rna l smoke h abit, so cioe co n o m ic status , ed uc ati o n Gestational d iabetes , h ype rt ens ion , pr ee clam p sia , ec la m p sia – Ear ly p re te rm b irt h (< 32 we ek s) an d late pr et er m b ir th (3 2– 37 we ek s) EDI-2 scores w ere significant ly lower in ea rly -b o rn p re te rm s tha n in H C s , in p ar tic ul ar in “Bod y di ssatisf acti o n” an d “Drive for th innes s” sub scales 4 S ack s et al. 2 016 Po pula tio n coho rt stud y (So rok a University Me dic al C en ter, Isr ae l 199 1– 2 014 (n = 2 3 1 ,2 71) EDs (n = 4 8 6 ) M ater n al ag e, ma te rna l ob esi ty Gestational d iabetes mell itus (type A1 an d type A2) – Ge sta tio na l ag e at birth E D and o the r p sy ch ia tr ic dis o rd er s in the of fsp rin g we re asso cia te d with gestational d iabetes mellit us 2 Su et al . 20 16 Po pula tio n-ba sed co hor t (De n ma rk 197 3– 2 000 (n = 1 ,034 ,53 -9) an d S we de n 197 0– 1 997 (n = 1 ,246, 560) AN (n = 5 878 ), BN (n = 1 722 ), m ixe d E D (n = 3 159 ), HCs (n = 2 110 ,75 5 ) Maternal loss of a cl o se relativ e 1y ea r p ri o r to or dur ing pr eg na ncy –– – ED, B N, and m ix ed ED were as so ciate d with ma te rn al ex pos ur e to p re na ta l los s 4 Razaz et al. 2018 Retrospective Swe d is h co hor t stu dy (1 992 –20 02, n = 486 ,68 8 ) AN (n = 2 414 ) M at er na l B MI , ye ar s o f ed uc ati on, m ater n al ag e at de liv er y, smo k e h abit Multiparity Vaginal d eli v ery, vaginal in str u me nta l de liv er y, el ec tiv e ces ar ea n sec tion , em er ge nc y ces ar ea n section Birth w ei ght fo r ge sta tio na l ag e, ge sta tio na l ag e at delivery AN was associ ated wit h h igh er m ater n al ag e, h igh er m ater n al ed uc ation , mul tiparity, and preterm bir th Th e rate o f A N d ecr ea se d with m ate rn al o v erwe igh t and o bes ity in a do se-re sp ons e m an n er 5 AN anorexia nervosa, BN bulimia nervos a, HC healthy con trol, ED eating diso rder, EDI -2 Ea ting D isor der In v entor y -2 ,EA T-26 E ati ng At titud e T est-26, BI TE Bulimic Inve sti g ator y T est ,FSS fe ma le sam e-se x twins ,FO S female opposite-s ex twins, MOS male oppo site-sex twin s, MSS male same-sex twins, SS sa me se x, OS oppos ite sex, VP T very preterm, BMI body mass index
Culbert et al.2008,2013; Raevuori et al.2008; Baker et al.
2009; Nicholls and Viner 2009; Smith et al. 2010; Wehkalampi et al.2010; Coombs et al.2011; Quinton et al.
2011; Vellisca et al. 2013; Micali et al.2015; Sacks et al.
2016). MMAT scores were lower for cross-sectional and case-control (ranging from 2 to 4 points) than cohort studies (ranging from 3 to 5 points).
Notwithstanding the aforementioned weaknesses, some da-ta gathered by the most robust studies should be acknowl-edged (see Table2): in fact, mixed diagnoses of EDs were associated with maternal stress during pregnancy and preterm birth; still, BN was consistently associated with maternal psy-chosocial stress during pregnancy. Finally, multiple factors, according to the available data, resulted to be related to the onset of AN in the offspring: higher maternal age, preeclamp-sia and eclamppreeclamp-sia, multiparity, hypoxic complications, prema-turity or preterm birth (< 32 weeks), and being small for ges-tational birth size.
Maternal factors
Maternal age (16 studies)
A total of 16 studies assessed maternal age as a possible factor linked to the risk for AN or BN (Cnattingius et al. 1999; F e i n g o l d e t a l . 2 0 0 2; L i n d b e r g a n d H j e r n 2 0 0 3; Montgomery et al. 2005; Favaro et al. 2006, 2008; Wehkalampi et al. 2010; Nosarti et al. 2012; Allen et al.
0 2 4 6 8 10 12 14 16 18 20
Gestational age, birth size and size for gestational age Apgar score or dismaturity signs Season of birth Forceps or vacuum delivery Premature rupture of the membranes Cesarean section delivery Hypoxic complications Cephaloematoma Breech delivery Effect of sex hormones Pre-eclampsia, eclampsia and pregnancy hypertension Gestational diabetes Vaginal bleeding
Multiparity Maternal viral infection Vitamin D deficiency Maternal age Maternal weight Maternal alcohol drinking
Ne o n at al Fa ct ors Obs te tr ic co m p li ca ti ons Pr egn anc y C o m p lic at io n s Ma te rn fa ct o rs
studies across categories of maternal factors, pregnancy complications, obstetric complications, and neonatal factors
Table 2 Results summary of the studies included in this review grouped by diagnoses of eating disorders
Eating disorders (EDs) Anorexia nervosa (AN) Bulimia nervosa (BN) Factors supported by more robust evidence •Maternal stress during pregnancy •Preterm birth •Higher maternal age •Preeclampsia and eclampsia •Multiparity •Hypoxic complications •Prematurity or preterm birth (< 32 weeks) •Small for gestational age or lower birth size •Maternal stress during pregnancy Factors supported by less robust evidence •Gestational diabetes •Vit. D deficiency •Low maternal weight •Viral infection during pregnancy •Season of birth (spring) •Maternal smoke habit •Vit. D deficiency •Dysmaturity signs 0 20 40 60 80 100 120 Neonatal factors Obstetric complications Pregnancy complications Maternal factors
low fair high very high
2013; Goodman et al. 2014; Romero-Martínez and Moya-Albiol2014; Tenconi et al. 2015; St-Hilaire et al. 2015; Lofrano-Prado et al.2015; Sacks et al.2016; Razaz and Cnattingius2018). Five studies out of 16 found that higher maternal age was significantly associated with an increased risk of AN (Cnattingius et al.1999; Lindberg and Hjern2003; Goodman et al. 2014; Tenconi et al. 2015; Razaz and Cnattingius2018). A register study found instead that adoles-cents with mothers who were young at the time of birth had a lower risk of developing AN compared with the adolescents of mothers who were 25–28 years old at birth (Lindberg and Hjern2003).
Maternal weight (7 studies)
Out of a total of 7 studies addressing maternal weight (Montgomery et al.2005; Wehkalampi et al. 2010; Allen et al. 2013; Romero-Martínez and Moya-Albiol 2014; Matinolli et al. 2016; Sacks et al. 2016; Razaz and Cnattingius2018), the majority did not show significant asso-ciations between maternal body mass index (BMI) and the onset of either AN or BN in the offspring. In contrast, a recent study found that the risks of AN in girls born at term decreased with maternal overweight and obesity in a dose-response man-ner (Razaz and Cnattingius2018).
Maternal cigarette smoking (2 studies) and alcohol
drinking (7 studies)
Only 2 studies investigated maternal alcohol use and both failed to show any associations between maternal alcohol use and EDs onset in the offspring (Feingold et al. 2002; Allen et al.2013). Seven studies investigated instead the role of maternal cigarette smoke (Montgomery et al. 2005; Nicholls and Viner 2009; Wehkalampi et al. 2010; Allen et al.2013; Goodman et al. 2014; Matinolli et al. 2016; Razaz and Cnattingius 2018), reporting an association be-tween maternal smoking and BN diagnosis in the offspring, even after controlling for confounding factors such as off-spring BMI in adulthood or variation between childhood and adult BMI (Montgomery et al. 2005). In contrast, another study found a strong negative association between mother’s smoking and AN, but this was substantially attenuated upon adjustment for parental education (Goodman et al.2014). Still, all the other studies did not identify an association (Nicholls and Viner2009; Wehkalampi et al.2010; Allen et al. 2013; Matinolli et al. 2016; Razaz and Cnattingius
2018).
Maternal stress during pregnancy (3 studies)
Only 3 studies assessed maternal stress during pregnancy and EDs diagnosis in the offspring and all consistently found a
significant association (Taborelli et al.2013; St-Hilaire et al.
2015; Su et al.2016). A large population-based cohort study found that girls who were born from mothers who lost a close relative from 1 year before the beginning of pregnancy to the whole duration of pregnancy had an increased risk of suffering from an EDs than healthy controls, with similar results for mixed EDs and BN, but not for AN (Su et al. 2016). Similarly, it has been observed that the daughters of mothers with chronic anxiety during pregnancy had an increased risk of AN (Taborelli et al.2013). Additionally, maternal stress in the third trimester of pregnancy was associated with elevated scores on a screening tool for EDs (St-Hilaire et al.2015).
Pregnancy complications
Preeclampsia, eclampsia, pregnancy hypertension (9 studies), and maternal anemia (3 studies)
Nine studies investigated preeclampsia, eclampsia, pregnancy hypertension (Cnattingius et al. 1999; Foley et al. 2001; Feingold et al.2002; Lindberg and Hjern2003; Favaro et al.
2006,2008; Tenconi et al.2015; Matinolli et al.2016), and three maternal anemia (Favaro et al.2006; Nicholls and Viner
2009; Tenconi et al.2015). Out of 9 studies, only 3 of them found that AN was significantly associated with preeclampsia (Lindberg and Hjern2003; Favaro et al.2006; Tenconi et al.
2015), while only in one work (Favaro et al.2006) an associ-ation with maternal anemia during pregnancy was found. Nevertheless, the same group disconfirmed such an associa-tion in a more recent study (Tenconi et al.2015).
Gestational diabetes (7 studies)
Seven studies assessed the role of gestational diabetes (Cnattingius et al.1999; Favaro et al.2006,2008; Nicholls and Viner 2009; Tenconi et al.2015; Matinolli et al.2016; Sacks et al.2016). Out of the available studies, only 2 found an association between gestational diabetes and EDs in the offspring, the first on a sample with mixed ED diagnoses (Sacks et al. 2016) and the latter on a sample with AN (Favaro et al.2006). However, a more recent study did not confirm this datum (Tenconi et al.2015).
Maternal viral infection (2 studies)
Two studies analyzed the association between in utero viral infection exposition, in particular rubella (Foley et al.2001; Favaro et al.2011) and chickenpox (Favaro et al.2011). Only one study found that exposure to rubella or chickenpox during the sixth month of pregnancy was associated with an in-creased risk of developing AN in the offspring (Favaro et al.
One study assessed the role of vitamin D deficiency in preg-nancy, finding that EDs were predicted by low maternal vita-min D level at 18-week pregnancy, even after controlling for family sociodemographic factors, BMI, and depressive symp-toms (Allen et al.2013). However, BN was the only disorder in which the risk remained significantly increased when EDs were assessed separately.
Effect of sex hormones (12 studies)
Six studies assessed prenatal androgen exposure using the 2D:4D ratio (Klump et al.2006; Smith et al.2010; Coombs et al.2011; Quinton et al.2011; Romero-Martínez and Moya-Albiol2014; Culbert et al. 2015). In general, the 4th digit tends to be longer than the 2nd in males, whereas in females the 2nd and 4th digits tend to be of equal length (Berenbaum et al.2009). Lower 2D:4D ratios (second finger shorter than the fourth finger) point to higher prenatal androgen exposure (Berenbaum et al.2009). Two studies (Klump et al.2006; Culbert et al.2015) found that ED symptomatology [i.e., body dissatisfaction (Klump et al.2006), weight preoccupation (Klump et al.2006), binge eating (Klump et al.2006), com-pensatory behaviors (Klump et al.2006), and disordered eat-ing (Culbert et al.2015)] was associated with lower levels of prenatal testosterone. In males, greater prenatal testosterone exposure is associated with less disordered eating, less drive for leanness, but increased drive for muscularity (Smith et al.
2010). Two other studies found that AN was instead signifi-cantly associated with higher testosterone exposure during pregnancy (Quinton et al. 2011; Romero-Martínez and Moya-Albiol 2014), while BN was associated with lower levels of prenatal testosterone (Quinton et al.2011).
Six studies indirectly investigated the role of prenatal sex hormone effects in opposite-sex twin cohorts (Culbert et al.
2008,2013,2015; Raevuori et al.2008; Baker et al. 2009; Lydecker et al.2012). The highest levels of disordered eating were both observed in same-sex and opposite-sex female twins (Culbert et al.2008). In a subsequent study (Culbert et al. 2013), disordered eating was not associated with opposite-sex or same-sex twins in pre-early puberty. However, during later phases of puberty, females from opposite-sex twin pairs exhibited less restrictive eating behav-ioral patterns than females from same-sex twin pairs. Other three studies (Raevuori et al. 2008; Baker et al. 2009; Lydecker et al.2012) did not support the hypothesis that hav-ing a female co-twin increases ED risk in either male or female twins, but another found that lifetime prevalence of AN was 1.6–3.3% in women from opposite-sex twin pairs, while it was 2.9–5.1% in women from same-sex pairs (Raevuori et al.2008).
Out of 5 studies assessing the role of multiparity in the risk of EDs onset (Cnattingius et al. 1999; Feingold et al. 2002; Nosarti et al. 2012; Goodman et al. 2014; Razaz and Cnattingius2018), only 2 of them found an association with later offspring diagnosis of AN (Goodman et al.2014; Razaz and Cnattingius2018).
Vaginal bleeding (7 studies)
Despite 7 studies assessing the role of vaginal bleeding during pregnancy, none of them found an association with offspring ED diagnosis/symptomatology (Cnattingius et al. 1999; Shoebridge and Gowers2000; Foley et al. 2001; Feingold et al.2002; Favaro et al.2006,2008; Tenconi et al.2015).
Obstetric complications
Three studies found that an increasing number of obstetric complications was correlated to a higher risk of EDs in the offspring, specifically AN (Foley et al. 2001; Favaro et al.
2006) and BN (Foley et al. 2001; Favaro et al. 2006; Lofrano-Prado et al.2015), and a lower age of onset of the EDs (Favaro et al.2006). Few obstetric complications have been associated with BN, but only one study found an asso-ciation between bulimic symptoms in college students and the presence of any obstetric complications at birth (Lofrano-Prado et al.2015).
Hypoxic complications (7 studies)
Seven studies assessed hypoxic complications, namely, um-bilical cord wrapped around the neck, need for O2, and pla-cental infarction (Foley et al. 2001; Feingold et al. 2002; Lindberg and Hjern2003; Favaro et al.2006,2008; Nicholls and Viner 2009; Tenconi et al.2015). As a result, only 3 studies found an association between hypoxic complications and AN (Lindberg and Hjern 2003; Favaro et al. 2006; Tenconi et al.2015) or BN (Favaro et al.2006).
Breech delivery (5 studies)
Out of 5 studies assessing breech delivery (Foley et al.2001; Feingold et al.2002; Lindberg and Hjern2003; Favaro et al.
2006; Tenconi et al. 2015), only one study (Lindberg and Hjern2003) found an association with later AN diagnosis. Cephalohematoma (6 studies)
Cephalohematoma was investigated by 6 studies (Cnattingius et al. 1999; Lindberg and Hjern 2003; Favaro et al.2006,
of them found an association with AN diagnosis in the off-spring (Cnattingius et al.1999; Lindberg and Hjern2003). Premature rupture of the membranes (8 studies)
Eight studies assessed premature rupture of the membranes (Cnattingius et al.1999; Foley et al. 2001; Feingold et al.
2002; Lindberg and Hjern2003; Favaro et al.2006,2008; Goodman et al.2014; Tenconi et al.2015). Only one study found an association with AN (Lindberg and Hjern2003) but was then disconfirmed by a later larger work (Goodman et al.
2014).
Cesarean section delivery (8 studies) and forceps or vacuum delivery (8 studies)
Eight studies investigated the role of cesarean section delivery (Cnattingius et al.1999; Shoebridge and Gowers2000; Foley et al.2001; Feingold et al.2002; Goodman et al.2014; Micali et al.2015; Lofrano-Prado et al.2015; Razaz and Cnattingius
2018) and forceps or vacuum delivery (Cnattingius et al.
1999; Shoebridge and Gowers 2000; Foley et al. 2001; Favaro et al.2006,2008; Goodman et al. 2014; Tenconi et al.2015; Razaz and Cnattingius2018). Only one study found a weak evidence of an association with AN diagnosis (Goodman et al. 2014) while another (Micali et al. 2015) found that cesarean section was instead associated with com-pensatory behaviors.
Neonatal factors
Gestational age, birth size, and size for gestational age (18 studies)
Eighteen studies assessed prematurity in terms of gestational age, birth size, or birth size for gestational age (Cnattingius et al.1999; Shoebridge and Gowers2000; Foley et al.2001; Feingold et al.2002; Lindberg and Hjern2003; Favaro et al.
2006,2008; Nicholls and Viner2009; Wehkalampi et al.
2010; Nosarti et al.2012; Allen et al.2013; Goodman et al.
2014; Micali et al.2015; Tenconi et al.2015; St-Hilaire et al.
2015; Matinolli et al. 2016; Sacks et al.2016; Razaz and Cnattingius2018).
Gestational age (< 32 weeks) has been consistently found to be associated with EDs, even adjusting for confounders (Nosarti et al.2012; Foley et al.2001; Goodman et al.2014; Cnattingius et al.1999; Lindberg and Hjern2003; Razaz and Cnattingius2018). With more detail, low gestational age was associated with later AN diagnosis with an odds ratio ranging from 1.9 (95% CI 1.2–3.3; Lindberg and Hjern2003) to 3.2 (95% CI 1.6–6.2; Cnattingius et al.1999).
Three studies found that AN diagnosis was associated with being small for gestational age at birth (Cnattingius et al.
1999) or having a Ponderal Index < 25 (Favaro et al.2006; Tenconi et al.2015).
Concerning BN, two studies found that BN was associated with low birth weight for gestational age (Favaro et al.2006; Tenconi et al. 2015); however, another study reported the opposite result (Goodman et al.2014).
Two studies on unaffected individuals found that adoles-cents and young adults born preterm showed lower scores on eating psychopathology (i.e., drive for thinness, body dissat-isfaction, and bulimia) than those who were not born preterm (Wehkalampi et al. 2010) even after controlling for con-founders (Matinolli et al.2016).
Apgar score or dysmaturity signs (7 studies)
Seven studies assessed Apgar score (Cnattingius et al.1999; Shoebridge and Gowers 2000; Lindberg and Hjern 2003; Nosarti et al.2012) or dysmaturity signs (Favaro et al.2006,
2008; Tenconi et al.2015) such as hypotonia, hyporeactivity, hypothermia, tremors, and feeding problems at birth. One study found that AN diagnosis was associated with low Apgar score at birth (Lindberg and Hjern2003); in keeping with these findings, the other two studies found that hyporeactivity was a significant independent predictor of the development of AN even after adjusting for confounders (Favaro et al.2006; Tenconi et al.2015). Additionally, the same studies found neonatal hyporeactivity and early eating difficulties as adjusted risk factors for BN (Favaro et al.2006; Tenconi et al.2015). In another study, the presence of signs of neonatal dysmaturity influenced the development of high harm avoidance, a risk factor of EDs (Favaro et al.2008). Season of birth (5 studies)
Five studies assessed season or month of birth and the associ-ation with EDs providing consistent support to an associassoci-ation of AN with being born in spring (Morgan and Lacey2000; Favaro et al.2011; Vellisca et al. 2013; Winje et al.2013; Allen et al.2013).
Discussion
The aim of this systematic review was to highlight the association between prenatal and perinatal factors and the sub-sequent development of EDs, investigating the hypothesis that these factors could impair neurodevelopment, similarly to the model proposed for schizophrenia (Geddes and Lawrie1995; Verdoux et al.1997; Geddes et al.1999; Cannon et al.2000; Clarke et al.2011; Rapoport et al.2012). When analyzing the main findings of this review, it should be also borne in mind that it has been brought to the surface the inconsistency of the available body of evidence on this topic and the lack of a
between prenatal and perinatal factors and clinical variables in EDs. Nevertheless, some relevant main findings emerged as well: first, maternal stress during pregnancy and preterm birth emerged as the most supported factors impacting on a diag-nosis of EDs in the offspring. Similarly, maternal stress during pregnancy was robustly associated with the onset of BN. Finally, the association between prenatal and perinatal factors and AN resulted to be complex and many-sided: in fact, higher maternal age, preeclampsia and eclampsia, multiparity, hypoxic complications, and prematurity or preterm birth (< 32 weeks) or being small for gestational age or with a low birth size were the most sound factors in the association with the onset of AN in the offspring.
That said, in keeping with the second aim of this work, future lines of research can be outlined in order to bridge these gaps in the literature: for example, no studies investigated binge eating disorder (BED) and further works may want to tackle the aforementioned methodological weaknesses (i.e., composite variable for prenatal and perinatal risk factors; lack of a shared definition of such risk factors) with ad hoc study designs. As a first step, as suggested by literature (Krug et al.
2013), all factors should be divided into four groups: pregnan-cy complications, labor and delivery complications, and fetal distress signs/neonatal complications. As a second step, other candidates proposed by this review could be added as well, including: mothers’ characteristics (i.e., age, smoke habit, weight, stressful events during pregnancy) and timing (sea-sonality). Doing so, it will be finally possible to conduct a meta-analysis of these data yielding quantitative results as well.
With more detail, the main findings for each category (i.e., maternal factors, pregnancy complications, obstetric compli-cations, and neonatal factors) are described below.
Maternal factors
With respect to maternal factors, maternal age has been deep-ened by a number of robust studies finding that a higher ma-ternal age was significantly associated with an increased risk of AN in the offspring (Cnattingius et al.1999; Feingold et al.
2002; Favaro et al.2011; Goodman et al. 2014; Razaz and Cnattingius2018). However, Lofrano-Prado and collabora-tors (Lofrano-Prado et al.2015) found a contrasting result, observing that AN symptomatology in healthy students was 0.5 times lower for those students born from the oldest mothers (> 25 years old). This conflicting result may be due to the numerous possible confounding factors, such as the application of psychometric assessments to a non-clinical sample or a sociocultural selection bias. Physiopathogenesis underlying the association of the diagnosis of AN in the off-spring and a higher maternal age is yet to be clarified and could be due both to a greater risk of pregnancy complications
tal factors linked to older mothers, so future studies are needed to clarify these matters.
Recent evidence indicates that another maternal factor, namely, obesity and metabolic diseases, may have a long-term impact on psychiatric conditions of the offspring, such as attention deficit hyperactive disorder, autism, and schizo-phrenia (Rivera et al.2015). In contrast, in the field of EDs, only one study found that the risk of AN in girls born at term decreased with maternal overweight and obesity in a dose-response manner (Razaz and Cnattingius 2018). However, such a finding was not confirmed in the sibling control anal-yses, so other genetic or familiar environmental factors may be involved as well.
Out of seven studies available, maternal smoke was report-ed as significant only by two studies with contrasting results (Montgomery et al.2005; Goodman et al.2014). In fact, on one hand, a positive association with BN, even after control-ling for confounding factors such as offspring BMI in adult-hood or variation between childadult-hood and adult BMI, was reported (Montgomery et al.2005), but on the other hand, a negative association between mother’s smoking and AN was shown, even if attenuated upon adjustment for parental edu-cation (Goodman et al. 2014). Although a larger number of studies (i.e., 7) investigated the association between maternal alcohol use and EDs onset in the offspring, no significant data emerged; since this datum is not in line with other fields of psychiatry (Pagnin et al.2019), future studies are needed to clarify this issue.
Interestingly, psychosocial stress was found to be strongly associated with both EDs and BN in the offspring, on the basis of all the available studies (i.e., 3) that supported this datum with robust evidence (Taborelli et al.2013; St-Hilaire et al.
2015; Su et al.2016). Also, maternal stress has been reported to entail a greater risk of impulsive and compensatory behav-iors, as hypothesized also in other fields of psychiatry (Abbott et al.2018). This line of research needs a deeper investigation because it could underlie an important link between endocrine functions, genetics, and temperamental traits. Stress activates the HPA axis, increasing the release of glucocorticoids (St-Hilaire et al.2015) that could cross the maternal placenta and impact on the development of metabolism, fetal growth, and immune functions during pregnancy. Glucocorticoids could also affect the development of the fetal HPA axis, causing an alteration in stress-response mechanisms, emotional dys-regulation, and increased risk for anxiety disorders and EDs in childhood and adulthood (Meyer and Hamel2014; St-Hilaire et al.2015).
Pregnancy complications
Concerning pregnancy complications, gestational diabetes could alter fetal neurodevelopment during critical periods
exposing the fetus to elevated glucose levels (Georgieff2006). Out of seven studies, two found an association between ges-tational diabetes and EDs in the offspring (Favaro et al.2006; Sacks et al. 2016), although subsequent work partially disconfirmed such findings (Tenconi et al.2015). Similarly, more research is needed also on the role of viral infection during pregnancy: only the study by Favaro et al. (2011) re-ported that exposure to rubella or chickenpox during the sixth month was associated with an increased risk of developing AN in the offspring.
Animal studies suggested that transient prenatal vitamin D deficiency is associated with altered brain development (Ali et al.2018) and low maternal vitamin D during pregnancy was identified as a significant predictor of later schizophrenia (McGrath et al.2010,2011) and autism (Ali et al.2018) in the offspring. Surprisingly, only one study was conducted in the ED field, reporting data in line with those of general psy-chiatry: in fact, EDs were predicted by low maternal vitamin D level at 18-week pregnancy, even after controlling for fam-ily sociodemographic factors, BMI, and depressive symptoms (Allen et al.2013). However, BN was the only disorder in which the risk remained significantly increased when EDs were assessed separately, so no definitive conclusions can be drawn.
Exposure to testosterone during pregnancy has been as-sociated with organizational permanent effects of eating be-havior: in animal models, prenatal testosterone exposure increased food intake in male mammals, while in females low levels of testosterone were associated with later restric-tive eating behavior (Donohoe and Stevens 1983; Madrid et al. 1993). Lower levels of prenatal testosterone exposure have been associated with body dissatisfaction, weight pre-occupation, binge eating, and compensatory behaviors in females (Klump et al.2006). It has been also suggested that the relatively low level of testosterone before birth in fe-males permits their brains to respond to estrogens at puberty when the hormones activate the genes contributing to dis-ordered eating in vulnerable girls (Klump et al. 2006). Prenatal exposure to male hormones could be indirectly investigated in adult females using the finger-length ratios (2D:4D), a sexually dimorphic trait that correlates with pre-natal androgen exposure (Klump et al.2006) or in opposite-sex twins cohorts, where the female fetus is exposed to higher levels of testosterone by sharing the womb with the male fetus (Resnick et al. 1993; Cohen-Bendahan et al.
2004,2005). The hypothesis that higher prenatal testoster-one exposure could increase food intake and protect against t h e d e v e l o p m e n t o f d i s o r d e r e d e a t i n g s y m p t o m s is intriguing although debated. Studies of 2D:4D ratios have yielded more positive evidence than those examining fe-males from opposite-sex twin pairs, but the overall results are very controversial. Future studies should focus on direct assessment of sex hormone levels during pregnancy and
perform a better confounder analysis on the other risk factors.
Obstetric complications
Obstetric complications that seem to have more robust evi-dence of association with later AN onset are hypoxic compli-cations (Lindberg and Hjern 2003; Favaro et al. 2006; Tenconi et al. 2015), breech delivery (Lindberg and Hjern
2003), and cephalohematoma (Cnattingius et al. 1999; Lindberg and Hjern2003). Preeclampsia and eclampsia, se-vere hypoxic and fetal hypoperfusion pregnancy complica-tions, were associated with a later diagnosis of AN in three more robust- evidence cohort studies, two from the same ex-panded pool of patients (Lindberg and Hjern 2003; Favaro et al.2006; Tenconi et al.2015). Observation of neuropsycho-logical deficits (Galderisi et al.2003), subtle neurological ab-normalities (Gillberg et al.1994), and nonreversible morpho-logical brain changes (Katzman et al.1997; Chowdhury et al.
2003) might suggest that impairment in neurodevelopment could be one of the possible pathways for the development of an ED (Connan et al.2003). Obstetric complications might have more than one role in their etiopathogenesis: they could cause hypoxia-induced damage to the brain thus impairing the neurodevelopment of the fetus (Cannon et al.2000). Also, the adequacy of nutrition during pregnancy and the postnatal pe-riod could influence the adults’ nutritional status and their appetite programming throughout life (Jones et al. 2017). Perinatal hypoxia/ischemia could cause disturbances of the dopaminergic system that persists in adulthood and impairs the neurotrophic signaling critical for pre- and postnatal brain development (Giannopoulou et al.2018).
Despite eight studies investigating the role of cesarean sec-tion delivery, only weak evidence is available on the associa-tion with AN diagnosis (Goodman et al.2014) or ED symp-tomatology (Micali et al. 2015). Similarly, also data on the premature rupture of the membranes garnered an overall weak association with EDs.
Neonatal factors
Prematurity, in particular very preterm birth (≤ 32 weeks), or being small for gestational age and birth size have been asso-ciated with several cohort studies to AN (Cnattingius et al.
1999; Foley et al.2001; Lindberg and Hjern 2003; Favaro et al. 2006; Goodman et al. 2014; Razaz and Cnattingius
2018) and EDs (Nosarti et al. 2012). Interestingly, a clear dose-response pattern has been found between lower gesta-tional age and higher risk for AN, with a gradient observed even within the term (births at 37 weeks of gestation) (Goodman et al.2014). Cnattingius et al. (1999) showed that among girls born very preterm, the risk of subsequent devel-opment of AN was higher among girls who were small for
with higher birth weight for gestational age (OR 2.7, 95% CI 1.2–5.8). Less clear is the association between BN and birth weight: two cohort studies (Favaro et al.2006; Tenconi et al.
2015) from the same population found that BN was associated with being born small for gestational age; however, another study found the opposite result (Goodman et al.2014). Micali et al. (2015) despite not having found any associations be-tween perinatal predictors and ED psychopathology, observed that those very preterm adults that at the age of 21 years pre-sented with ED symptoms had a smaller gray matter volume in the posterior cerebellum and a smaller white matter volume in the fusiform gyrus bilaterally at the age of 14–15 years. Early alteration of the cerebellum sub-networks linked with somatosensory, interoceptive, and emotional processings was recently found (Gaudio et al.2018). These findings, if con-firmed by further studies, could help to explain the abnormal integration of somatosensory and homeostatic signals, which may lead to body image disturbances in AN.
Broadly speaking, premature newborns need to face a dif-ficult environment that increases stress potentially influencing the psychic and brain development in turn generating epige-netic changes. Follow-up studies often report neurocognitive inabilities with multi-level minimal impairments (Fumagalli et al.2018; Nist et al.2019). In the same vein, predisposing factors for EDs could impact not only directly on the relation-ship with food but also indirectly (i.e., socio-emotional and/or neuropsychological difficulties) increasing individuals’ vul-nerability to factors occurring later in the lifespan, for exam-ple, cultural factors and hormonal changes in adolescence.
The findings that healthy individuals born preterm scored lower on eating psychopathology than HCs born at term (Wehkalampi et al.2010; Matinolli et al.2016) are apparently i n c o n t r a s t w i t h s o m e a f o r e m e n t i o n e d s t u d i e s . Notwithstanding, these inconsistencies could be due to a sub-optimal diagnostic assessment (EDI-2 and not the ICD/ DSM gold standard) or to a sample selection bias or to the lack of adjustment for confounders. Future studies on healthy in-dividuals born preterm are warranted to better understand their eating style.
Interestingly, dysmaturity signs (e.g., hyporeactivity) have been linked to personality alterations in AN (Favaro et al.
2006; Tenconi et al. 2015) and BN (Favaro et al. 2006; Tenconi et al.2015). As shown by Favaro et al. (2008), neo-natal dysmaturity influences the development of particular temperamental dimensions (Cloninger et al.1993), such as harm avoidance (HA), a temperament dimension that has been associated with a higher risk of AN onset (Atiye et al.2015). HA reflects the tendency to respond intensely to aversive stimuli and involves anticipatory worry about possible prob-lems (Favaro et al.2008). It is considered a marker of emo-tional vulnerability to depression (Kampman and Poutanen
2011) not only because individuals with high HA are more
cover from depression.
Seasonality is still a controversial topic that could under-lie many other factors, such as gestational vitamin D, expo-sure to infectious agents, temperature and weather, and/or pregnancy and birth complications, all of which have the potential to influence fetal or infant neurodevelopment. Results are mixed, with studies supporting the season of birth hypothesis for generic EDs (Eagles et al. 2001; Watkins et al.2002; Waller et al.2002), although this as-sociation is lost when both AN (Button and Aldridge2007; Vellisca et al.2013; Winje et al.2013) and BN (Morgan and Lacey 2000; Button and Aldridge2007) are studied separately. Given the several methodological issues affect-ing these data (e.g., different latitudes, the accuracy of di-agnosis, sample sizes, and comparison groups), caution is required when reading these findings.
Conclusions
The investigation of the association of prenatal and perina-tal factors with later onset of psychiatric conditions is par-ticularly hard to perform from a methodological standpoint. This is even more true when such an evaluation is applied to quite rare conditions like AN (Hoek2006). Notwithstanding, the available body of evidence supports maternal stress during pregnancy and preterm birth as associated with the develop-ment of mixed diagnoses of EDs; still, BN was consistently associated with maternal psychosocial stress during pregnan-cy. Finally, multiple factors were reported to have an impact on the onset of AN in the offspring, namely, higher maternal age, preeclampsia and eclampsia, multiparity, hypoxic com-plications, prematurity, or preterm birth (< 32 weeks), and being small for gestational birth size. However, our review contributed also to shed light on the plethora of methodolog-ical inconsistencies and flaws that characterize these lines of research (e.g., inclusion biases, self-report assessments of the EDs, lack of a shared definition of prenatal/perinatal factors, to name a few), potentially generating new ideas on how to tackle these weaknesses and finally provide a meta-analysis on this clinically relevant topic. More studies on larger sam-ples evaluating multiple factors with a longitudinal design— the most fruitful research methodology given the research questions—are necessary to draw more solid conclusions on this topic. Also, as reported earlier (Krug et al.,2013), a shared definition of risk factors is required; in this light, the classifi-cation system adopted in this review (i.e., maternal factors, pregnancy complications, obstetric complications, and neona-tal factors) could be a starting point to promote the additional debate on prenatal and perinatal factors in the field of EDs in turn encouraging well-designed studies.
