Andersen, Melvin E.

Clewell, Harvey J.

Longnecker, Matthew P.

Verner, Marc-André

Environmental Health Perspectives

Harvard University - DASH 

 Prenatal PCB-153 Exposure and Decreased Birth Weight: Verneret al. Respond  (Article begins on next page)The Harvard community has made this article openly available.Please share how this access benefits you. Your story matters.Citation Verner, Marc-André, Melvin E. Andersen, Harvey J. Clewell, andMatthew P. Longnecker. 2014. “Prenatal PCB-153 Exposure andDecreased Birth Weight: Verner et al. Respond.” EnvironmentalHealth Perspectives 122 (4): A89-A90.doi:10.1289/ehp.1307796R.http://dx.doi.org/10.1289/ehp.1307796R.Published Version doi:10.1289/ehp.1307796RAccessed February 19, 2015 3:52:06 PM ESTCitable Link http://nrs.harvard.edu/urn-3:HUL.InstRepos:12152842Terms of Use This article was downloaded from Harvard University's DASHrepository, and is made available under the terms and conditionsapplicable to Other Posted Material, as set forth athttp://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAAEnvironmental Health Perspectives  •  volume 122 | number 4 | April 2014  A 89Perspectives | CorrespondenceAll EHP content is accessible to individuals with disabilities. Fully accessible  (Section 508–compliant) HTML versions of these articles are available at  http://dx.doi.org/10.1289/ehp.1307796 and http://dx.doi.org/10.1289/ehp.1307796R. The correspondence section is a public forum and, as such, is not peer-reviewed. EHP is not responsible for the accuracy, currency, or reliability of personal opinion expressed herein; it is the sole responsibility of the authors. EHP neither endorses nor disputes their published commentary.Prenatal PCB‑153 Exposure and Decreased Birth Weight: The Role of Gestational Weight Gainhttp://dx.doi.org/10.1289/ehp.1307796Verner et al. (2013) recently questioned whether the association between cord levels of PCB-153 (poly  chlorinated biphenyl-153) and birth weight reported in our recent meta-analysis (Govarts et al. 2012) might be attrib-utable to the influence of gestational weight gain (GWG), a factor that may be related to both PCB-153 concentrations and birth weight. By using simulated data in a physio-logically based pharmaco  kinetic (PBPK) model, Verner et al. (2013) concluded that The association between prenatal levels of PCBs and birth weight may be strongly confounded by the effect of [GWG] on both blood PCB levels and birth weight. In our recently published meta-analysis (Govarts et al. 2012), the influence of weight gain was considered only in a sensi-tivity analy  sis because we did not have this information from many cohorts at that time. Since the publication of that article, we have obtained more individual-level data on GWG for a number of the cohorts, allowing us to repeat these analyses to further assess such influence. Seven of the 12 birth cohorts that partici  pated in our previous meta-analysis (Govarts et al. 2012) had data on GWG available, for a total of 4,473 mother–child pairs. GWG data from 3 cohorts was extracted from pre  natal records, whereas for the other cohorts the classification was based on mother’s recall. In most cohorts, weight in late pregnancy was obtained at birth or at some weeks before delivery, but in two cohorts these data were obtained some years after birth. In two cohorts, both measured and self-reported data on mother’s weight was available, and an excellent cor-relation was observed (Spearman r = 0.95; p < 0.001). In the present reanalysis of the data, we also estimated the changes in fat mass (FM) as a function of GWG (Butte et al. 2003). Spearman correlation coeffi-cients were calculated between PCB-153 and GWG/FM and between GWG/FM and birth weight. We first estimated the associa-tion between cord serum PCB-153 and birth weight using linear multivariate-adjusted regression models in each cohort separately, and then we used mixed-effect models to estimate the combined effect (pooled analysis). We included absolute GWG or estimated FM as additional potential confounders in the models. The absolute GWG and estimated FM distributions were relatively similar among cohorts (mean + SD was 13.9 ± 5.3 kg for GWG and 5.5 ± 4.5 kg for FM). We found low correlations between PCB-153 and GWG/FM and between GWG/FM and birth weight (r < 0.18). The effect estimate of the combined analysis yielded a negative asso-ciation between PCB-153 and birth weight equivalent to a 293-g reduction [95% con-fidence interval (CI): –536, –50] in birth weight per 1-µg/L increase in cord serum PCB-153. After including absolute GWG or estimated FM in the model, the strength of the association was reduced by 48% [–153 g (95% CI: –340, 30)] and 31% [–204 g (95% CI: –411, 0)], respectively.Our reanalysis of earlier data with some new data confirms that GWG may indeed confound the relationship between PCB-153 and birth weight; however, when we included in the model either absolute GWG or esti-mated FM, which is a more precise estimate of maternal lipid gain (Butte et al. 2003), we still observed an important reduction in birth weight as PCB-153 levels increased. We cannot exclude the possibility of residual confounding due to potential measure  ment error of GWG, which may further reduce the effect toward the null. However, two of the included cohorts showed high correla-tions between measured and self-reported weight, suggesting that misclassification due to maternal weight reports is likely to be small and negligible. Misclassification could result from inaccurate assessment of FM. In a recent study, Maple-Brown et al. (2013) observed that maternal age and pre  pregnancy body mass index can be related to an increase in gestational FM, suggesting that it is worth considering both of them in models assessing fat mass. As suggested by Verner et al. (2013), we have considered GWG as a potential con-founder because it increases the volume of lipids diluting PCB levels in blood (Glynn et al. 2011) and increases birth weight of the offspring (Siega-Riz et al. 2009). However, other than a confounding factor, GWG could be an intermediate factor on a causal path between PCB-153 exposure and birth weight. If this is the case, then controlling for GWG in the models would lead to an over adjustment  bias (Schisterman et al. 2009) in the effect estimates and would be inappropriate if the main aim is to estimate the total (and not the direct) effect of PCB-153 on birth weight. In conclusion, in interpreting the findings by Verner et al. (2013) one should take into account that PBPK models, although useful, are based on many assump-tions. The only way to verify them is through testing in population-based studies. Our analysis clearly indicates that attributing all the effect of PCBs on birth weight to GWG appears an oversimplification. The authors declare they have no actual or potential competing financial interests.Eva Govarts,1 Maribel Casas,2 Greet Schoeters,1 Merete Eggesbø,3 Damaskini Valvi,2 Mark Nieuwenhuijsen,2 and Jens Peter Bonde,4 on behalf of the ENRIECO, OBELIX, and CHICOS Consortia1Environmental Risk and Health, Flemish Institute for Technological Research (VITO), Mol, Belgium; 2Center for Research in Environmental Epidemiology (CREAL), Barcelona, Spain; 3Department of Genes and Environment, Norwegian Institute of Public Health, Oslo, Norway; 4Department of Occupational and Environmental Medicine, Copenhagen University Hospital Bispebjerg, Copenhagen, DenmarkE-mail: mcasas@creal.cat RefeRencesButte NF, Ellis KJ, Wong WW, Hopkinson JM, Smith EO. 2003. Composition of gestational weight gain impacts maternal fat retention and infant birth weight. Am J Obstet Gynecol 189(5):1423–1432.Glynn A, Larsdotter M, Aune M, Darnerud PO, Bjerselius R, Bergman Å. 2011. Changes in serum concentrations of polychlorinated biphenyls (PCBs), hydroxylated PCB metabolites and pentachlorophenol during pregnancy. Chemosphere 83:144–151.Govarts E, Nieuwenhuijsen M, Schoeters G, Ballester F, Bloemen K, de Boer M et al. 2012. Birth weight and pre-natal exposure to polychlorinated biphenyls (PCBs) and dichlorodiphenyldichloroethylene (DDE): a meta-analysis within 12 European birth cohorts. Environ Health Perspect 120:162–170; doi:10.1289/ehp.1103767.Maple-Brown LJ, Roman NM, Thomas A, Presley LH, Catalano PM. 2013. Perinatal factors relating to changes in maternal body fat in late gestation. J Perinatol 33:934–938.Schisterman EF, Cole SR, Platt RW. 2009. Overadjustment bias and unnecessary adjustment in epidemiologic studies. Epidemiology 20:488–495.Siega-Riz AM, Viswanathan M, Moos MK, Deierlein A, Mumford S, Knaack J et al. 2009. A systematic review of outcomes of maternal weight gain according to the Institute of Medicine recommendations: birthweight, fetal growth, and postpartum weight retention. Am J Obstet Gynecol 201:339–414.Verner MA, McDougall R, Glynn A, Andersen ME, Clewell HJ III, Longnecker MP. 2013. Is the relationship between pre-natal exposure to PCB-153 and decreased birth weight attributable to pharmacokinetics? Environ Health Perspect 121:1219–1224; doi:10.1289/ehp.1206457.Prenatal PCB‑153 Exposure and Decreased Birth Weight: Verner et al. Respondhttp://dx.doi.org/10.1289/ehp.1307796RIn our recent paper (Verner et al. 2013), we suggested that gestational weight gain (GWG) confounded the associa  tion between pre  natal PCB-153 (poly  chlorinated A 90  volume 122 | number 4 | April 2014  •  Environmental Health PerspectivesCorrespondencebiphenyl-153) exposure and birth weight observed in the meta-analysis by Govarts et al. (2012). Govarts et al. have now per-formed additional analyses in which they accounted for GWG in cohorts where this information could be abstracted from medi-cal records or questionnaires. Their effort is comm   endable and sheds light on results from both our paper and their meta-analysis. In line with our findings, they reported that adjusting for GWG in statistical models of PCB-153 and birth weight substantially reduced the strength of the association, without completely attenuating it. In Govarts et al.’s reanalysis, adjust-ment for GWG resulted in a reduction in the association from a 293-g decrease [95% confidence interval (CI): –536, –50] in birth weight per 1-µg/L increase in cord serum PCB-153 to 153 g (95% CI: –340, 30), which represents a 48% reduction in the effect estimate. In comparison, our analyses using pharmacokinetic modeling suggested    that 79% of the 150-g (95% CI: –240, –50) reduction in birth weight per 1-µg/L increase in cord serum PCB-153 reported in the original paper by Govarts et al. (2012) may be attributable to GWG. It is difficult to speculate how much more attenua  tion of the PCB-153–birth weight association would occur if it were possible to accurately mea-sure gain in fat mass during pregnancy—the underlying, true confounder—and adjust for it. The data presented by Butte et al. (2003) show that only 57.8% of the variability in the amount of fat mass gained in pregnancy is explained by GWG. Sensitivity analyses to assess the influence of such an improved adjustment would be of interest. In their letter, Govarts et al. touched on the assumptions of pharmaco  kinetic models. Both meta-analyses of observational data (Greenland and O’Rourke 2008) and pharmaco  kinetic simulations of epidemio-logic associations have their strengths, and both can produce results that may appear more precise and conclusive than warranted. In those settings where both approaches can be applied, their results can be combined and used to make an improved inference about an association that neither method can defini-tively quantify. The example of PCB-153 and birth weight in which confounding by GWG was revealed by pharmaco  kinetic modeling and subsequently accounted for in statistical models demonstrates how these two comple-mentary approaches can work hand in hand to generate more robust effect estimates.Whether some causal (or perhaps any) association exists between environ  mental PCB-153 exposure and birth weight is probably beyond the resolution of currently available or practicable methods.This study was supported by the American Chemistry Council (ACC) Long-Range Research Initiative and the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. M.-A.V. conducted this study as a consultant for the Hamner Institutes for Health Sciences, an independent nonprofit organization. M.P.L. received no compensation from the ACC. The authors certify that their freedom to design, conduct, interpret, and publish research was not compromised by any sponsor.Marc-André Verner,1,2 Melvin E. Andersen,3 Harvey J. Clewell III,3 and Matthew P. Longnecker41Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA; 2Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 3The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina, USA; 4Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USAE-mail: marcandre.verner@channing.harvard.eduRefeRencesButte NF, Ellis KJ, Wong WW, Hopkinson JM, Smith EO. 2003. Composition of gestational weight gain impacts mater-nal fat retention and infant birth weight. Am J Obstet Gynecol 189(5):1423–1432.Govarts E, Nieuwenhuijsen M, Schoeters G, Ballester F, Bloemen K, de Boer M, et al. 2012. Birth weight and pre-natal exposure to polychlorinated biphenyls (PCBs) and dichlorodiphenyldichloroethylene (DDE): a meta-analysis within 12 European birth cohorts. Environ Health Perspect 120:162–170; doi:10.1289/ehp.1103767.Greenland S, O’Rourke K. 2008. Meta-analysis. In: Modern Epidemiology (Rothman KJ, Greenland S, Lash TL, eds). 3rd ed. Philadelphia:Lippincott, Williams, & Wilkins.Verner MA, McDougall R, Glynn A, Andersen ME, Clewell HJ III, Longnecker MP. 2013. Is the relationship between pre-natal exposure to PCB-153 and decreased birth weight attributable to pharmacokinetics? Environ Health Perspect 121:1219–1224; doi:10.1289/ehp.1206457.

Prenatal PCB-153 Exposure and Decreased Birth Weight: Verner et al. Respond

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Prenatal PCB-153 Exposure and Decreased Birth Weight: Verner et al. Respond

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