Document 3N9bn2Q0bymkgwkjnY0kXzvk3

HN.R.evi.ew er -- A, EHP content i ....... ible to individuals with disabilities. A fully ...... ible (Section SO8 ..... pliant) HTML version of this article is available at http://dx.doi,org/10.1289/ehp.1307893. TThhee NNaavviiggaattiioonn GGuuiiddee---EEvviiddeennccee--BBaasseedd MMeeddiicciinnee MMeeeettss EEnnvviirroonnmmeennttaall HHeeaalltthh:: `Systematic Review of Human Evidence for PFOA Effects on Fetal Growth Systematic Review of Human Evidence for PFOA Effects on Fetal Growth Paula Johnson.PatriceSutton!Dylan 3. Atchley Erica Kostas Juloon Lam?Saunak Sen? Paula L Johnson,7 Patrice Sutton,~ Dylan S. Atchley,~ Erica Koustas,2 Juleen Lam,2 Saunak Sen,3 Karen A- Robinson414 DaniAe. AxanedTrad cey J. Wooo Karen A. Robinson,4,5,6 Daniel A. Axelrad,7 and Tracey J. Woodruff~ {Program on products HathadhEnvcrman,Uneroyf Ctr Son Franccs, OnnCalf USA: Oio g 1program on Reproductive Health and the Environment, University of California, San Francisco, Oakland, California, USA; 2 Oak Ridge Ft Ros Gt cura ono, hen ois Institute for Science and Education (ORISE) Postdoctoral Fellowship, National Center for Environmental Economics, Office of Policy, mt tfo s n argon OF. USA po ofset s BotsUnt Cail U.S. Environmental Protection Agency, Washington, DC, USA; 3Department of Epidemiology and Biostatistics, University of California, Er edepa embassy San Francisco, San Francisco, California, USA; 4Department of Medicine, 5Department of Epidemiology, and 6Department of Health Policy a Urry Soin: Maton A Homa e or m rsSh Pn & Management, Johns Hopkins University, Baltimore, Maryland, USA; 7National Center for Environmental Economics, Office of Policy, 03 Ertan Pranaon Kore Worton BE USK U.S. Environmental Protection Agency, Washington, DC, USA uc Th NuiCoblemel a deed ome he do ba aiioesxocmaietpricmahry slpieed 0 BACKGROUND: The Navigation Guide methodology was developed to meet the need for a robust ES May "ajomied oli sina fy method of systematic and transparent research synthesis in environmental health science. We ee petcf em priya sented conducted a case study systematic review to support proof of concept of the method. OREN cETPA Mao SEARED GE eae eles ma mdb on n Sea] OBJECTIVE: We applied the Navigation Guide systematic review methodology to determine whether Santapn ooben PEON sd ohn TT Como a developmental exposure to perfluorooctanoic acid (PFOA) affects fetal growth in humans. Merve Wa rd ee ne oh Noida Gate meting edb ae sme ed METHODS: We applied the first 3 steps of the Navigation Guide methodology to human 0 nin ULSS en evi epidemiological data: 1) specify the study question, 2) select the evidence, and 3) rate the quality a ame | oe es and strength of the evidence. We developed a protocol, conducted a comprehensive search of the Emool fe yeal poe, mim literature, and identified relevant studies using prespecified criteria. We evaluated each study for a rates wotwoossuf Horio pm risk of bias and conducted meta-analyses on a subset of studies. We rated quality and strength of the SR entire body Sai, of human evidence. Rusti We demi 1 bn dic it me out nin cit, nd 9 ofBe wet ey i pent RESULTS: We identified 18 human studies that met our inclusion criteria, and 9 of these were ee ee ma pn Loni a ml elem on ie combined through meta-analysis. Through meta-analysis, we estimated that a 1-ng/mL increase rr i EO ascans 83 09% Ch 98.273 ine rk Forse in serum or plasma PFOA was associated with a -18.9 g (95% CI: -29.8, -7.9) difference in birth `weight. Weconcluded ha theikofbis cro std ws om,andwesigned s "moderme" weight. We concluded that the risk of bias across studies was low, and we assigned a "moderate" quality rating 0theoverallbodyof humanevidence. quality rating to the overall body of human evidence. Conctuson: On the bakof this fit aplication ofthe Navigation Guide systematic review CONCLUSION: On the basis of this first application of the Navigation Guide systematic review meshdeog:wecoholhsther lie" tv leettndele spon 95 Sy,WE ltt heevincd eforthe methodology, we concluded that there is "sufficient" human evidence that developmental exposure E CrmaE u nFSs. ey 5,Ka.Lm) Sen Robin KkDA, PFO doePEi ONe hs b, eeed to PFOA reduces fetal growth. `Woodruff T}. 014 The Nigaton Guide--eviencebusedmedicine metsenvionment ea CITATION: Johnson PI, Sutton P, Atchley DS, Koustas E, Lam J, Sen S, Robinson KA, Axelrad DA, Woodruff TJ. 2014. The Navigation Guide--evidence-based medicine meets environmental health: mt io a ds orPEON mod pk. Ee Hod Pepe Pomc nn cl ppc nd systematic review of human evidence for PFOA effects on fetal growth. Environ Health Perspect TEE honogg op 122:1028-1039; http://dx.doi.orgllO.1289/ehp.1307893 clinical research are primarily applied to randomized controlled clinical trials, the evidence streams for environmental health science are different. The Navigation Guide systematic review methodology was developed to apply best practices in research synthesis in clinical medicine and environmental health to the evidence streams common in environ- mental health sdence (i.e., experimental toxi- cological studies and observational human saatbbuooduiuettts)thhienesosirtrdreeernngtothreaocfheeavvniiddoeevnneccreaell(cWonocoludsriuofnf et al. 20I Ia). Additional background on the Navigation Guide is given in a companion <c0onmemnenatraryy((WWooodruff and SSuattvoonn WWee uundnertdookeaacncaaseossttuouddyykttoo 2014). aappppllyy tthhee Niavoigatnion GGuuiiddeemmesethheoddoollooggyy.. FFoorr tthhiiss ffiirnskt case study, we evaluated the evidence for the effects of exposure to perfluorooctanoic add (PFOA) on fetal growth. PFOA has been used f1or1>> 3500 yyearns in tthhee mmanaufanctuureofoffflfaluuoorcroo.- polymers used in industrial applications and consumer products to impart certain charac- Introducti;on Resch Counc 2011). Such meds (rsPsreAgcvekn.e2(0E0nP6R;) U0S1, 2EvWionemesnctl Introduction damm bell a eg Te A Fo ee rn Synthesizing environmental health research om mismote rian {GRADE Working Group 00: Tigi brn Gponts and he dnc of a: from multiple streams ofevidence is critical to ing cms mp eh 20 Grn S01) hd es ort wih fore (py oe translating the science into improved health a a s amee to Bee me oe outcomes. Robust, systematic, and transparent bode ch yb st bi aha in ibyof Apr 207, Fo 207, 200% methods of research synthesis are an identien oes ht e r coc: Akhooh me of bd ing Rio 301 US FASO. Inion, fied need in environmental health (National Research Council 2011). Such methods already exist to evaluate clinical evidence (GRADE Working Group 2012; Higgins and Green 2011) and include steps such as developing a prespecified protocol, a comprehensive search, and rating the quality of the evidence. Although methods of synthesizing teristics, such as fire and stain resistance [Prevedouros et al. 2006; U.S. Environmental Protection Agency (EPA) 2012]. We selected PFOA for evaluation based on pervasive human exposure and the evidence of assodations with fetal growth (Agency for Toxic Substances and Disease Registry 2009; Apelberg et al. 2007; Fei et al. 2007, 2008; Kato et al. 201 l; U.S. EPA 2012). In addition, Be ee Address correspondence to P.I. Johnson, California Department of Public Health, Occupational Health Branch, 850 Marina Bay Parkway, Building P, Richmond, CA 94804 re USA. Telephone: (510) 620-5711. E-mail: paula.johnson@cdph.ca.gov ca gi Sp un. Supplemental Material is available online (http://dx.doi.org/10.1289/ehp. 1307893). eo cE pe ein Cost fo em es Vike bi Ofofech md We acknowledge the following persons for their contributions: K. Guyton [National Center for Environmental Assessment, Washington Division, Office of Research and ee ee et rg ba Development, U.S. Environmental Protection Agency (EPA)] for assistance with developing evidence evaluation methodologies and identifying relevant toxicological databases; K. Thayer, A. Rooney, and A. Boyles (Office of Health Assessment and Translation, National Toxicology Program), L. Bero [Department of Clinical Pharmacy, University Ee hie not odAces Bo, ef at Fok od on.CH of California, San Francisco (UCSF)], and L. Zeise (Reproductive and Cancer Hazard Assessment Branch, Office of Environmental Health Hazard Assessment, California Environmental Protection Agency) for assistance with developing risk of bias and evidence evaluation criteria; C. Lau (National Health and Environmental Effects Research ENemt a gos5 Eyos obs: sh3 fm ao Harris od Po He Co Laboratory, Office of Research and Development, U.S. EPA) served as a perfluorooctanoic acid (PFOA) subject matter expert; T. Horvath (Prevention and Public Health Group, mt I i PreTe Dn Se Loo and Co-Managing Editor of die Cochranc Review Group on HIV/AIDS at UCSF) for training and assistance widi developing our search strategy; J. Pan (UCSF) for assistance widi eb ho htLKi RA 3 Hoek data extraction and thoughtful comments. Finally, we are grateful to M.-H. Chen, IC Choi, L.R. Goldman, R. Kishi, J.-H. Lee, and M. Marcus for their kind and timely response to et Beet Re rua aa requests for additional data and information and to the anonymous reviewers who helped to improve this manuscript. ent Ro ElotHAE TST te pi CAML 7, El. This research was funded through grants from New York Community Trust and the U.S. EPA through a contract with Abt Associates (GMA-0-6-UCSF 17288). E.K. and J.L. ete Pog Ge Nder Be a, C4 Sy were supported in part by appointments to the Internship/Research Participation Program at the National Center for Environmental Economics, U.S. EPA, administered by the mC Sy Shamebe Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. EPA. For 2009~013, support for the development and dissemination of the Navigation Guide methodology was provided by the Clarence Heller Foundation, the Passport Foundation, the Forsythia Foundation, om lyPin, Hs Ect be ed oni Ae bo elon at Pera, ew Ve Comte Tn, i UCR the Johnson Family Foundation, the Heinz Endowments, the Fred Gellert Foundation, the Rose Foundation, Kaiser Permanente, the New York Community Trust, the UCSF RRS Institute for Health Policy Studies, Planned Parenthood Federation of America, National Institute of Environmental Health Sciences (ES018135 and ESO22841), and U.S. EPA STAR grants (RD83467801 and RD83543301). T.J.W is a faculty member at the Philip R. Lee Institute for Health Policy Studies, UCSF. ments eb sel vest do ma ret ot soto 5. A Fr he US. EP The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the U.S. EPA. Further, the U.S. EPA does ree de ln not endorse the purchase of any commercial products or services mentioned in the publication. T i y CP oe 14d lo be 310 The authors declare they have no actual or potential competing financial interests. Received: 15 November 2013; Accepted: 23 June 2014; Advance Publication: 25 June 2014; Final Publication: 1 October 2014. 1028 1028 ia 1 Cor14 + Eddh sn ecs VOLUME 1221 NUMBER 10 I October 2014 . Environmental Health Perspectives 22558844..00000011 EExxhhiibbiitt ent ue. 22558844 State of Minnesota v. 3M Co., Court File No. 27-CV-10-28862 Sptematc review of FOR and human ft growth un Systematic review of PFOA and human fetal growth och bccodonsdoo 3d ht add1b lan ou corn: os nd foned there have been inconsistent conclusions about eta mon enTON ty in, tech tom omgb ree e the evidence of an assodation between PFOA Ep Ea Oe nfo ucioh rh DAA eh ly re and fetal growth (DeWitt et al. 2009; Hekster a mc md eon 00%, Key omfor chsbw,h kdsm peofson ct snd hcl et al. 2003; Jensen and Leffers 2008; Kennedy Bt Koi bina 00 mt ve por rd Cora 0 go nfs 20 et al. 2004; Kudo and Kawashima 2003; Lau oe indena 0 Bonn bm So oF 2 00 comand ml et al. 2004, 2007; Lindstrom et al. 2011; a200 Fo tk 15: od Ma, Te SL We ombeg Tokbed Sos shi rnd on as Olsen et al. 2009; Post et al. 2012; Steenland rire Sota 20 Emme et, Bowe perd iePAI et al. 2010; White et al. 2011). Lh ret,ms cite te bana Solent? or We In this review, we evaluate the human Cpidemaigi idence ining PFOR of Semmes gpm ebtinonioe, St 3 RatetheQualityandScrength epidemiologic evidence relating PFOA ont oflpo in heNigion coms 11 My 013, and herdnote OFthe idence exposure to fetal growth using the Navigation ema roe pc.To kn 33.37 Api S03 Toph bs Werad the alsynd sahof Guide systematic review approach. The results orheNoa ga Code mab ad ok bso stn woes cig okW.m of applying the Navigation Guide methodbrivishui acbnanm patos ng wd pide enon ology to the nonhuman evidence are presented Es Brin in another review (Koustas et al. 2014), and Es mi he NooGnoo 8 cod od hi oe of the results of applying the Navigation Guide a ea ee ee ek es methodology to integrate the human and hnSoe am pain ol woe rang eq of coe mh nonhuman evidence streams are presented in a frapebentiity bnrireWesat WaBvaogBneonnartto third review (Lam et al. 2014). in hh or 0 FON wo chs awa pe). MeMtehthooddss Weacio s mhecerlic Eeaode Wed Wefe br hd n We assembled a review team with expertise in he dofsynrion,cin lth tsbt themain outcomeofthe dywin a amt disap by the fields of systematic review, environmental iinspeniilne tseou y, ead Weert tisk actors weg. ao xon ft o ree el health, epidemiology, biology, statistics, and propogandaAdeeb pbBl i We eh pd risk assessment to develop a a prespecified roo cig nn in nt WTe S to CC'Rts Rw protocol for conducting the systematic review [onaryof Calfmin an Franotc Torey Sabin 1) nd DAD i (Fig amd Gre 20nd 1heAp)ne [University of California, San Francisco EE Wsa RobinHoh oot ot kk et eh echhl'oom (UCSF) Program on Reproductive Health nb Eo 203,Min r bo ch os emi hs (Vaat2013 We tanh and the Environment 2013]. More informatt tion about the review team is available in the a ee a mt companion commentary by Woodruff and Senin, vt red tug lc. cr fom edod lnh Sutton (2014). Sp 1 Spey he Sudy Quoion 28 etSaT 1L3)LsanNt PSenk R eE ti mentId S ob Step 1. Specify the Study Question Orvio aeme he quo: a rp rn orth 20% am0,eWes m Our objective was to answer the question: mr aa Ee Eee Br ca Si in Leet ep ems "Does fetal developmental exposure to PFOA a ions affect fetal growth in humans?" We developed bd Orel en De e e Ar a PECO (partidpants, exposure, comparator, EE ET and outcomes) statement, which is used as ing on meh ato edt n y ond SpWokotf Enero an aid to developing an answerable question itn nd Brn 007 Our FCO. it lhl deo ee ea oa kof (Higgins and Green 2011). Our PECO eonsned llr. Wexaed wif oa in "orof roc"we ly statement included the following: Tats epageapa re wided +To tae tw ete wii azn madeanpeh orad oe Participants: humans who are studied [rarai bu pi vise a during the reproductive/developmental time eT ty ats ramen +3 merc Ve dedch of doin period (before and/or during pregnancy or El yor a PLO wp panel. ow Stpba boo oly development) orem xpos to PFOA (CAS? mand or emmbpt ih a ao Exposure: exposure to PFOA (CAS# ean g meen + Eempn rmdrsl S St aaD 335-67-1) or its salts during the time before mans alr fan prtans fo mach admin Ot ptr pis conn pregnancy and/or during pregnancy for toms eo a i Ce EbonEee Bhete cro: females or direcdy to fetuses ar Saul Ws onan eer en. oe tL Comparators: humans exposed to lower lockofFON hn me ig onto rman pid Spl levels of PFOA than the more highly exposed Bs on aod on Fkot poh iwivs Sa nn Sot Rk humans (i.e., a comparison across a range ty So Dna uy of io ofexposures) Gece: fy on el grote DoToru e og bs P11. Sate it Fon ra ams Outcomes: effects on fetal growth, bi wi no osmaorf, DSA) wok pecubes fd in ab|Tew cio srs birth weight, and/or other measures of size, hs doomb aks Wepre (113 3d SAD pdmmabsmd such as length. he ofa wt samt iofit doco SStept22..eSSeellp eecctt tthheeEEvviiddeennccee Sa mil Vedorred HT Se et BE nie Swag Search methods. We developed search terms Ee ae es Ls am tt to identify relevant literature by using the es os ras (5 au LEoan Bais Fao medical subject headings (MESH) in PubMed opersimateed au parsers mms esomtdobel Suh ducmton sh out oto re (http://www.ncbi.nlm.nih.gov/pubmed) and Ee oo ie d Tow at rpn o amon ae amh meoron other key words for five articles known to us and that we judged to be relevant to our study question. Our search was not limited by language or publication date. The search terms for each database, which indude terms related to the exposure, the outcome, and the human subjects, are provided in Supplemental Material, Table S1. We searched PubMed (30 April 2012), Embase (http://www.dsevier. com/online-tools/embase; 7 May 2012), Web of Science (http://apps.webofknowledge. com/; 11 May 2012), and other databases (23-27 April 2012). The specific databases searched and numbers of records retrieved are provided in Supplemental Material, Table $2. We also hand searched the reference lists of all included studies and used Web of Science to search for articles that cited the included studies. Study selection criteria. We sdected studies meimnaesawusuhrrieecddhoorhrucemusitaimmnaatteeexddp,, aoansnuddraeasstssooodPacFtiioOanAiswowiwnitatshhs tbtal growth were evaluated. We did not require fetal growth to be the main outcome of the study. We screened studies for inclusion using a structured form in DistillerSR (Evidence Partners; http://www.systematic-review.net). Two review authors (P.I.J. and D.S.A.) independently conducted a tide and abstract screen of the search results to determine whether a reference met the inclusion criteria; studies that were not excluded based on the tide and abstract were screened through a full-text review. A third author (P.S.) screened 5% of the search results at the tide/abstract and fulltext stages for quality assurance. Following the screening and in the case of discrepant results between reviewers, the initial two reviewers (P.I.J. and D.S.A.) discussed each discrepancy and brought in the third reviewer (P.S.) if necessary to discuss and decide on the status (include/exclude) of each discrepancy. We excluded studies if The article did not contain original data or observations Study subjects were not humans Exposure to PFOA was not measured in, or estimated for, the study subjects PFOA exposure was not measured or esti- mated during the reproductive/developmental time period (any time before or during pregnancy for women, or directly in fetuses, including cord blood) Fetal or infant growth or birth weight was not measured. Data collection. Two review authors (P.I.J. and D.S.A.) worked together to extract the data from all of the included articles. We compared hathlalacot wfwatahsseiinenxddteerpapecentnedddeendntlalytyacewxtirtuhactterhdebbasyayamacetthhddiiarrtdda researcher 0. Pan; UCSF) for quality assurance and quality control. We planned to discuss any discrepancies among the three extractors to come to a consensus. We collected details of the study characteristics, exposure assessment, outcome measurements, and information used to assess risk of bias using a structured form in DistillerSR; we created this form by combining aspects of existing criteria and checklists (Guyart et al. 201 lb; Higgins and Decks 2011; von Elm et al. 2008). We contacted study authors to obtain data needed for the analysis that were not reported in the published artides. Step 3. Rate the Quality and Strength of the Evidence We rated the quality and strength of the evidence by a) assessing "risk of bias," defined as characteristics of a study that can introduce a systematic error in the magnitude or direction of the results of the study (Higgins and Green 2011), for each included study; b) rating the quality of the evidence across all studies; and c) rating the strength, or certainty, of tAhAewsseeevisisndineggncttehheearcirrciosksksooaflfblbisiataussdffiooersre(eaFacicghhuirinencc1ll)uu. ddeedd study. We assessed risk of bias for each included study using an instrument we developed by adapting existing risk of bias guidance used to evaluate human studies in the clinical sciences: the Cochrane Collaboration's Risk of Bias tool (Higgins and Green 2011) and the Agency for Healthcare Research and Quality's criteria (Viswanathan et al. 2012). We also included the funding source and declared conflicts of interest as a potential source of bias based on empirical data from studies conducted on pharmacological treatments that repormd evidence of bias associated with funding source (Krauth et al. 2013; Lundh et al. 2012). We considered whether the study received "support from a company, study author, or other entity having a financial interest in the outcome of the study" (see Supplemental Material, "Instructions for Making Risk of Bias Determinations"). Although we refer generally to this risk of bias domain as "conflicts of interest," we only assessed competing financial interests in this case study. We assigned each risk of bias domain as "low risk," "probably low risk," "probably high risk," "high risk," or "not applicable" (risk of bias area not applicable to the study). Our protocol provided specific instructions for each classification to help ensure consistent interpretation. The specific risk of bias instrument is provided in Supplemental Material, "Instructions for Making Risk of Bias Determinations." A summary of the criteria for "low risk" of bias for each domain is outlined in Table 1. Two review authors (P.I.J. and D.S.A.) independently made and cdaocchusmuednyteadcrriossk oafllbdioams adientesr.mWihnaetniontshefoser each study across all domains. When these two authors could not reach consensus on a risk of bias domain, two other authors (P.S. and J.L.) reviewed the results. If upon further discussion the four authors were unable to reach agreement on a risk of bias [ER -- Environmental Health Perspectives VOLUME 122 I NUMBER 10 I October 2014 0201029 22558844.00000022 nH ohonet. Johnson et al. di fi po ss don in, he Noss 200 bee cond dex com fm bon yw determination for a particular domain, the mr catiwoo i n om dim mls porrtor ae more conservative judgment was selected Ei a rowdes a Jnof lama (207 Kim ct, 00 1h sw dk mid orcua se ut: (e.g., if one reviewer made a judgment of Eo worse miwmces id Boas Wt af oA IAL aeonwse Wome "low risk" and the other made a judgment of tly ow aerloeyAE act ia (Fo, 2007: We dts wee pron ve id ea "probably low risk," the "probably low risk" Poon fos ot imS. Sree aoSee judgment was used). So iioam th cons nthe Whee emir of PFOA en th 1 ihwihpe ang 7s malig In addition to the instructions in the Pkweal Shoutts. nWg s do seca s Solon. 4srs PE Ws eg Pol protocol, we made the following derisions for im be Siig and dosing ko cySo. nd As ra Fane ound 3 rnd by sa er, rating the blinding and confounding risk of Fo Som. Wi ty3dhe erm sal wis coals on ot meSawhnmod tel bias domains. We judged a study to be low ofr idan dd he rs am come i (Gomi: ad We fn oe ionmodo risk ofbias for blinding when it described that Iie aewe ado 0 be aborn, or ct 0),whe by Sh Cras rhb th ly specimen samples were coded or otherwise Tonia ade sat sob italy is ootsoesoey. abo lin fh rsdoe) blinded. We judged a study to be probably ookof hn drd yPr dol ha ht Wh aw. th mtb 3 1% pr he low risk of bias when it described only partial Hine Seed neo to 1 3300 doh be mim blinding or described methods that would Raely ded vets he copms aa. corded companfr nat have effectively blinded investigators to the on I exposure and outcome groups (e.g., exposure propmyttpipeted J nr el was measured separately, and birth weight ir Cn fom hoi onl Ot moni We ruare poinStaCa LD). We ed the man" was obtained from a hospital record). Our ton ondr oeSofi oir abhi gatasBn open SATA lhe Repo criterion for designating low risk of bias for Sovireoonotiiissougm ml noFROn R(nade o adamobmforsts confounding required that studies account oon oi rand, hos w+ amandae)a3 Ss rt Fh gy for only two potential confounders, those we Some a mporant cmon: deemed the main "important" confounders. Based on existing data and a priori knowledge inmp mie dm Wokelbin [rm-- of the exposure and outcome of interest in all shesis,wedecided hac Tl 9 90 rrr | Got srmsat the studies, we derided that maternal age and Try mares gestational age were the main "important" Fecal conde oral he ldod Se. potential confounders for all the included Foi Not and emir et oy En studies. Maternal age and gestational age may da wa PEON peo Fk Dem be correlated with PFOA exposure and fetal rom (Fca, 2007, bdo a growth (Fei et al. 2007; Halldorsson et al. So Ole 209, Veco is toi Sette ctr 2012; Ode et al. 2013). We considered studies Sow i of efroblny mene TE | SS vs "low risk" of bias for confounding if the study i free] ls ome He piel authors accounted for both maternal age and prospe oratbip tedonr. JE TIS rams ate gestational age in their design or analysis or if td hosSot vlog bk + ein in Convio they reported that either confounder did not inns sini ven TRON + rns | - nin mL influence associations between PFOA and the me rgakWendt +Sart Se a outcome being asessed. We considered studies h on wo larsdl bt Mp high risk of bias if the study authors did not "cn oremcd of pando te account for either maternal age or gestational ndetal Wh hy dk atet age, and probably high risk if they did not em he mi ES account for gestational age in the data analysis ia te as of bhwh 6 Sess | Biers but restricted the analysis of birth weight to a arate bee a term births due to the potential for residual Confounding by ewadons ge ams Pmt iy confounding by gestational age among mbt fever fee term births. Daeol audmi eeenWe me Data evaluation and meta-analysis. We rs assessed the following study characteristics to determine whether studies were combinable Er mec am mer fo rom Pw. Dri of nianGd sri ro at wd ot in yd. in a meta-analysis: measure of fetal growth or a dei pena sac, SH outcome, study design, exposure assessment, and data analysis. We compared different ddaam Me compaIrTedE vat Sy i fs tsp otvn tn measures ofexposure, such as cord or maternal ron a Geenmine whet ha rs TE Twit ST serum, to determine whether they were pati Boma tng of RON TSS TT comparable. Biomarkers and timing of PFOA en | a a -- exposure assessments differed across studies, Ee PO a edes Essent Ee enemas that is, PFOA was measured at different times Sn na fm ps Dipa s er ws e3 e a Seeoy ar ors oo jue these during pregnancy in cord serum, maternal serum, and maternal plasma. Despite these ene, hsv neo ghcome SIE te oan con gies differences, there was evidence of high correoto of PRO concemrmions Seven Smt lation of PFOA concentrations between ke ee os So pt who fo tn these matrices within the same populations: Monroy et al. 2008); between cord and second or third trimester maternal serum or plasma (Fei et al. 2007; Kim S et al. 2011); and between first and second trimester maternal plasma (Fei et al. 2007). We combined studies in the meta-analyses with different measures of PFOA based on this concordance. We also assessed the following study design and data analysis parameters to determine which studies were combinable: the exposure and outcome statistic (continuous, dichotomous, or other scale), whether studies measured actual birth weights or only recorded whether the birth weight was "low" (i.e., < 2,500 g) and which variable was the dependent or independent variable in models of estimated effects. We contacted study authors to request information needed for meta-analysis. We requested linear regression modd coefficients for the association between a 1-ng/mL increase in PFOA (modeled as an untransformed continuous variable) and each outcome from authors if they were not reported, or, if less burdensome for authors, the raw data needed to calculate the estimated difference in birth weight. When raw data were provided, we used linear regression models to calculate estimates of change in birth weight per nanogram per milliliter of serum PFOA. We evaluated potential confounders as provided by study authors, one at a time compared with an unadjusted model. We adjusted the regression models by the covariates provided by the study authors if inclusion of the covariate changed the estimate by > 10% compared with the unadjusted model. We conducted computations for linear regressions, meta-analyses and heterogeneity statistics using STATA, version 12.1 (StataCorp LP). We used the "metaan" command in STATA with the DerSimonianLaird random-effects method for all metaanalyses to account for potential heterogeneity Risk of bias Risk of bias is determined for each individual stud~ Domains Recruitment strategy Blinding Exposure assessment Confounding Incomplete outcome data Selective reporting Conflict of interest Other bias Determinations (for each risk of bias domain) Low risk Probably low risk Probably high risk High risk Quality of evidence Quality is rated across all studies. Human evidence begins as "moderate quality" and may be downgraded (-1 or -2) or upgraded (+1 or+2) according to factors. k~. Downgrade factors Risk of bias across studies Indirectness Inconsistency Imprecision Publication bias Upgrade factors Large magnitude of effect Dose response Confounding minimizes effect Rating (based on all quality factors) High quality Moderate quality Low quality Strength of evidence Strength is rated across all studies. The final ratings represent the level of certainty of toxicity. Considerations ~- Quality of body of evidence Direction of effect estimates Confidence in effect estimates Other compelling attributes of the data that may influence certainty Rating (based on aft strength considerations) Sufficient evidence Limited evidence Inadequate evidence Evidence of lack of toxicity Figure 1. Overview of Navigation Guide systematic review methodology used for rating the quality and strength of the human evidence. Table 1. Summary of risk of bias designations for individual human studies. Risk of bias domain Low risk of bias designation~ Recruitment strategy Blinding Exposure assessment PecTelee cutomedita Confounding Incomplete outcome data Selective outcome reporting Conflict of interest Other bias Participant recruitment protects against selection bias Knowledge of exposure is prevented when assessing outcome Risk of exposure misclassification is minimized through validated methods heymissing ccm data rc sy ive iss Important potential confounders were appropriately accounted Any missing outcome data is not likely to introduce bias for All outcomes specified in methods have been reported Study free of support from individual or entity having financial interest in outcome of study Study appears to be free of other sources of bias (Fcrra.2o000m ;KimmSKecrak 2001; between cord and maternal serum at birth (Fromme et al. 2010; Kim SK et al. 2011; Soorbammm RA T aComplete criteria for each risk of bias designation are provided in Supplemental Material, "Instructions for Making Risk of Bias Determinations." 1030 1030 en 12a 10 4 +EntePgs VOLUME 122 I NUMBER 101 October 2014 . Environmental Health Perspectives 2255844..00000033 Senate of POA ar ai rows un Systematic review of PFOA and human fetal growth ci So ad a 950. my be consol df. ss oft hima dng 03 across studies (DerSimonian and Laird 1986). a a Snir: We used estimates of association between DE To Worn PFOA and fetal growth and the standard be ye oil Sn edo Teme ol sghof ey error from each study to calculate an overall En SL EES Wh effect estimate for the following fetal growth I FR SeIELR measures at birth: weight, length, head circumEL ference, and ponderal index (birth weight eg i wey int Spe cio of Be cs cmos divided by length cubed, multiplied by 100). itoma Low ot cos (lk ln se ch he To test statistical heterogeneity across the a a ata) Lay oS el study estimates, we estimated the variance Em aot corresponding to the between-study varii bn oy Why ability, and tested the null hypothesis that a er Erna the between-study variability was absent. on We used the Cochran's Q statistic for this EE mes test, which follows a chi-square distribution eo rs ttmates et a or rs with n - 1 degrees of freedom (df), where n Ba irene Sy otsoboe is the number of studies. We considered a ay J res p-value of _< 0.05 statistically significant. We Cy Lamy, calculated and evaluated the I2 test statistic e Ga ae hho mac ot vhe y mg bottchiosnv.e cha of c em n orrd [I2 = 100 x (Q - df)/Q], which is an estimate of the percentage of the variability among ea bes tS medsso ARESod rd study estimates that is due to heterogeneity Ee rather than chance (Higgins and Green 2011). EE Fe Tr We conducted sensitivity analyses to deterom eda at. Odd So BAST 00 mine the effect of including estimates from ets ma toSeal: 2 ref sons studies with differing characteristics or high Fret a risk ofbias. i, A irr Rating the quali{y ofevidence across studies. mE el The possible ratings for the overall quality of eyofcn re gh "md comhpl ian arndTeldor heae or omn ndopis the body of evidence were "high," "moderate," roy Same EE or "low." Following the approach estabEE lished by the Grading of Recommendations Th TanimmiinT air Assessment Development and Evaluation meats (GRADE) method used in the clinical scence formaking, evidence-debcaissioends prading or upgradingthe cadence, cons RESUIES sciences for making evidence-based decisions i oki oo i CRAB ps lt Ouedrd for medical interventions (GRADE Working EE a ame Group 2012), we determined the final rating al i Vto elh nds ee bio i 20 by assigrfing a prespecified initial quality rating ee of onc lh coating. oeda heSgc acsas n forthe.of she 17 ances cotathirnledof to the body of evidence, and then considering iT i oe Lr ya adjustments ("downgrades" or "upgrades") to Bo ets "Se he agof to lossro oa Bl Meso the quality rating based on the characteristics Pri milrti i oo dott rkrigid Jobo ke) ofthe studies constituting the body ofevidence Ee a ua (Balshem et al. 2011). GRADE guidelines, ro [tiie developed for clinical interventions, assign a experimental human studies an initial rating at oe of "high" and observational studies an initial HeSn BS. tri ay tyts rating of "low" quality (Balshem et al. 2011). Til Ioarra -- a However, there is variability in the quality of, amd nc oll chronhes em meee of studies, and not all observational studies el niray i2a03tTs Er Sr ds are low quality (Viswanathan et al. 2012). In a Ee AI, environmental health, human observational i data are usually the most directly applicable i vale Fordecommakin echt bey ite oa wes ilSv emt data available for decision making because Lo me? ethical considerations virtually preclude T a ay iiinn, Socpn sm amc.e human randomized controlled trials (RCTs) may be considered as "high" quality data if they are comparable to RCTs; however, this was not relevant to this case study, and thus the criteria for determining comparability with RCTs is not yet developed. We assessed the overall body of human evidence for downgrading and upgrading the prespecified "moderate" quality rating based on eight factors (Table 2). In addition, because we were primarily concerned with underestimating true positive associations in evaluating the potential for publication bias, we therefore considered a) whether the body of evidence was dominated by early studies with negative associations, particularly if the studies were small; b) whether studies were uniformly small; c) if there were enough studies to conduct an examination of patterns of study results (e.g., funnel plots) that might suggest publication bias; d) if we obtained unpublished studies with results that differed from published studies; or e) whether a comprehensive literature search was performed. Possible ratings were 0 (no change from "moderate" quality), -1 (onelevel downgrade), -2 (two-level downgrade); +1 (one-level upgrade), or +2 (two-level upgrade). The review authors independently evaluated the quality of the evidence and then compared their ratings and rationale for each quality factor. We resolved discrepandes between individual author ratings through discussion until consensus was reached. We were conservative in our judgments of downgrading or upgrading the evidence, consistent with the GRADE approach (i.e., we required compelling rationale) (Guyatt et al. 201 la). We recorded the collective rationale for decisions on the eight factors and for the final rating. Rating the strength of the evidence across studies. Rating the strength of the evidence across the human studies summarizes the human evidence; this summary will allow for the integration of human and nonhuman streams of evidence, ultimately leading to a concise statement about a chemical's toxidty (Woodruffet al. 2011a). We rated the overall strength of the body of human evidence based on a combination of four considerations: a) quality of the body of evidence (i.e., the rating from the previous step); b) direction of the effect estimate; c) confidence in the effect estimate (likelihood that a new study would change our conclusion); and d) other compelling attributes of the data that may influence certainty (Figure 1). We compared the results of rating the strength of the human evidence to the definitions specified in the Navigation Guide for "sufficicnt cvidcncc of toxicity," "limitcd evidence of toxicity," "inadequate evidence of toxidty," or "evidence of lack of toxidty" (Table 3). We based the rating categories for the strength of the evidence on those used by the International Agency for Research on Cancer (IARC 2006). We used criteria and considerations used by IARC (2006), the U.S. Preventive Services Task Force (Sawaya et al. 2007), and the U.S. EPA (1991, 1996) for the type of evidence considered for each of these strength of evidence categories. Review authors independently evaluated the strength of the evidence according to the same four considerations and compared their evaluations, resolved discrepancies by discussion, and recorded the collective rationale for derisions. Results Included studies. Our search retrieved a total of 3,023 unique records, of which 17 articles met the inclusion criteria (Figure 2). One of the 17 articles contained the results of two separate data sets (Savitz et al. 2012b), and hand searching the reference lists of the 17 included articles identified 1 additional study not yet indexed in the databases searched. Therefore, we included a total of 19 data sets in our analysis (Table 4). The studies Table 2. Factors for evaluating the quality of the body of human evidence. Evaluation factors Summary of criteria Downgrading factors Risk of bias Indirectness Inconsistency Imprecision Study limitations include a substantial risk of bias across the body of evidence. Evidence was not directly comparable to the question of interest [i.e., population, exposure, comparator, outcome (PECO)]. Estimates of effect in similar populations were widely different (heterogeneity or variability in results). Studies included few participants and few events (wide CIs). ihhnuumemnaavnnirooonbbsmseeerrnvvataattliioohnneaaalllthsstt.uuW ddiieeessbaaettga""nmmobodydeerrraaattitene"g" rLenbEepmpip rap quality to capture both the limitations of observational data and their recognized value in assessing associations between exposure EE and health outcomes and disease etiology in SI sT oSpe environmental and clinical sciences (Woodruff Publication bias Upgrading factors Large magnitude of effect vn Dose response Confounding minimizes effect `mamennedtnatSalluhthtuuommnaa2nn0d1da4ca)taa.o~orTr h""ennnaatuatvraealieleaxbxplpeeer,riiemmxeepnneetsrsi""- -- Studies were missing from body of evidence, resulting in an over- or underestimate ofafects fom mgenre. of true effects from exposure. The rating was upgraded if modeling suggested that confounding alone was Lt unlikely to explain associations that were judged to be of large magnitude. Ew The rating was upgraded if the relationship between dose and response in one or EE multiple studies and/or the dose response across studies were consistent. TR EC a Ber The rating was upgraded if the consideration of all plausible residual confounders I or biases would underestimate the effect or suggest a spurious effect when wwhoewed results show no effect. TRA WARTS Environmental Health Perspectives VOLUME 1221 NUMBER 10 I October 2014 won1031 264.0004 2584.0004 un rma Johnson et al. ei Ty TST stig covered the years 1988-2009, included popuCy Wt Sy lations located in nine countries, and ranged EE from 17 to 11,737 study subjects (Table 4). CEME ET EE Risk of bias assessment for individual Gr hie his sa studies. We concluded that there was generI RT CE ally low risk of bias across the 19 data sets Ee wr, or (Figure 3A). According to the Navigation ee En Guide criteria, we identified confounding, hs Loiwowmnah exposure assessment, and conflict of interest LT i Ee as the most common types of risk of bias EE raalallay (Figure 3B). Although we considered risk EL a a of bias separately for each outcome (birth I weight and other fetal growth measures), oe ess 4d mo He with veopct 10. Ped commschet cots 1malin) poe cominrashewsh the results did not differ with respect to i a outcome, so only one summary is presented Frohne SE LERe in Figure 3 (see also Supplemental Material, Ey Tables $3-$21). One exception was Maisonet ERT ei Deli et al. (2012) (see Supplemental Material, Table $13), for which we designated a higher risk of bias for fetal growth measures other than birth weight because of a large amount of missing data for outcomes other than birth weight in that study. Statistical analysis. We found no discrepancies in the data with respect to different data extractors. We made 13 requests to study authors for additional data for our meta-analysis. Six study authors responded; 3 provided the requested statistics and 3 provided individual-level data from which we calculated the summary statistics. We plotted continuous effect estimates (11 studies) to visually assess the range, precision, and dose response data for evaluating the relationship between PFOA and birth weight (Figure 4). A summary plot of all odds ratio A: E RT E amL ai r Table 3. Strength of evidence definitions for human evidence,a P-- s ---- Senor oil Strength rating f-- e -- Sufficient evidence of toxicity P r RCE r R e (19 biof bd ehand Limited evidence of toxicity rey BE EEE a E E E s T y T ,NL M hr nEi yatn y anae eay: Inadequate evidence of toxicity -- DD S a D E S n E er n rT E hr E Da, L nnull a l Soinamp e eoe e niee Evidence of lack oftoxicity Definition A positive relationship is observed between exposure and outcome, where chance, bias, and confounding can be ruled out with reasonable confidence. The available evidence includes results from one or more well-designed, wellconducted studies, and the conclusion is "unlikely to be strongly affected by the results of future studies."b A positive relationship is observed between exposure and outcome, where chance, bias, and confounding cannot be ruled out with reasonable confidence. Confidence in the relationship is constrained by factors such as "the number, size, or quality of individual studies" or "inconsistency of findings across individual studies."b As more information becomes available, the observed effect could change, and this change may be large enough to alter the conclusion. "The available evidence is insufficient to assess effects" of the exposure. The evidence is insufficient because of "the limited number or size of studies," low quality of individual studies, or "inconsistency of findings across individual studies."~ More information may allow an assessment of effects. No relationship is observed between exposure and outcome; and chance, bias, and confounding can be ruled cut with reasonable confidence. The available evidence includes consistent results from more than one well-designed, wellconducted study at the full range of exposure levels that humans are known to encounter, and the conclusion is unlikely to be strongly affected by the results of future studies.OThe conclusion is limited to the age at exposure and/or other conditions and levels of exposure studied. r Lg i s MS SII, TSuellbey For ealll sifo 'qhe Navigation 6uide rates the quality and strength of evidence of human and nonhuman evidence streams separately e as "sufficient," "limited," "inadequate," or "evidence of lack of toxicity," and then these two ratings are combined SE ny, STC UNC I to produce one of five possible statements about the overall strength of the evidence of a chemical's reproductive/ developmental toxicity. The methodology is adapted from the criteria used by IARC to categorize the carcinogenicity Ily C ma r s ir of substances (IARC 2006) except as noted. ~'Language for the definitions of the rating categories were either from or estimates for low birth weight (< 2,500 g) is presented in Supplemental Material, Figure S 1. We combined data from 10 studies in the meta-analyses of the association between PFOA exposure and measures of fetal growth. Within the 10 studies, there were 9 data sets on birth weight, 5 data sets on length, 4 data sets on ponderal index, and 4 data sets on chest circumference. The studies that were not included in the metaanalyses (n = 9; Table 4) generally reported a statistical estimate that was not combinable with the others. The majority of the studies reported a continuous regression estimate with PFOA as the independent variable and fetal growth as the dependent variable. If a study reported an alternate statistic such as an odds ratio, mean, or correlation coefficient and we were unable to obtain data from the authors, then the study could not be combined with the majority of studies in the meta-analysis (Table 4). From the meta-analysis of 9 studies (4,149 births) of birth weight, we found an overall estimate of-18.9 [95% confidence interval (CI): -29.8, -7.9] g birth weight/ng/mL increase in serum or plasma PFOA (Figure 5, Table 5). We did not find a high level of heterogeneity among the studies in this meta-analysis (Cochran's Q = 12.92; p = 0.12; I2 = 38%). We judged the study of Savitz et al. (2012b) to have "probably high" risk of bias for the exposure assessment domain based on its retrospectively modeled maternal serum PFOA (see Supplemental Material, Table S 18). However, because this judgment fell within the uncertain ("probably") arm and because others may make a different judgment about the risk of bias, we also conducted the meta-analysis including this study (Table 5). The addition of Savitz et al.'s estimate [from study II, Bayesian calibrated estimate of -0.185 g/ng/mL (95% CI:-0.313,-0.058)] to the meta-analysis did not change the direction of the overall assodation but reduced its adapted from descriptions of levels of ceRainty provided bythe U.S. Preventive Services Task Force levels of ceRainty regarding net benefit (Sawaya et al. 2007). CoB pepmboR r E I] Shenwiee semorpag iraoPFsOA Records identified {Rm |i JER RE GO iine through PubMed i SL NE | pt (n = 2,268) Unique records identified through toxicological web sites (n = 45) Unique records identified through Web of Science (n = 386) Unique records identified through Embase (n = 324) ( Ifo fl Ewb oTm L a luygge]] TSo iBm heemdn dtinnh(ene Records screened based on title and abstract review (n = 3,024) I E J | imee d, Full-text articles assessed for eligibility (n = 248) I | Er ng aud eFtong Studies included in qualitative synthesis (n= 18 articles; n = 19 data sets) I Bmrer Studies included in quantitative synthesis In = 9) Unique records identified through hand searching ~Lto(wn=nl) e? I Fie or hoi vested reso eeTh ary geousan ERY (baanFI f39%A 037T Fo . Figure 2. Flowchart showing the literature search and screening process. The primary goal of our search A re rr was to obtain comprehensive results; therefore, our search was not limited by language or publication FS CE LL date. The search terms for each database are provided in Supplemental Material, Table $1. magnitude from an estimated 18.9-g reduction in birth weight/ng/mL serum or plasma PFOA to a 15.4-g reduction (95% CI: -26.5, -4.3), and increased the heterogeneity (from an I2 of 38% to 72%) (Table 5). Only one study that we included in the meta-analysis for birth weight was assigned a high risk of bias for confounding (Fromme et al. 2010). This study was small and contributed litde weight (< 1%) to the overall effect estimate. Omitting the study of Fromme et al. (2010) from the meta-analysis reduced mtmahtaeteemddag118n8.i.9t9u-gderreooddfuatchateioonanisisnnobdbiairtnithohnwweferioiggmhht/nannggm/emsltLi.- serum or plasma PFOA to a 17.4-g reduction (95% CI: -26.8, -8.0) and reduced the heterogeneity (from an I2 of 38% to 27%). Fei et al. (2007) was the only study that we included in the meta-analysis that was assigned a high -1032 ---- VOLUME 122 I NUMBER 101 October 2014 . Environmental Health Perspectives 2684.0005 2584.0005 Systematic rein of PFOA a han fort oth Hu Systematic review of PFOA and human fetal growth Table 4. Summary of study characteristics evaluating developmental exposure to PFOA and fetal growth in human observational studies. so gten t"s Rut sows seersee"e TmToiOnr) aennemaa Source Fetal growth measuresa S---- i me Studies included in morn-analyses Toot BURA Mm Sheol TS Gm 8m 1 " Apelberg et al. 2007 BW, L, HC, PI Zend" BER Bohm Tme fmm RF i Chen et al. 2012 BW, L, HC, PI ies Si Dae ERD Maes aves 5 I Fei et al. 2007b BW REED oe HE dma EEE NMED WEN OX I Fei et al. 2008b L, HC, PI,CACd fe oy eum Sm 1 I Fromme et al. 2010 BW ESE afr & GeaCn maw vam hme I Hamm et al. 2009 BW, SGAd mean The S SIRO GRE oe CE I Kim S et al. 2011 BW RET Wife 8 SND WE WNL JR. 8 i Maisonet et al. 2012 BW, L, PI Births (n) Location Study period 293 429 1,400 1,400 33 252 43 422 Baltimore, MD (USA) Taipei, Taiwan Denmark Denmark Munich, Germany Edmonton, Canada South Korea Great Britain 2004 2005 2004 1996 2003 19965003 2007 2008 2005 2006 2008 2009 1991 1992 Wenn NUCRGY @ Sw ARES Menino 13 " Washino et al. 2009 BW, L, HC, PI, CCd 428 hea, WEE 8 To Neem rn 1 " Whitworth et al. 2012 BW, SGA,dLGAd 849 Aan os Studies excluded from morn-analysis rer Arbuckle et al. 2012 BW 100 adn WG Gham ER Maen De 3 Cymer Halldorsson et al. 2012 BW 665 Sapporo, Japan Norway Ottawa, Ontario, Canada Aarhus, Denmark 20025005 2003 2004 2005 2008 1988 1989 e star an Wo 0 Siw mm Cows Ge 11 OhpiOknMame Kim SK et al. 2011 BW 17 Seoul, Korea 2007 Sample matrix Measurement timing Median PFOA (ng/mL) Reason for omission from meta-analysis Cord serum Birth 1.6 NA Cord serum Birth 1.7 NA Maternal plasma 1st trimester 5.2 NA Maternal plasma 1st trimester 5.2 NA Cord serum Birth 1.4 NA Maternal serum 15-16 weeks 1.5 NA Cord serum Birth 1.2 NA Maternal serum 15weeks 3.7 NA (median) Maternal serum 23 35 weeks 1.3 NA Maternal plasma 17 weeks to term 2.2 NA Cord serum Maternal serum Cord serum Birth 30 weeks Birth 1.6 BW is not the dependent model variablee 3.7 Only mean BW per PFOA quartile given 1.1 Only PFOMBW correlation given Monroy et al. 2008 Mcdse w oWs) mE Were Mune W Camel Nolan et al. 2009 Sed WWE mDaawe OEE = Aas Germs 6158He outtuT to Savitzetal. 2012a Sean Wm ame WEN Nepean 1 Aras Savitz et al. 2012b Ei Cn mm aT (study I) Sawdmm WU amie WI omy Dim 72103 ieda rem Savitz et al. 2012b a pti fenst) Em (study II) Sess Wm ga hee TRAN Wen hwns 22 Orhaesnd Stein et al. 2009 BW 101 Ontario, Canada 2004 2005 Cord serum Birth 1.6 BW is not the dependent model variablee BW 1,555 Ohio (USA) 2002 2005 Water service area Preconception or NA Categorical ecological exposures during pregnancy BW 10,189 Ohio and West 1990 2006 Retrospectively During pregnancy 6 15.9 High risk of bias for exposure Virginia (USA) modeled maternal assessment; only dichotomous serum outcome of low BWr BW 8,253 Ohio and West 1990 2004 Retrospectively During pregnancy 7.7 High risk of bias for exposure Virginia (USA) modeled maternal assessment; (included estimate serum from Study II in sensitivity meta-analysis)r BW 4,547 Ohio and West 1990 2004 Retrospectively During pregnancy 7.2 18.3 High risk of bias for exposure Virginia (USA) modeled maternal assessment; (Included in serum sensitivity morn-analysis)r BW 1,589 Ohio and West 2000 2006 Maternal serum Up to 5 years 21.2 Only dichotomous outcome of Virginia (USA) postnatal low BWr Ra SoBe er Ee aT ee ee ma Fei Abbreviations: AC, abdominal circumference; BW, bir~h weight; CO, chest circumference; HC, head circumference; L, length; LGA, large for gestational age; NA, not applicable; PI, ponderal index; fay SGA, small for gestational age. AEE orre crt m0 ep Se i et sea nail fetal growth measures at bir~h, bFei et al. (2007) and Fei et al. (2008) are studies of the same population. ~Because the analysis of PI was stratified, it was not combined in the meta-analysis of PI. dOnly two studies measured SGA, and only one study each measured AC, CC or LGA; no meta-analysis was conducted for these measures, eSerum PFOA was the outcome variable estimated in the Be re teEte Ed model, fBecause the studies af Nolan et al. (2009), Savitz et al. (2012a, 2012b), and Stein et al. (2009) were conducted in the same geographical area, participants may overlap; therefore, we did not consider these studies for simultaneous inclusion in meta-analysis. n Sr"SALLI s Low risk Bia) Probably low risk Probably high risk ~ LEYHigh risk [prt Apelberg et al. 2007 Arbuckle etal. 2012 SET Chen et al. 2012 Ee Fei et al. 2008 mem Fei et al. 2007 are Fromme et al. 2010 Halldorsson et al. 2012 ---- Hamm et al. 2010 KimS et al. 2011 men Kim SK et al. 2011 wilh, Maisonet et al. 2012 pprreya Monroy et al. 2008 po wm od L cmeP [or y =o000: Confounding EE EFEH oe 5E5H: Incomplete outcome data Li I -- Selective outcome reporting [i ii -- I oo2d ocnoneA tesn I[S EE RC S05= Other sources of bias i:" ii ." '" i ~ ~ ~ ~ ~ ~ I I I I I I Nolan et al. 2009 Savitz et al. 2012a rmanll pl Savitz et al. 2012b (study 1 ) sim=e fEe S Savitz et al. 2012b (study 2) 0 25 ~50 Percent 75 100 Stein et al. 2009 Washino et al. 2009 wn ET Whit~vorth at al. 2012 Ft Sryof hi fb es yl so 1) ch cd sn oly Ad gn ages Figure 3. Summary of the risk of bias judgments (low, probably low, probably high, and high risk) for each included human study (A) and (B) given as percentages nde es Fn nf Gb dC tsHorr A hr, across all included human studies. Risk of bias designations for individual studies are assigned according to criteria provided in Supplemental Material, "Instructions RLSobers for Making Risk of Bias Determinations." Entec ot 2 ee 4 Environmental Health Perspectives VOLUME 122 I NUMBER 10 I October 2014 1033 1033 22658844..00000066 un hon ets. Johnson et al. of io foc ort, Opi: wi aose cone otowl to vip owell cond risk of bias for conflict of interest. Omitting a (olmaisoEs omgenl that study increased the magnitude of the asso- et ssi abo FO af Dheho vas ms i i hsp ciation from an estimated 18.9-g reduction in Ee birth weight/ng/mL serum or plasma PFOA to iy dy elii paotr pte ppt a 22.7-g reduction (95% CI: -36.9, -8.4) and Donn en did not change the heterogeneity. a Ee a We found through meta-analysis that FEO sp wo oat d wi bc ted eons So neoi od PFOA exposure was also associated with a Ea lower values of other fetal growth measures i 1 ng ocean becpats Ve sao vl a la 91 at birth (Table 5). A 1-ng/mL increase in FOAr Si iwy i n 200 Ved serum or plasma PFOA was associated with a hangs ooo 313 pgpv rl plc fr dt og a-0.1 (95% CI: -0.1, -0.02) cm change riln 201 03 CHAE, oni OOo OAS Bo. in birth length, a -0.01 (95% CI: -0.03, dinold3-0 cng iso pod nn a FORCompan 0.01) change in ponderal index, and a -0.03 Ln i (95% CI: -0.1, 0.01) cm change in head EE a circumference. Individual study estimates a em on included in these analyses, and weights al ak ae hd olin of pgm pote oc Jon ren (onthe pe assigned to each, are provided in Supplemental frei eolocind Cobos So 000 p i Material, Tables $22-$24. tact ol ctw 335 de os cio oo Snell Cor2n159s8, We explored the potential effect that a new dy gh oe os of ih ct HAAR 0 ret ha 2,Second, 013,14 390), study might have on our meta-analysis ofbirth weight to assess our confidence in our overall conclusion that there is an inverse relationship between PFOA and birth weight. First, we determined a hypothetical effect estimate necessary to shift our meta-analysis under two scenarios: a) that the 95% CI of the metaanalysis overlaps zero (becomes statistically insignificant), and b) that the meta-analysis effect estimate is greater than zero (moves in the opposite direction). We assumed that the new hypothetical study would have a standard error of 5.18 g/ng/mL, equal to the smallest in our group of studies (Fei et al. 2007). By inserting the values for the hypothetical study's standard error and effect estimate into the meta-analysis, we found that another new study would have to have an effect estimate of 18 g/ng/mL in the positive direction in order to enlarge our CIs to overlap zero, and 225 g in the positive direction to shift our effect estimate to greater than zero. Second, to investigate how residual confounders might influence the meta-analysis, we conducted a separate meta-analysis using only unadjusted estimates from all the studies. Because Hamm et al. (2010) provided only an unadjusted estimate and p-value on a natural log (In)transformed scale, we made a log transformation for this study to obtain the untransformed estimate, and the standard error was calculated from the ,0-value (Altman and Bland 2011; Higgins et al. 2008). We found that the overall unadjusted estimate for change in birth weight was -30.9 (95% CI: -49.3,-12.5) g/ng/mL increase in serum or plasma PFOA. Compared with the effect estimate from the unadjusted meta-analysis, the adjusted estimate ( 18.9 g) was closer to the null but more precise with less heterogeneity (unadjusted analysis: Cochran's Q = 23.27, p = 0.002, I2 = 66%; adjusted analysis: Cochran's Q = 12.92, p = 0.12, I2 = 38%). Study ERR Apelberg et al. 2007 Apelberg et al. 2007 Apelberg et al. 2007 Eo Apelberg et al. 2007 Apelberg et al. 2007 Chen et al. 2012 mw Chen et al. 2012 SET Fei et al. 2007 Rg Fei et al. 2007 ET Fromme et al. 2010 PFOA increase em In ng/mL In ng/mL 25th to 75th percentile 25th to 75th percentile ng/mL IEIn ng/mL ng/mL ng/mL ng/mL ng/mL osPFOA range (ng/mL) 0.3~.1 0.3~.1 1.22.1 1.22.1 0.3~.1 geomean(stdev) = 1.84(2.23) EIST geomean(stdev) = 1.84(2.23) BR < LLOQ 41.5 NE< LLOQ 41.5 --0.54~4.20 Covariatus ga ga, ma, bmi, race, par, sink, sex, ht, wig, dia, hyp 9a mn ga, ma, bmi, race, par, smk, sex, ht, wtg, dia, hyp ga, ma ga, ma, bmi, par, cot, sex, edu, delmode paga, ma REET ga, ma, bmi, pa r, smk, sex, SES, gabd ga, ma, bmi, pa r, smk, sex, SES, gab& PFOS -None mr RE w4i pigy Hamm et al. 2010 Hamm et al. 2010 Hamm et al. 2010 Bi Hamm et al. 2010 msm Kim S et al. 2011 In ng/mL ng/mL lstto 2nd tertile (ng/mL) Brey lstto 3rd tertile (ng/mL) -ng/mL Ma isonet et a I. 2012 Ma isonet et a I. 2012 i Maisonet et al. 2012 Nolan et al. 2009 nm Ge Nolan et al. 2009 1st to 2nd tertile 1st to 3rd tertile ng/mL Lowto mid exposure Lowto high exposure <LOD <LOB < LOB Swe <LOB 18 18 < 1.1 to 1.12.1 <1.1to>2.1 18 wan 0.&3.23 < 3.1 to 3.14.4 < 3.1 to > 4.4 21.0 16.4 NA NA SERGERRE ga, ma, race, grav, mwt, matht, smk, sex ga, ma, race, gray, mwt, matht, smk, sex ga, ma, ra ce, grav, mwt, matht, smk, sex ga, ma, ra ce, grav, mwt, matht, smk, sex a ga, ma, par ga, bmi, par, sink ga, bmi, par, smk sno ga, bmi, par, smk ga, ga2, ga3, ma, race, sex, SES ga, ga2, ga3, ma, race, sex, SES ie ptmipemimi Ce 53 Dm S avitz et a I. 2012b, study II S avitz et a I. 2012b, study II S avitz et a I. 2012b, study II S avitz et a I. 2012b, study II 25th to 75th IQR (In PFOA) 100 ng/mL PFOA lst/2ndquintileto3rdquintile lst/2nd quintile to 4th quintile 1.92 100 ng/mL 3.9 <8.9to8.9 <19.6 3.9 < 8.9 to 19.643.1 rr S avitz et a I. 2012b, study II Washino et al. 2009 Washino et al. 2009 lst/2ndquintileto5thquintile Iogl0PFOA Iogl0PFOA 7]3.9 <8.9to53.1 1897.0 ND 5.3 ND 5.3 ga, ma, par, edu, smk, exposyr, state ga, ma, par, edu, smk, exposyr, state ga, ma, par, edu, smk, exposyr, state ga, ma, par, edu, smk, exposyr, state = ga, ma, par, edu, smk, exposyr, state ga Sn ga, ma, bmi, race, par, smk, sex, edu, bsp o=s et, o Ci EnIJ im aa Washino et al. 2009 Whitworth et al. 2012 Whitworth et al. 2012 Whitworth et al. 2012 ng/mL ng/mL 1st to 2nd quartile 1st to 3rd quartile ND 5.3 median (IQR) = 2.2(1.64.0) < 1.65 to 1.652.24 < 1.65 to 2.254.03 ma, ga 9a, ma, bmi, par ga, ma, bmi, pa r ga, ma, bmi, pa r wisyhy Whitworth et al. 2012 1st to 4th quartile < 1.65 to > 3.03 ga, ma, bmi, pa r EE a Estimate z, I~ Estimate included in mata-analysis [] I~ Estimate that can be used to evaluate dose response 500 400 300 200 100 0 100 200 300 400 Change in birth weight (g) J Figure 4. Summary of data extracted from all studies of PFOA exposure that included continuous outcome of birth weight. The PFOA increase is the exposure contrast being compared in each study. Squares represent data for which there was an exposure gradient that can be evaluated in considering dose response a nt enon fhe in upgrading the quality of the evidence. Error bars indicate 95% CIs. Savitz et al. (2012b) presented additional alternative estimates based on different modeling se te eG ee Eo ho et i et assumptions that are not included here due to space limitations. Covariate abbreviations: bmi, body mass index; bsp, blood sampling period; cot, serum cotinine; delmode, delivery mode; dia, diabetes; edu, maternal education level; exposyr, year of exposure estimate; ga, gestational age; gabd, gestational age at blood ran ae Stee a mSOt Y, E FAO PA:BSE SalPAY draw; geomean(stdev), geometric mean (geometric SD); grav, gravidity; ma, maternal age; ht, maternal height; hyp, hypertension; mwt, maternal prepregnancy EA tai.sG o eptput FL seseass or ak SE So SH n AT 2: ,A weight; NA, not applicable: NB, not detected; par, parity; PFOS, serum perfluorooctane sulfonic acid; SES, socioeconomic status; sex, infant sex; smk, smoking i Ab en: ot oe ac si hs So Vo oom Po) status; state, state of residence; wtg, maternal weight gain during pregnancy. This figure was created using Meta Data Viewer (http://ntp.niehs.nih.gov/help/ browsers/metadata/index.html) (Boyles et al. 2011). 1031034 i o-------- VOLUME 1221 NUMBER 101 October 2014 . Environmental Health Perspectives 26040007 258410007 Sytem revi of FOR and aman fetal grant Systematic review of PFOA and human fetal growth onQduoywofsheobr pdgorfadeidhee.rWienddof U ing un ndacximu rcs. Ad loui ghhe at fc se as,dwc cxombemdivcic dmoore not downgrade or upgrade the rating of Comatose am foe ePE Io Emberetge eames Siwearmvmged the human evidence on any of the criteria, Tekin naoer thy f ths human acu rn teCt lrnswil mre hy woud, eben resulting in an overall quality of the human hin raof ndogu (Te. 2nd Wht we subtalar conrad wh poe dun evidence rating of "moderate" (Table 6). i sok ao s abi es ouwhan wi: omth ooundo. Mt otis dom There were not enough studies to utilize a o or l oe s ion my Brcba t dorct oin nt rove aFd Somme funnel plot analysis to assess publication bias. homeswed oe sy gm of th CRADEsph oma any onto ani of However, we did not find any suggestion of eblcaion at aig ut oad net imma Soa cmd sedowtdon nd ne mre publication bias according to the considerarng lpg He pe tions we assessed, that is, we conducted a Com ertrsai h mde found ince (a1n 2017)n Bo his ficsof rd comfounin comprehensive literature search and found Soh arth os Tonio ss htcme sr hrm vA, studies of variable sizes and funding sources hey con Figs with generally consistent findings. Seen ofthebyof dency wmann Strength of the body of evidence rating. Our sag fhe cnc commons 1 Our strength of the evidence considerations Tn wi] aim sum wcrc as follows: Tiyof da er mn l. Quality ofbody of evidence: moderate Dicom cam dog = di av Direction of effect estimate: decreasing birth wweieigghhttwwiitthhiinnccrreeaassiinnggeexxpposousruere ttoo PPFFOOAA +Conn aecen: ally i Confidence in effect estimate: unlikely that new yo ean ctce ua SR. a new study would have an effect estimate vodmate herb he me ] that would make the results of the metail ei mgm ns H [E-- analysis null or statistically insignificant ral emt Other compelling attributes of the data that rrar memes ed may influence certainty: none. Vi Sopa sh rans she | Fa We compared these considerations to the hry Te micah g definitions in Table 3 and conduded that there rat amet: tap mes] sainssnnn was "sufficient" human evidence that exposure PRO grove hn to PFOA affects fetal growth in humans. ey ov J imma Discussion Based on ths fi pplcion of he = = = Based on this first application of the fost butimatid sty Navigation Guide systematic revie~v methoio cohtn Shre pee ts fe ir grst 140d ho lt ma dology, we concluded that there was suffi- an dnc of an acon bene Amp RAS a ah FOR FaSh CHETh cient evidence of an association between FON pone and red ol nh BEEROe EBD AG 43 3 ts hs eB rsof PFOA exposure and reduced fetal growth. Bm I TALE Br Our conclusion that the human data were i vob nm" guy ST EI 0N rr dee pe rtand sufficien~ was based on "moderate" quality eevviiddeennccse,, 3a mmeecta--aannaalylsissceusitmimataitinngg a3 ddeeccrree- ncn th eight non PEO fut (M0 marl 9 Boh i, dt Ao 1 hh Fo co ment in birth weight in relation to PFOA Coot hh ddsh te con a, ob, VR ByHwkg A GovFt a exposure in which we judged that the confiToni me si do oh. ot Sta, Eo, Sep Te dence bounds were narrow, and our confi- dence that a new study would be unlikely to et yt uma ntLOY vrsbran aWh eo have an effect estimate that would change the coll dlc cmoftdo cams eat Let os eo eb rdeca , overall effect estimate of the meta-analysis. The smallrmecsanaoifyotchesr el Sapporo Pia A ay The smaller meta-analyses of other fetal Ch an aan growth measures were also consistent in the Fitness btSreyst sstego ps se direction ofthe effect estimate. Sne t Mb MRSE e de stge etmees set man The existence of unmeasured confounders ikea beposible wih avatar TE YY will always be possible with observational priepiifedwriter va. J i. Re studies, but we decided to not let this underin ur ky ke tenn S prp i CL CodwnB mine our ability to make a statement about he salable a. Aion ormaton wim mas mo x the available data. Additional information hac areconandsholdinomFare rysis that may arise can and should inform future oWen litwtce ole org vm momen wm es 0 conclusions. We felt that we could rule out oat wh rie mienecr Fh evtmter waio)eUf i _Aomn{meamrm WRom8 confounding "with reasonable confidence" (Table 3, definition of "Sufficient evidence ctor ee ae Re em Epa ee IEE of toxicity") based on our assessment of the bled, We did oo fd any oxide, a Er no Ahr available data. We did not find any evidence `sing sani roid conn, Set es Eo SA yy suggesting substantial residual confounding. tthe of a elcfg aps no Se RD et tie Lo To get an idea of how residual confounding me FS et a Oe Ba HT brs may influence the effect estimate of the Sadao bowen TRO cxpour and 22 EH or ST RE association between PFOA exposure and Fnwe wecondsecamod Se SL okey BR Ws birth weight, we conducted a meta-analysis using unadjusted estimates. Although the unadjusted meta-analysis had a larger effect estimate (i.e., adjusting for confounders attenuated the estimate), the CIs were wider and there was substantial heterogeneity among the unadjusted studies. As in the Bradford Hill considerations for causation, the GRADE approach considers consistency in effect estimates when evaluating confidence in the association and rating the quality of evidence (Schunemann et al. 2011). Because the effect estimates were more homogeneous after adjustment, we considered it more likely that the adjusted estimate was closer to the true assodation. If adjustment resulted in more heterogeneity, we would have been more concerned with potential residual confounding. Although this analysis does not prove that residual confounding does not exist, it did not uncover any evidence of unmeasured confounders, and we considered this as support for our interpretation that substantial effects of residual confounding are unlikely. Apelberg et al. 2007 q]4.0 ( 125.2, 2.7) 2.9% Fei et al. 2007 10.6 (208, ~].5) 27.5% Hamm et al. 2010 ee ri | Washino et al. 2009 12.4 (~2 8, 8.0) 16.0% asenaen 22.6 (q]0 8,15.6) 6.7% Fromme et al. 2010 213.0 (~123.7, 2.2) 0.3% Kim Set a I. 2011 154.1 ( 83.5, 391.7) 0.2% Whitworth et al. 2012 28.4 (q]0 3, 3.5) 8.9% Maisonet et al. 2012 44.2 (~48, 13.5) 15.8% Chen et al. 2012 11.2 (260, 3.7) 21.7% Overall effect 18.9 (29 8,~.9) 100% 400 200 0 200 400 Effect size Figure 5. Results of meta-analysis for birth weight (n = 9 studies, 4,149 births) shown as effect estimates [change in birth weight in grams per nanogram of PFOA per milliliter of serum or plasma (95% CIs)]. The percentages are weightings of the individual studies in the meta-analysis according to the inverse of the variance, and the sizes of the boxes are scaled accordingly. The dashed line indicates the overall effect estimate derived from the DerSimonian-Laird random effects meta-analysis, and the diamond gc indicates /B = 38%. stmates were adusied 0 folows Apeber et af.(07) maternal age and the 95% CI of the overall effect estimate. Heterogeneity statistics: Cochran's Q Estimates were adjusted as follows: Apelberg et al. (2007): maternal age and g=gee1ss2tt.a9at2i;otnpia=olan0ag.ag1ee2l.;; Fei et al. (2007): maternal age, gestational age, quadratic gestational age, infant sex, socio-occupational status, parity, smoking, prepregnancy body mass index, and gestational week at blood draw; Harem et al. (2010): maternal age, gestational age, race, gravidity, maternal prepregnancy weight, maternal height, smoking status, and infant sex; Washino et al. (2009): maternal age and gestational age; Fromme et al. (2010): unadjusted; Kim S et al. (2011): maternal age, gestational age, and parity; Whitworth et al. (2012): maternal age, gestational age, prepregnancy body mass index, and parity; Maisonet et al. (2012): smoking, prepregnancy body mass index, previous live birth, and gestational age; Chen et al. (2012): maternal age and gestational age. Table 5. Summary of meta-analyses for associations of fetal growth measures with serum or plasma PFOA. Fetalgrowth measure No. of studies No. of births Effect estimate from meta-analysis [per ng/mL(95% CI)] p-Value for /2 Cochran's Q heterogeneity (%) Birth weight (g) 9a Birth weight (g), 10b sensitivity analysis Length (cm) 5c Ponderal indexd 4e Head circumference (cm) 4f 4,149 8,501 2,853 1,510 2,497 18.9 (~9.8, ~.9) 15.4 (~6.5, ~4.3) 0.06 (43.09, 43.02) 0.01 (43.03, 0.01) 0.03 (43.08, 0.01) 12.92 31.91 3.03 8.03 4.05 0.12 38 0 72 0.55 0 0.05 63 0.26 26 Individual study estimates for outcomes other than birth weight are provided in Supplemental Material, Tables $22-$24. aMeta-analysis (n = 9 birth weight studies) includes Apelberg et al. (2007), Chen et al. (2012), Fei et al. (2007), Fromme et al. (2010), Hamm et al. (2010), Kim S et al. (2011), Maisonet et al. (2012), Washino et al. (2009), and Whi~orth et al. (2012). ~Sensitivity analysis: Meta-analysis (n = 10 birth weight studies) includes the same studies as included in the 9-study metaanalysis plus an additional estimate from Savitz et al. (2012b) (high risk of bias for exposure assessment). %leta-analysis for length includes Apelberg et al. (2007), Fei et al. (2008), Chen et al. ',2012), Maisonet et al. (2012), and Washino et al. (2009). #Ponderal index equals birth weight divided by length cubed, multiplied by 100. eMeta-analysis for ponderal index includes Apelberg et al. (2007), Chen et al. (2012), Maisonet et al. (2012), and Washino et al. (2009). 'Meta-analysis for head circumference includes Apelberg et al. (2007), Fei et al. (2008), Chen et al. (2012), and Washino et al. (2009). noche 2 we 4 Environmental Health Perspectives VOLUME 122 I NUMBER 101 October 2014 1035 1035 | 22558844..00000088 Bn Joon Johnson et al. a -- We also considered alternative hypotheses ie rly vnFOXSpon Gomer fo me, dod bt a duane oe. Heth for the relationship between PFOA exposure nd i ahs Fo ant a bot pttthe pda psy vedo hm wi and birth weight. For instance, an author onclicso k m. Seven ok phndpmol beseof encua 0 bly of one of the studies included in our metani orlth he pets Sin ep har cp in Or cn Sot her anh analysis proposed that the pharmacokinetics ee ey op macs Seong Seti ori 2h i Ae ot kn m ot of PFOA during pregnancy may influence the oni enPRON yrds les thtme aca ins, (Ste2007 ys sis olsents. relationship between PFOA body burdens and Te eh cht oa mo dt te So id or f La ca. to becspores Htdamsof fetal growth such that associations may be due ns cnaey htrtc0af 2045Oval ve oan kdand vn lyro nd bi wc fo acl to reverse causality (Whitworth et al. 2012). |Wpptomytumeiekcip inl hpi aphid That is, mothers of lower-birth-weight babies pe ot ve e.Cpa. an on seoben moan ud,whch doo rr oo might experience less plasma volume expannf oboe cs e PRON. oh ad amr rainTh.s, carahl cai,o Kp sion and therefore reduced dearance of PFOA Te ma eat Eke Gps 1 ostowied gec obee through glomerular filtration. To investigate he Pot f ybol ht oav io e ws FOR. te bof ot omg ri OE the plausibility of an alternate hypothesis of en smi we hot ins aponr snotgh um bind, he Nomio. Cob aessens reverse causation, we searched for evidence on the relationship between fetal growth and glomerular filtration rate, including relationships within the hypothesized causal pathway (i.e., between fetal growth and plasma volume expansion, and between plasma volume expansion and glomerular filtration rate) (for a list of studies that we systematically reviewed, see the Supplemental Material of Lam et al. 2014). Overall we found limited and inconsistent data that were inadequate to draw conclusions on the association between fetal growth and glomerular filtration rate. Thus, although we did not find evidence to suggest that the observed assodation between PFOA exposure and fetal growth can be explained, 180 mafia yf oc odsehof ce POA tlgut foolcied Bo fb ddsoped Table 6. Summary of findings, quality of evidence, and strength of evidence for PFOA and fetal growth,a Tar ory or cpm apo ROA Quality factorb Ratingc Basis W Be W Pep W e Note pam ni ia rosa ale Downgrade Risk of bias across studies iicss A 0 tEd atee nna a tonm SEmSatE" lfDpooEnoOdiNlhithaergougthhhagstrNoowoualnfsdawaNotiheagarhcy3ohnen0xay0pmio%isSSneawodtiibohtno Indirectness There is no indication that there is substantial risk of bias across the body of available evidence, particularly for the studies included in the meta-analysis. 0 The studies assessed population, exposure, and outcome of interest. wholly or partially, by reverse causality, we cannot disprove this hypothesis. Nevertheless, we derided at this time there was no compelling evidence of reverse causation to justify altering our conclusions about the strength of the evidence. As others have pointed out (Savitz 2007), future studies should attempt to better separate biological determinants of body burdens and birth weight from a causal effect. In addition, experimental animal studies, in which dosing prior to outcome assessment precludes reverse causality, support our conclusions about the human data. On the basis of our companion review applying the Navigation Guide systematic review methodology to the nonhuman evidence, we conduded that there is sufficient evidence that fetal developmental ~xposure to PFOA reduces fetal growth in animals (Koustas et al. 2014). We also considered that studies of the population that was highly exposed to PFOA through groundwater contamination found little evidence of an association with low birth weight (Nolan et al. 2009; Savitz E er Ta ra ny reviirhDareeaes hfoemdmtaisbol riofobithcwo eag Soi Inconsistency Kim etd201 es rs id GOCSE theconstcaleiofbnircu hweiogh u (Savsi 0 With the exception of two small studies (Fromme et al. 2010; et al. 2012a, 2012b; Stein et al. 2009) and on Kim S et al. 2011), results across studies are generally consistent the continuous scale of birth weight (Savitz in the magnitude and direction of effect estimates. The results of the meta-analysis for birth weight do not appear to be strongly et al. 2012b). However, these studies differed influenced by an individual study. The results of all four meta- from the studies included in our main meta- ee led mesru.Si th op.cetcama analyses for change in the fetal growth measures are consistent analysis with respect to exposure estimation as iin i rtasmea U nh ib ckna nSpmorbedok Imprecision rans Oe s CTEbip A e Tn p e TTLahsE TpmSooAmleopfeivnnl,dnpd pooaeurp)npoafereten,sme Publication bias in the direction of overall effect estimates. described in the risk of bias assessment; that 0 We judged that the CI of the meta-analysis for birth weight is is, these studies estimated exposure based on sufficiently narrow. residence (ecological exposure), retrospective 0 We found no reason to suspect publication bias. The search was comprehensive, and the studies were generally consistent modeling of several parameters, or maternal among their findings, regardless of size or funding source. postnatal exposure, and these studies primarily ut EET Upgrade examined odds of low birth weight (< 2,500 g) tes oestrous be a han nb weg ona Large magnitude of effect 0 We did not consider the estimated effects large. rather than a change in birth weight on a Ee Sos nyc comin ole Wed okcontac Dose response 0 Several studies in which association was modeled by categorized continuous scale. We did not conduct a meta- Crtns 0 Veem daassomvaoy t sswatatssnt bbosRowi foonbssms iab(deso eipohspo lwainan) Confounding minimizes effect tani oss ee Pp bt weno OOvveeranllcquoaltityooffmevidiencce (inetitiiall 0 MMooddeerraattee incremental exposure showed evidence of a dose response SNSN Ol relationship, but review authors agreed that the evidence was not compelling enough for an upgrade. We did not find evidence to suggest that possible residual Moat +1 moda.(aseweero gga or confounders or biases would reduce effect estimate. Moderate + (0) - moderate. (There were no upgrades or analysis with odds ratios for low birth weight pbpreocvraiudseoedtstohvhiifsseimwmeaesdsatsuuudrerieee3sadnn(ddthbrbeeeceapucsoepaaualcuacotonisnottniienns).- uous change in birth weight provides more iinnffoorrmmaattiiocsn thhannddiichotomized bbiirtkhwweieigghh.t. am pas an teea ea, bocwondeo 2rmwsa,s rating is "moderate") downgrades to change quality from the initial rating). We did, however, conduct a meta-analysis SEW Wee Rn hag tm fo Summary of findings from NA We found decrements in fetal growth associated with PFOA including an effect estimate from one of the a rt Jo hilar ig meta-analysis Soman Sofa terap, or ato rol ogo, Summary of qualitative findings foo e r--r Te on ma e roTb le, i ne ore 012and0undmira Strength considerations Bits WM bscmetus cup ooy siofmPFOdsAeonmap6l]egoeah y cbce Quality of body of evidence Direction of effect estimate exposure (see results from meta-analyses in Table 5). studies that retrospectively modeled exposure NA Studies not included in the meta-analyses presented mixed results, (Savitz et al. 2012b) and found minimal mostly insignificant associations between PFOA and fetal growth (Figure 4; see also Supplemental Material, Figure $1 ). change in the results (Table 5); these results did not change our conclusions. NA Moderate NA Birth weight decreased with increasing exposure to PFOA. Although the magnitude of the effect estimate of PFOA on fetal growth may not be EENIEIEL, WN DICT Smidorndledemdi orci Confidence in effect estimate NA It is unlikely that a new study would have an effect estimate that considered large at the individual or clinical Ser ra i oi. lk rant chsilo would make the results of the meta-analysis null or insignificant. level, it is important to consider implications orem tepoplAmaimi nt,t Other compelling attributes of the data that may influence certainty Ota tories Ses. f tone ns ve lon e t Se ecsrs Spe pron lingi e 20r 12, s From Overall strength of evidence NA None Sufficient Based on our analysis and interpretation of the evidence, we concluded that there is a positive association between exposure and outcome, and we believe with reasonable confidence that chance, bias, and confounding can be ruled out as an explanation at the population level. A relatively modest and subclinical effect size may be associated with substantial population burden if the exposure is prevalent (Bellinger 2012). From the meta-analysis we found an overall estimate CEASE Ss OiCL 08, 79) 3b for the association. The available evidence includes results from of-18.9 (95% CI: -29.8, -7.9) g birth yet kc, in ighlng nee1 to las one or more well-designed, well-conducted studies, and we Ee rt lr] believe that our conclusion is unlikely to be strongly affected by re lotse n HSU RS Noon Pamir Say 20-004 the results of future studies (see the definition in Table 3). Tom = ie Sag lg in sm NA, not applicable. ene Sh ee e RO om To aSee the Supplemental Material of Lam et al. (2014) for additional details of rating quality and strength. ~'Criteria for downgrading and upgrading quality are presented in Table 2. CA "0" quality rating indicates there were no upgrades or 8 Gof prea women (Wood downgrades for each factor being evaluated across the body of evidence. weight/ng/mL increase in serum or plasma PFOA (Figure 5). In the National Health and Nutrition Examination Survey 2003-2004, there was a 3.0-ng/mL difference in serum PFOA between the 50th and 95th percentiles of pregnant women (Woodruff et al. 10361036 oe12 0 or 01 EntHo egies VOLUME 1221 NUMBER 101 October 2014 . Environmental Health Perspectives 22558844..00000099 tematic ew of PO and human fetal roth nu Systematic review of PFOA and human fetal growth 2010, The gin. cus, mold nd wer lc 1 cade fn dy he ctGi l ndeo "i"n kof 201 lb). This 3.0-ng/mL change, multiplied NTE ton on os la ok cane by the meta-analysis result of-18.9 g/ng/mL en rl. = He oassniytc rill s uti: Seveassant Ss ema PFOA, yields a 56.7-g change in birth weight Scr hen pcre To ie 4 Jabs sma of he i, comin mr ht tc ct yo across these percentiles. To give a public Bmme feari od aot neh hon as Boma pon oyerk health context to interpret this change in birth EE eT only weight on a population level, we used 2010 D ot e eigen ety oem he pont dct2 nb oned mmf U.S. National Vital Statistics birth weight data Be a a aren from the National Center for Health Statistics REHS iri4 202) The NCI gh db pp bo parc Bwec re sgn dv (NCHS) (Martin et al. 2012). The NCHS Bn ames osNp Tm Bas hae paamon Soa Cos birth weight data are grouped into 500-g i WeSr hb lo 4 on dro cy cd Tho gsi of ht bins. We assumed that the data follow a skew Hiitb ndCoas00%, ce ft nrwml lf ma dm mnt nd hr rol t-distribution (Azzalini and Capitanio 2003), ming com Gob masons (Kn a 201 3 i ms sm doc allowing us to fit a continuous distribution to ett mba set en ly SeA r scrR . om mysah of nth the grouped data and producing a better fit to Sran the data than assuming a normal distribution. Ving et ete prions. td eset edd e(oe fn it he ot CBA Using the fittcd distribution, thc proportion of Ei ei 50 lw Bc 0 am 2010: Wino a he cht nsof ce babies weighing < 2,500 g (low birth weight) SWE ci 2507 nr 00 What 200, nis Tn ssi yy od ooh was 8.6%. We estimated a 56.7-g increase Te wpe amr in birth weight associated with a reduction nse THON oa Soh 3 compensa hae of oh prio coed in serum PFOA from the 95th to the 50th ol mm hh meg 0 ch a Joi, Oot ch ned hb nap anda by GRADE percentile. If the average birth weight in 2010 aly er marienod S053 are whch es ammeter id were increased by 56.7 g, the proportion of Pir 3580f wok rely B10 17 dg tices lbs ago hoy of en or wn babies < 2,500 g would theoretically fall to Ta OH CL S08ne ig ws enh ond lm OT post 7.6% (95% CI: 7.0~8.2%), a reduction in the oloo bk ef aeneaaaeta c ho re a or e poeeee e Sehhst garst proportion of low birth weight babies in the and were able to include that study in the meta-analysis. The meta-analysis provided a quantitative summary of the studies, combining and weighting studies to integrate information across multiple studies, and effectively increasing the power to detect an association among a group of studies that might otherwise appear to have disparate findings. Although there was a high level of consistency in the direction of the estimated effects except for one very small study in the meta-analysis (Kim S et al. 2011), a statistically significant inverse association between PFOA exposure and fetal growth was not detected in several individual studies, (Chcn et al. 2012; Hamm et al. 2010; Washino et al. 2009; Whitworth et al. 2012). The objective of our search was to be as comprehensive and inclusive of relevant research as possible. Our search identified 3,023 records, which were narrowed down to 17 during the title/abstract or full-text screening steps. Although our search retrieved many references that were irrelevant to our misclassification fell under "other" risk of bias and was not a problematic risk because the outcomes were standard birth measurements that did not vary across study groups. However, it is possible that in future cases of other outcomes more attention will need to be given to potential bias in the assessment of those outcomes. Because we were simultaneously developing and applying the Navigation Guide method, a limitation of this revie~v is that we did not antidpate and define a priori all the benchmarks we ultimately used for rating the quality and the strength of the evidence, such as our analysis of what a new study would have to find in ordcr to changc our confidcncc in the effect estimate and direction of the metaanalysis. In assessing quality and strength according to factors and considerations that had not been prespecified, we conducted further analysis and abided by GRADE's principle to be conservative in changing the rating of the body of evidence up or down (Balshem et al. 2011). It may be impossible to anticipate all instances for which a judgment UHHo.owSwe. veoevfre,ar,bobbuetcae1u%sec,tothhraee4pp0ou,op0up0lus0altabiteaioobnniesmmeineddiaiaanyneoaofr.f om eySoa S kn JRO. Th ere t mos. Cet de eb serum PFOA may be only about 3 ng/mL, this metofie FOR apn wm 1 ll tyof pe fe cApov estimated benefit of reducing PFOA exposure ef Si ms and increasing birth weight may not be attribpr Ci Tian aanm t Seoalb eTee Barer fefeetct A uted equally across the population. Individuals bbe oh Jebel wilt mda end with already low levels of PFOA (i.e., below Se yebeobn X toenern odwll om rae mab the median) may not benefit, and individuals lerh cit ee, ok tshabpcmaoly 2 rly with the highest levds would benefit the most. ue oncom tat hrvn fhm koe in chm fm ron, Fy caperofs Our conclusion that there was suffiSEeTE ee ot oe ress cient evidence that developmental exposure Ee a Ee eon sy EE o a wm to PFOA was associated with reduced fetal pti meh Stn nt Tap bn growth differed from the findings of an i expert panel appointed to review the human SETC FON(T C3 Sime ond Reon of Obi Si Conclusion health effects of PFOA (C8 Science Panel BOTT atone so FON pty, (STROBE sds the boof sour leion and the 2011). The panel concluded that PFOA ty oxii hveh on FS0e 08,ebma rsd Nip Gs cco vecondo was probably not linked to low birth weight a So ara and that the evidence of small reductions in Neg Sn wag in aio ts FOR ho Comawiscorc onben FOR pennd od average birth weight in relation to PFOA a Er EE To aD me exposure was inconsistent. Our review chamed ea crdue and heron nado Jorn ofthe nh hemer Jn.No crm Honesvt candrk occurred at a later date and therefore induded ee mats ae Se re es more recent publications. These later publica- om Chen a 20 Mt co 2075 to cou edd he karl i cd elchant, and dope he tions (Chen et al. 2012; Maisonet et al. 2012; Sv205e vet mda et calols 2 To 253m rt of mn co Whitworth et al. 2012) were included in our aT em wT a Bea meta-analysis, showing consistent results and al ection i bh wohacitod Out sk afb tot ah bd lini com codmidiknwilh ogn an overall reduction in birth weight assodated TROcmt Oot ai re Aba te Sot Wiens ca The lo obe with PFOA exposure. Our protocol specified Comairmashaming or ing Sok fbr of Ba ar alyAa me fe Ron contacting authors as a means to obtaining cold2 oekoorl vari(Fama sk 205 obfy nd: additional data or data on a scale that could preventablefrybelibe inReiman driv be combined in a meta-analysis, and this Coapredscm ing may pl (Sat 3. 07. Th ek of an ur.h Tomod contact proved essential in including many es arama edi Vi Smo gon seman ad nto che eoo f pe ins of the studies in the meta-analysis (Apelberg SChe0 n 010 mer mun wot dpb be is rapae)n et al. 2007; Chen et a[. 2012; Fromme et al. So iS 00h Ma. i we desl rly cto yo Fahtn e 2010; Kim S et al. 2011; Maisonet et al. So Wabi 00Int oe ib lsmea seo ome oloaf 2012; Washino et al. 2009). In addition, by Coc rtok ta veniam: nfmTron,ve Wap Comwecr contacting authors of one of the included Ee snare Eo a minh studies (Wang et al. 2011), we were alerted do yo he amn cho pun fw man Fr cnt ce mmegan or to an additional study on the same cohort en Co TE) a:podsm in soko mon under review at the time (Chen et al. 2012) esextxcucldluuyssiqioounnecsrctirioietrneir,aiba,,escscacrureseeeennwiinneggatpthhpeelireredeffeeprrreeensnpcceeescswifwaieasds efficient. The average time to screen an abstract was 12 sec, and we excluded the majority, of irrelevant references in < i 0 hr. The process from search to rating the quality and strength of the human evidence was about 9 months. A limitation to this review, and to all reviews in general, is that reviews are based on the available data, which may be insufficient in depth or breadth or may be otherwise limited. Future reviews could be strengthened if more investigators followed standardized reporting criteria such as the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines (von Elm et al. 2008), enabling improved quality assessment. In addition, we found that contacting study authors was essential to obtaining the data necessary to include some of the studies in the meta-analysis. Not all study authors were able to provide data that could be included in the meta-analysis. Future efforts in meta-analysis could also be supported by data repositories. Our risk of bias tool also had limitations. Although there is existing guidance for assessing risk of bias of human observational studies (Viswanathan et al. 2012; Wells 2014), there is no universally accepted tool (Sanderson et al. 2007). The risk of bias domains "exposure assessment" and "confounding" were less developed than other domains that were transferred more directly from established evidence-based risk of bias tools. Additionally, in future reviews, we will consider the assessment of outcome as a separate risk of bias domain. For this ease study, potential bias resulting from outcome 3oasrsyydssettceeimmsaitaoitniccmrreeuvvsiiteewbwes; ttmhheearrdeeeffoorirnee,,thttheheecporpinrnidncudicpptlleeossf we used for addressing these instances will be integrated into future protocols. A protocol, a set of instructions, and definitions does not, however, take the place of expert judgment. The strength of systematic review methods is that, as new studies become available, a condusion can be systematically and transparently reevaluated. Finally, the components of the Navigation Guide methodology that were not taken from empirically supported preexisting methods need validation in future cases. Conclusion On the basis of our evaluation and the Navigation Guide criteria, we concluded that there is sufficient evidence of an association between PFOA exposure and reduced fetal growth. There may be remaining uncertainty. However, we investigated residual confounding and evidence for reverse causality via reduced renal clearance, and despite the cross-sectional nature of the human evidence, our judgment was that chance, bias, and confounding could be ruled out with reasonable confidence. The proof-of-concept case study demonstrates the use of the Navigation Guide to efficiently apply the rigor and transparency of systematic review methodology to environmental health questions. The method does not take the place of expert judgment, but it requires transparency in the rationale exercised by the experts. Further refinement and proof-of-concept applications of the Navigation Guide methodology will continue, with the ultimate goal of supporting timely evidence-based recommendations for the prevention of harm to public health. AG BT Environmental Health Perspectives VOLUME 1221 NUMBER 10 I October 2014 10371037 25840010 2584.0010 = omanas. Johnson et al. os REFERENCES wp ---- Agency for Toxic Substances and Disease Registry. 2009. THESIEITMIIS Draft Toxicological Profile for Perfluoroalkyls. Atlanta, GA: Agency for Toxic Substances and Disease Registry. EMERGE Available: http://www.atsd r.c dc.g ov/toxprofiles/tp200.pdf [accessed 29 August 2014]. m me m Altman DG, Bland JM. 2011. Howto obtain the confidence ESTA Green S, eds). Available: http://handbook.cochrane.org/ chapter1/1 selecting studies and collecting data.htm [accessed 29 August 2014]. wi on corny Higgins JPT, Green S, ads. 2011. 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