Environment International 60 (2013) 209–216

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Maternal dietary intake of dioxins and polychlorinated biphenyls andbirth size in the Norwegian Mother and Child Cohort Study (MoBa)

Eleni Papadopoulou a,b,c,⁎, Ida H. Caspersen b, Helen E. Kvalem b,d, Helle K. Knutsen b, Talita Duarte-Salles e,Jan Alexander b, Helle Margrete Meltzer b, Manolis Kogevinas a,f,g,h,Anne Lise Brantsæter b, Margaretha Haugen b

a Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spainb Division of Environmental Medicine, Norwegian Institute of Public Health, Oslo, Norwayc Pompeu Fabra University, Barcelona, Spaind Bjørknes College, Oslo, Norwaye International Agency for Research on Cancer (IARC-WHO), Lyon, Francef IMIM (Hospital del Mar Research Institute), Barcelona, Spaing CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spainh National School of Public Health, Athens, Greece

⁎ Corresponding author at: Division of Environmental MPublic Health, P.O. Box 4404, Nydalen, NO-0403 Oslo,fax: +47 21076686.

E-mail address: eleni.papadopoulou@fhi.no (E. Papado

0160-4120/$ – see front matter © 2013 Elsevier Ltd. All rihttp://dx.doi.org/10.1016/j.envint.2013.08.017

a b s t r a c t

a r t i c l e i n f o

Article history:Received 29 April 2013Accepted 30 August 2013Available online 23 September 2013

Keywords:DietPregnancyDioxinsPCBBirth weightMoBa

Maternal diet not only provides essential nutrients to the developing fetus but is also a source of prenatalexposure to environmental contaminants. We investigated the association between dietary intake of dioxinsand PCBs during pregnancy and birth size. The study included 50,651 women from the Norwegian Mother andChild Cohort Study (MoBa). Dietary information was collected by FFQs and intake estimates were calculated bycombining food consumption and food concentration of dioxins, dioxin-like PCBs and non-dioxin-like PCBs.We used multivariable regression models to estimate the association between dietary intake of dioxins andPCBs and fetal growth. The contribution of fish and seafood intake during pregnancy was 41% for dietary dioxinsand dioxin-like PCBs and 49% for dietary non-dioxin-like PCBs. Further stratified analysis by quartiles of seafoodintake during pregnancywas conducted.We found an inverse dose–response association between dietary intakeof dioxins and PCBs and fetal growth after adjustment for confounders. Newborns of mothers in the upper quar-tile of dioxin and dioxin-like PCBs intake had 62 g lower birthweight (95% CI:−73,−50), 0.26 cm shorter birthlength (95% CI:−0.31,−0.20) and 0.10 cm shorter head circumference (95% CI:−0.14,−0.06) than newbornsofmothers in the lowest quartile of intake. Similar negative associations for intake of dioxins and dioxin-like PCBswere found after excluding women with intakes above the tolerable weekly intake (TWI = 14 pg TEQ/kgbw/week). The negative association of dietary dioxins and PCBs with fetal growth was weaker as seafood intakewas increasing. No association was found between dietary dioxin and PCB intake and the risk for small-for-gestational age neonate. In conclusion, dietary intakes of dioxins and PCBs during pregnancy were negativelyassociated with fetal growth, even at intakes below the TWI.

© 2013 Elsevier Ltd. All rights reserved.

1. Introduction

During pregnancy the developing fetus is dependent on nutrientsupply from the mother, and the maternal diet can influence the statusof the intra-uterine environment (Cetin et al., 2013). A suboptimalintra-uterine environment, caused by malnutrition or nutrient restric-tion, can affect fetal growth and contribute to the risk of developingadult diseases (Barker, 1998). Additionally, maternal diet is linked toprenatal exposure to several environmental pollutants which enter

edicine, Norwegian Institute ofNorway. Tel.: +47 21076563;

poulou).

ghts reserved.

the mother's body as food contaminants, such as dioxins andpolychlorinated biphenyls (PCBs) (Arisawa et al., 2005).

Dioxins and PCBs are toxic, lipophilic and highly persistent environ-mental pollutants which bioaccumulate in the food chain. For non-occupationally exposed populations, diet is the main source of exposureto such contaminants. Seafood consumption is themajor intake pathwayfollowed by meat, dairy products, eggs and added fats, but main foodcontributors might differ with differing food patterns between popula-tions (EFSA, 2012; Liem et al., 2000). The ingested compounds are dis-tributed to the organs via the blood and stored in the adipose tissue(Henderson and Patterson, 1988). During pregnancy, accumulated di-oxins and PCBs are transferred from the mother to the fetus throughthe placenta (Mose et al., 2012; Tsukimori et al., 2013). In animal studies,high prenatal exposure to TCDD and PCBs has been linked to reduced

210 E. Papadopoulou et al. / Environment International 60 (2013) 209–216

birth size of the offspring (Bell et al., 2007; Golub et al., 1991; Heatonet al., 1995; Hochstein et al., 2001; Mably et al., 1992).

In humans, prenatal exposures to dioxins and PCBs can influencefetal body burden and have been related to impaired fetal growth,although the reported results are inconsistent (El Majidi et al., 2012;Lundqvist et al., 2006). In a recent meta-analysis of 12 European birthcohorts, researchers reported a 150 g reduction in birth weight per1-μg/L increase in maternal serum PCB 153, which is used as a markerof non-dioxin-like PCBs and is positively correlated with dioxins anddioxin-like PCBs (EFSA, 2005; Furst, 2006; Govarts et al., 2012). Severalmother–child studies have reported a negative association betweenprenatal exposure to concentrations of PCBs in maternal or cord bloodand birth size (Halldorsson et al., 2008; Patandin et al., 1998; Tanet al., 2009), while others have not found any association (Givenset al., 2007; Kezios et al., 2012; Longnecker et al., 2005; Wolff et al.,2007). Lack of association has been also reported by Halldorsson et al.,between maternal levels of dioxins and dioxin-like compounds, mea-sured by the DR-CALUX bioassay, and fetal growth (Halldorsson et al.,2009). Nevertheless, a potential reason for the inconsistent results be-tween epidemiological studies is the different analytes and the differentmeasurement techniques used in each study. Some studies have foundnegative associations between prenatal exposure to dioxins and PCBsand fetal growth in boys and null associations in girls, suggesting adifferent effect between genders (Hertz-Picciotto et al., 2005; Konishiet al., 2009).

Seafood intake during pregnancy is related to concentrations ofdioxins and PCBs in maternal blood (McGraw and Waller, 2009; Wanget al., 2009). However, studies examining the relationship betweenfish consumption and fetal growth have reported controversial results(Brantsæter et al., 2012; Grandjean et al., 2001; Guldner et al., 2007;Halldorsson et al., 2007; Thorsdottir et al., 2004), even for highly ex-posed populations eating very contaminated fish (Karmaus and Zhu,2004; Rylander et al., 2000; Weisskopf et al., 2005). Hence, the effectof prenatal exposure to dioxins and PCBs through the maternal diet onfetal growth is still not clear.

The aim of our study was to investigate the association betweendietary intake of dioxins and PCBs during pregnancy and fetal growthin the NorwegianMother and Child Cohort Study (MoBa). Furthermore,we assessed gender differences and differences by seafood intakeduring pregnancy.

2. Material and methods

2.1. Study population

This study is conducted within the NorwegianMother and Child Co-hort Study (MoBa), a prospective population-based pregnancy cohortstudy conducted by the Norwegian Institute of Public Health (Magnuset al., 2006). In brief, participants were recruited from all over Norwayfrom 1999 to 2008 by a postal invitation at 17–18 weeks of pregnancyand 38.7% of invited women consented to participate. The cohortincludes 91,000 mothers and 109,000 children. Data used in this studyare based on version 5 of the quality-ensured data files, released forresearch in June 2010. The study was approved by The Regional Com-mittee for Medical Research Ethics in South-Eastern Norway.

This study includes pregnant women recruited to MoBa in years2002–2008. According to our inclusion criteria, women with the firstparticipation in MoBa, with singleton births recorded in the MedicalBirth Registry of Norway (MBRN) and with complete information onsocio-demographic characteristics, exposure to tobacco smoke, weightgain and maternal diet during pregnancy, as well as birth outcomes,were eligible for the present analysis (n = 52,295). All information onmaternal and pregnancy related characteristics was collected by ques-tionnaires. After excluding 385 mother–child pairs with gestationalage b28 weeks or N42 weeks, 796 mother–child pairs due to implausi-ble maternal daily energy intake (b4500 kJ or N20,000 kJ) and 463

mother–child pairs with implausible weight change during pregnancy(b−30 k or N 50 k), a total of 50,651 women with their children wereincluded in our study. The cut-offs for plausiblematernal energy intakeswere established previously (Meltzer et al., 2008).

2.2. Dietary intake of dioxins and PCBs

The MoBa food frequency questionnaire (FFQ) (downloadable athttp://www.fhi.no/dokumenter/011fbd699d.pdf) was used to calculatethe dietary intake of dioxins and PCBs during pregnancy. This validatedsemi-quantitative FFQ was administered at 22nd week of pregnancyand was designed to assess dietary habits and supplement intakes dur-ing the first four to five months of pregnancy (Meltzer et al., 2008). Thevalidation study was focused on energy, nutrients, and specific foodgroups including seafood (Brantsæter et al., 2008, 2010). Pregnantwomen were asked to report their frequency of consumption of 255food and beverage items, by selecting one of 8–10 possible frequencies,ranging fromnever to several timesmonthly,weekly or daily. Daily foodconsumption (in g/day), energy (kcal/day) and fat (g/day) intakes wereestimated using FoodCalc (Lauritsen, 2005) and the Norwegian FoodComposition table (Rimestad et al., 2001).

Maternal dietary intakes of PCDD/Fs and PCBs during pregnancywere calculated by multiplying consumption with concentration ofcontaminants for each food item. The sum of the products was the totaldietary intake. The concentrations of PCDD/Fs and PCBs in Norwegianfood items have been published previously (Kvalem et al., 2009). Hence,we have estimated dietary intakes of seventeen 2,3,7,8-substitutedPCDD/Fs, twelve dl-PCBs (four non-ortho substituted PCBs (no-PCBs)PCB-77, 81, 126, and 169 and eight mono-ortho substituted PCBs PCB-105, 114, 118, 123, 156, 157, 167, and 189) and six non-dl-PCBs (sum ofPCB-28, 52, 101, 138, 153, and 180). Maternal intake of PCDD/Fs and dl-PCBs was expressed as toxic equivalents (TEQs) using toxic equivalencefactors established by the World Health Organization in 2005 (Van denBerg et al., 2006). The exposures under studywere the total dietary intakeof dioxins and dl-compounds (in pg TEQs/day) and the total dietary in-take of 6 non-dl-PCBs (in ng/day). Consumption of fish and seafood wasthe main contributor of dioxin and dioxin-like PCB intake (41%) andnon-dioxin-like PCB intake (49%). Briefly, for women with intakes of di-oxins and dioxin-like PCBs below the TWI and those with intake belowthe 97.5th percentile of non-dioxin-like PCBs, fatty fish was themain die-tary exposure contributor (31% and 43% respectively). In womenwith in-takes of dioxins and PCBs above the mentioned cut-offs, seagull eggs androe liver pâté were the main contributors (58% and 87% respectively). Amore detailed description of dietary exposure to dioxins and PCBs andfoods contributing to the exposure in the MoBa study is presented in anaccompanying paper by Caspersen et al. (2013).

2.3. Birth outcomes

The methodology for birth outcome collection and definition hasbeen described previously (Duarte-Salles et al., 2012). In brief, informa-tion on weight, length and head circumference measures at birth wasobtained from the Medical Birth Registry of Norway (Irgens, 2000).Gestational age was estimated using the first trimester ultrasound in98.2% of MoBa participants. In case of missing ultrasoundmeasure, ges-tational age was calculated as the interval between the last menstrualperiod and the date of delivery.

For births during 34 to 42 weeks of gestation, small for gestationalage (SGA) was defined as a newborn with birth weight below the10th percentile of newborns in MoBa according to the week of gesta-tional age at birth and parity. For births during 28 to 33 weeks, datafrom the Medical Birth Registry of Norway (MBRN) published in 2000were used to determine the 10th percentile of birth weight accordingto gestational age and parity (Skjaerven et al., 2000). Additionally, lowbirth weight (LBW) was defined as any full-term newborn with birthweight below 2500 g.

211E. Papadopoulou et al. / Environment International 60 (2013) 209–216

2.4. Statistical analysis

Weusedweight-adjusted exposure variables, by dividing dietary in-take of dioxins and dioxin-like compounds (in pg TEQs/kg bw/day) andnon-dioxin-like PCBs (in ng/kg bw/day) with maternal pre-pregnancyweight,whichwas self-reported atweek 17th of pregnancy. Additionally,maternal intake of dioxins and dioxin-like PCBs was dichotomizedaccording to the tolerable weekly intake (TWI) of 14 pg TEQ/kgbw/week (EU-SCF, 2001). Exposure and outcome variables wereevaluated regarding normality. For non-normal exposure variables,medians (IQR) and non-parametric Mann–Whitney or Kruskal–Wallistests were used for distributions and comparison between groups,while Spearman's correlation coefficient was used to assess correlationsbetween continuous variables. Anthropometric measurements at birthwere described as means (SD). Categorical data were expressed asfrequency and percentage (%) and differences in frequencies wereassessed by Pearson's chi-square test. Bonferroni correction was usedfor multiple comparisons.

Simple andmultiple linear and logistic regressionmodelswerefittedto estimate the association between maternal dietary intake of eitherdioxins and dioxin-like PCBs or non-dioxin-like PCBs with fetal growthmeasures. Exposure variables were divided into quartiles to evaluate

Table 1Prenatal dietary intake of dioxins and dioxin-like PCBs (in pg TEQ/kg bw/day) and non-dioxin-lchild pairs.

Dioxin and d(pg TEQ/kg

N (%) Median

Maternal age (years)b25 5492 (10.8) 0.5325–29 17,411 (34.4) 0.5430–34 19,329 (38.2) 0.56≥35 8419 (16.6) 0.59

Pre-pregnancy BMI statusNormal (≤25 kg/m2) 34,842 (68.8) 0.61Overweight/obese (N25 kg/m2) 15,801 (31.2) 0.44

Maternal educationb12 years 15,243 (30.1) 0.5213–16 years 21,847 (43.1) 0.55N17 years 12,539 (24.8) 0.59Missing/other 1022 (2.0) 0.54

ParityPrimiparous 26,320 (52.0) 0.55Multiparous 24,331 (48.0) 0.56

Type of deliveryNormal 43,523 (85.9) 0.55Cesarean 7128 (14.1) 0.54

Smoking during pregnancyNo 46,420 (91.7) 0.55Yes 4231 (8.3) 0.54

Alcohol during pregnancyNo 44,726 (88.3) 0.55Yes 5925 (11.7) 0.61

Parental incomeLow 13,501 (26.7) 0.54Medium 21,413 (42.3) 0.55High 13,488 (26.6) 0.57Missing 2249 (4.4) 0.57

Child's genderMale 25,906 (51.2) 0.55Female 24,745 (48.9) 0.55

Preterm birth (b37 weeks)No 46,071 (91.0) 0.55Yes 4580 (9.0) 0.55

Low birth weight (b2500 g)No 49,373 (97.5) 0.55Yes 1278 (2.5) 0.54

Small-for-gestational ageNo 46,956 (92.7) 0.55Yes 3695 (7.3) 0.54

a After Bonferroni correction statistically significant differences were for P-value b 0.002.

potential nonlinear relationships and trend tests were performed toevaluate dose–response relations. Several potential confounders wereassessed from a variety of maternal, paternal and pregnancy-relatedcharacteristics with established association with maternal dietaryhabits and birth outcomes. The retained covariates that resulted in achange in estimate N10% for either birth weight, SGA or LBW were:maternal age,weight gain during pregnancy, daily energy intake, parity,smoking during pregnancy, pre-pregnancy BMI (normal or overweight/obese), gestational age and child's gender. Maternal education has anestablished association with maternal diet and birth weight and wasincluded as a confounder since it provided a statistically significantimprovement in the adjusted model fit, as found by the likelihoodratio test. Other covariates (year of birth, type of delivery, parental in-come, paternal BMI, marital status, percentage of energy from fat, alco-hol consumption and exposure to passive smoking during pregnancy)were tested as potential confounders but did not meet our criteria ofinclusion.

In this population, fish intake has been previously positively associ-ated with fetal growth but is also the main source of dietary intake ofdioxins and PCBs in the Norwegian population (Brantsæter et al.,2012; Kvalem et al., 2009). We conducted stratified analysis by fittinglinear regression models to assess the association of dioxin and

ike PCBs (in ng/kg bw/day) according to maternal and birth outcomes for 50,651mother–

ioxin-like PCB intakebw/day)

Non-dioxin-like PCB intake(ng/kg bw/day)

(IQR) P-valuea Median (IQR) P-valuea

(0.38) 0.0001 2.18 (2.00) 0.0001(0.35) 2.24 (1.93)(0.36) 2.37 (1.98)(0.38) 2.57 (2.17)

(0.37) 0.0001 2.57 (2.11) 0.0001(0.29) 1.85 (1.59)

(0.39) 0.0001 2.20 (2.03) 0.0001(0.35) 2.31 (1.91)(0.36) 2.55 (1.91)(0.36) 2.27 (1.96)

(0.36) 0.0001 2.31 (2.01) 0.0001(0.37) 2.37 (2.00)

(0.36) 0.0005 2.34 (2.00) 0.0171(0.38) 2.30 (2.07)

(0.36) 0.0200 2.34 (2.00) 0.0907(0.41) 2.27 (2.15)

(0.36) 0.0001 2.30 (1.97) 0.0001(0.38) 2.64 (2.15)

(0.38) 0.0001 2.26 (1.98) 0.0001(0.36) 2.31 (1.98)(0.35) 2.46 (2.02)(0.41) 2.36 (2.26)

(0.37) 0.870 2.34 2.03 0.848(0.36) 2.33 2.00

(0.36) 0.043 2.34 2.00 0.048(0.37) 2.30 2.08

(0.37) 0.123 2.34 2.01 0.084(0.39) 2.24 2.03

(0.37) 0.084 2.34 2.01 0.052(0.37) 2.28 2.03

212 E. Papadopoulou et al. / Environment International 60 (2013) 209–216

dioxin-like PCB and non-dioxin-like PCB intake and birth outcomes byquartiles of fish intake.

We repeated our regression analysis after excluding 1129 (2.2%)women with dietary intakes of dioxins and dl-PCBs over the tolerableweekly intake to investigate the influence of elevated dioxin anddl-PCB intake to ourfindings. Further sensitivity analysiswas conductedfor primiparouswomenonly and by gender. All statistical analyseswereperformed with STATA (STATA version 11.1; Stata Corporation, CollegeStation, Texas).

3. Results

Dietary intakes of dioxins and PCBs during pregnancy according tomaternal characteristics and birth outcomes are presented in Table 1.The median intake of dioxins and dioxin-like PCBs was 0.55 pg TEQ/kgbw/day (IQR = 0.37) and of non-dioxin-like PCBs was 2.34 ng/kgbw/day (IQR = 2.01). Dietary intakes of dioxins and dioxin-like PCBswere positively correlated with energy (rho = 0.33, 95% CI = 0.32,0.34), fat (rho = 0.37, 95% CI = 0.36, 0.38) and seafood intake(rho = 0.52, 95% CI = 0.51, 0.53). Similar positive correlations werefound for dietary non-dioxin-like PCB intake with energy, fat and sea-food intake during pregnancy. Higher maternal age, education and pa-rental income were linked to higher dietary intakes of contaminants.Additionally, higher intakes of dioxins and PCBs were observed fornormal weight compared to overweight and obese women. Withinour study population, 1129 (2.2%) women had dietary intake of dioxinsand dioxin-like PCBs during pregnancy above the TWI. Additionally, di-etary intake of dioxins and dioxin-like PCBs was highly and positivelycorrelated with intake of non-dioxin-like PCBs (rho = 0.942, 95%CI = 0.941, 0.943).

Male and female newborns were equally distributed among themother–child pairs included in our study (Table 1). All anthropometricmeasurements were negatively, though modestly, correlated with ma-ternal dietary intake of dioxins and dioxin-like PCBs (rho = −0.05 to−0.04), as well as non-dioxin-like PCBs (rho = −0.06 to −0.05). Theprevalence of preterm birth, LBW and SGA was 9%, 2.5% and 7.3% re-spectively. Women with intake of dioxins and dioxin-like PCBs abovethe TWI had approximately 1% higher prevalence of preterm birth,LBW and SGA compared to women with lower intakes, though thedifferences were not statistically significant (Table 2).

Table 2Birth outcomes andnewborn characteristics according to prenatal dietary intake of dioxinsand dioxin-like PCBs above the tolerable weekly intake (TWI) for 50,651 mother–childpairs.

Dioxin and dioxin-like PCB intake above TWI

No (N = 49,522) Yes (N = 1129)

Mean (SD) Mean (SD) P-value

Gestational age (weeks) 40 (2) 40 (1) 0.004Birth weight (g) 3602 (539) 3526 (527) b0.001Birth length (cm) 50.4 (2.4) 50.0 (2.4) b0.001Birth head circumference (cm) 35.3 (1.6) 35.2 (1.6) b0.001

N (%) N (%) P-value

Child's genderMale 25,351 (51.2) 555 (49.2) 0.177Female 24,171 (48.8) 574 (50.8)

Preterm birth (b37 weeks)No 45,056 (91.0) 1015 (89.9) 0.211Yes 4466 (9.0) 114 (10.1)

Low birth weight (b2500 g)a

No 46,960 (99.3) 1067 (99.3) 0.903Yes 337 (0.7) 8 (0.7)

Small-for-gestational ageNo 45,921 (92.7) 1035 (91.7) 0.178Yes 3601 (7.3) 94 (8.3)

a Only full-term births.

We found an inverse dose–response association between dietaryintake of dioxins and dioxin-like PCBs and birth weight, length andhead circumference (Table 3). Newborns ofmothers in the highest quar-tile of dioxin intake had −62.1 g lower birth weight (95% CI −73.8,−50.5), −0.26 cm shorter birth length (95% CI −0.31, −0.20) and−0.10 cm shorter birth head circumference (95% CI−0.14,−0.06) com-pared to newborns of mothers in the lowest quartile of dioxin intake.For non-dioxin-like PCB intake in the highest quartile the reductionwas −40.9 g for birth weight (95% CI −52.0, −29.8), −0.21 cm forbirth length (95% CI −0.26, −0.15) and −0.06 cm for birth head cir-cumference (95% CI−0.09,−0.02). After stratifying by gender, we ob-served that the adjusted reduction in birth weight associated withintake of dioxins and dl-PCBs was −68.9 g (95% CI = −85.2, −52.2)for boys and−55.2 for girls (95% CI = −71.7,−38.6) (Supplementarytable). However, the difference between boys and girls was not statisti-cally significant. The reduction in head circumference was more pro-nounce in females than in males.

Additionally, we observed a negative association between maternaldietary dioxin and dioxin-like PCB intake above the TWI and birthweight, length and head circumference, compared to women withlower dietary intakes during pregnancy (Table 4). The risk for SGAwas not different for mothers with dioxin and dioxin-like PCB intakesabove the TWI, compared with lower intakes (OR = 1.2, 95% 0.9, 1.5).We found no dose–response association between maternal dietaryintake of either dioxins and dioxin-like PCBs or non-dioxin-like PCBswith gestational age (data not shown).

The adjusted associations between dietary intake of dioxins anddioxin-like PCBs and birth weight stratified by seafood intake arepresented in Fig. 1. Each square represents the regression coefficientand line edges represent the 95% CI for the association between dioxinsand dioxin-like PCB intake in the 4th quartile and birth weight. The ad-justed change in birth weight is compared with women in the 1st quar-tile of dioxins and dioxin-like PCB intake. The median intake of dioxinsand dioxin-like PCBs per quartile of seafood intake was 0.40 pgTEQ/kg bw/day (IQR = 0.22), 0.51 pg TEQ/kg bw/day (IQR = 0.26),0.61 pg TEQ/kg bw/day (IQR = 0.31) and 0.80 pg TEQ/kg bw/day(IQR = 0.51), respectively. We observed that newborns of motherswith seafood intakes of less than 25 g/day and in the 4th quartile ofdioxin and dioxin-like PCB intakes had −87.0 g (95% CI = −54.9,−119.2) lower birth weight than newborns of mothers with dioxinand dioxin-like PCB intakes in the 1st quartile and in the same categoryof seafood intake. The corresponding reduction in birth weight fornewborns of mothers with seafood intake 25–40 g/day, 40–60 g/dayand N60 g/day was −114.5 g (95% CI = −87.3, −141.8), −91.0 g(95% CI = −65.0, −116.9) and −78.4 g (95% CI = −49.1, −107.7),respectively. Likewise, a high dietary intake of non-dioxin-like PCBswas associated with −56.4 g (95% CI = −89.0, −23.8), −76.8 g(95% CI = −102.6, −51.0), −71.7 g (95% CI = −96.5, −46.8) and−49.8 g (95% CI = −78.3, −21.3) reduction in birth weight by sea-food category, respectively. Hence, the association between dioxinsand PCB intake in the 4th quartile with birth weight, compared to the1st quartile, was weaker as seafood intake was increasing. However,the differences between regression coefficients by categories of seafoodintake were not statistically significant.

4. Discussion

We investigated the association between dietary intake of dioxinsand PCBs during pregnancy and birth outcomes in 50,651 mother–child pairs from the Norwegian Mother and Child Cohort Study. Wefound that dietary intake of dioxins and PCBs was negatively associatedwith birth weight, length and head circumference.

In our study, dietary intakes of dioxins and dl-PCBs (0.56 pg TEQ/kgbw/day) and non-dioxin-like PCBs (2.49 ng/kg bw/day) were similar orlower than those reportedpreviously forwomen (Chan-Hon-Tong et al.,2013; Kvalem et al., 2009; Llobet et al., 2008; Perello et al., 2012;

Table3

Assoc

iation

sof

anddl-PCB

san

dno

n-dl-PCB

swithan

thropo

metricmea

suremen

tsat

birth.

Birthweigh

t(in

g)(n

=50

,651

)Birthleng

th(incm

)(n

=49

,684

)Birthhe

adcircum

ferenc

e(incm

)(n

=49

,684

)

Crud

emod

elAdjustedmod

elCrud

emod

elAdjus

tedmod

elCrud

emod

elAdjustedmod

el

Beta

(95%

CI)

Beta

(95%

CI)

Beta

(95%

CI)

Beta

(95%

CI)

Beta

(95%

CI)

Beta

(95%

CI)

Dioxinan

ddiox

in-likePC

Bintake

(pgTE

Q/kgbw

/day

)Q1(b

0.39

)Re

f.Re

f.Re

f.Re

f.Re

f.Re

f.Q2(0.39–

0.55

)−

24.2

(−37

.5,−

11.0)

−29

.0(−

39.5,−

18.5)

−0.03

(−0.09

,0.03)

−0.08

(−0.13

,−0.03

)−

0.05

(−0.09

,−0.01

)−

0.04

(−0.08

,−0.01

)Q3(0.56−

0.77

)−

49.2

(−62

.4,−

35.9)

−41

.7−(52.7,

−30

.7)

−0.17

(−0.23

,−0.11

)−

0.18

,−0.19

(−0.24

,−0.13

)−

0.11

(−0.15

,−0.07

)−

0.07

(−0.10

,−0.03

)Q4(N

0.77

)−

79.6

(−92

.8,−

66.3)

−62

.1(−

73.8,−

50.5)

−0.27

(−0.33

,−0.21

)−

0.26

(−0.31

,−0.20

)−

0.17

(−0.21

,−0.13

)−

0.10

(−0.14

,−0.06

)Ptren

db0.00

1b0.00

1b0.00

1b0.00

1b0.00

1b0.00

1Non

-dioxin-lik

ePC

Bintake

(ng/kg

bw/day

)Q1(b

1.59

)Re

f.Re

f.Re

f.Re

f.Re

f.Re

f.Q2(1.59–

2.34

)−

25.3

(−38

.6,−

12.1)

−23

.8(−

34.3,−

13.3)

−0.09

(−0.15

,−0.03

)−

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213E. Papadopoulou et al. / Environment International 60 (2013) 209–216

Schecter et al., 2001; Sirot et al., 2012). Overall, the dietary exposure todioxins and PCBs during pregnancy was among the lowest reported foran adult population in Scandinavian (Kiviranta et al., 2004; Tornkvistet al., 2011) or other European countries (De Mul et al., 2008; Fattoreet al., 2006; Fernandez et al., 2004;Windal et al., 2010), whichmight re-flect the decrease of contamination levels in Norwegian food. Accordingto the surveillance program conducted by the National Institute ofNutrition and Seafood Research of Norway, an average annual reductionof 0.1% and an overall reduction of 9% for dioxins and dioxin-like PCBsfrom 2004 to 2009 have been reported in farmed salmon which isthe best documented fish species with regard to dioxins and PCBs inNorway. For non-dioxin-like PCBs, the average annual and overall re-duction from 2002 to 2009 was 1.2% and 6%, respectively (NIFES). A de-clining trend in levels of dioxins and PCBs in breast milk of Norwegianmothers has been also observed the last 10 years, which might reflectdeclining food levels (NIPH, 2010). An overall decreasing tendency ofdioxins and PCBs in food from 2000 to 2010 has been also documentedby EFSA and by Scandinavian studies (EFSA, 2012; Glynn et al., 2009;Miller et al., 2013; Tornkvist et al., 2011).

We are the first to report a negative association between dietaryintakes of dioxins and PCBs and fetal growth. Our findings are in agree-ment with studies which have shown a negative relationship betweenmaternal or cord serum levels of dioxins and PCBs and birth weight(Govarts et al., 2012; Patandin et al., 1998; Sagiv et al., 2007; Tan et al.,2009). Interestingly, the negative relationship between dietary intakesof dioxins and dioxin-like PCBs and fetal growth was observed evenafter excluding women with intakes above the tolerable weekly intakelevel, implying that the observed negative relationshipswere not drivenby extreme intakes.

The contribution of maternal diet and particularly seafood intake tothe body burden of dioxins and PCBs is well established, while the ex-tent to which dietary intake of dioxins and PCBs can predict smallerbirth size is unknown. In large European mother–child studies oflow-exposed populations, seafood has been differently linked to fetalgrowth, with negative associations reported in Danish, French, Spanishand Swedish populations (Guldner et al., 2007; Halldorsson et al., 2007;Mendez et al., 2010) and positive associations reported in Norwegianand in French women (Brantsæter et al., 2012; Drouillet-Pinard et al.,2010; Guldner et al., 2007), while no effect was observed for Dutchpregnant women (Heppe et al., 2011). Brantsæter et al. reported a pro-tective association between fish intake and risk for LBW in Norwegianwomen (Brantsæter et al., 2012). In our study, the negative associationbetween maternal dioxins and PCB intake with birth weight remainedfor all categories of seafood intake, while it was weaker as the seafoodintake was increasing. Seafood consumption during pregnancy is sug-gested as an effective method to prevent preterm delivery and fetalgrowth retardation, as well as later adult diseases (Salvig and Lamont,2011; Swanson et al., 2012). Our findings, taken together with the ob-served protective association for LBW in Norwegian women, suggestthat the potential adverse effects of dioxin and PCB intake on fetalgrowth could be modified by seafood consumption. Evidence of thenegative effect of prenatal exposure to environmental contaminantsthroughmaternal diet, on child's health is growing,while the debate be-tween adequate nutrition and dietary toxicant exposure continues(Bushkin-Bedient and Carpenter, 2010; Genuis, 2008).

In our study, the reduction of birth weight related to high prenatalexposure to dietary dioxins and PCBs was greater in males than in fe-males, although the difference between genders was not statisticallysignificant. Previous studies have also reported negative associationbetween prenatal exposure to dioxins and PCBs and birth weight onlyin males, suggesting that they are more vulnerable than females(Hertz-Picciotto et al., 2005; Konishi et al., 2009; Sonneborn et al.,2008). According to animal studies, the reduction of fetal growth dueto high prenatal exposure to TCDD and PCBs is more pronounced inthe male offspring of exposed animals than in the female (Bell et al.,2007, 2010; Gray et al., 1997;Mably et al., 1992).Moreover, high dietary

Table 4Associations between maternal dietary intake of dioxins and dl-PCBs above the TWI andbirth outcomes.

Adjusted model

Beta (95% CI)

Birth weight (grams)Dioxin and dioxin-like PCB intake above TWI

No Ref.Yes −41.3 (−66.0, −16.7)

Birth length (cm)Dioxin and dioxin-like PCB intake above TWI

No Ref.Yes −0.22 (−0.34, −0.10)

Birth head circumference (cm)Dioxin and dioxin-like PCB intake above TWI

No Ref.Yes −0.06 (−0.14, 0.03)

OR (95% CI)

Risk for small-for-gestational ageDioxin and dioxin-like PCB intake above TWI

No Ref.Yes 1.2 (0.9, 1.5)

Risk for low birth weight (b2500 g)Dioxin and dioxin-like PCB intake above TWIa

No Ref.Yes 0.9 (0.4, 1.8)

Adjusted model includes maternal age, maternal education, weight gain duringpregnancy, energy intake, parity, smoking during pregnancy, pre-pregnancy BMI status,gestational age and child's gender.

a Only full-term births.

214 E. Papadopoulou et al. / Environment International 60 (2013) 209–216

intake of dioxins and PCBs was related to reduced head circumferencemostly in females, but the associations were weak. A reduction inhead circumference at birth has previously been linked with highserum levels of PCBs in maternal and cord blood, as well as breast

-119.2

-141.8

-87.0

-114.5

-54.9

-87.3

-145

-135

-125

-115

-105

-95

-85

-75

-65

-55

-45

-35

-25

-15

-5

5

<25 g seafood/day

Adj

uste

d ch

ange

in

bir

th w

eigh

t (i

n gr

ams)

Intakes of dioxins & dl-PCBs in thecompared to intakes in the low

25-40 g seafood/day

Fig. 1. Adjusted association between high (4th quartile) maternal dietary intake of dioxins andioxin-like PCBs, by categories of seafood intake during pregnancy. Description: Each square rebetween dioxin and dioxin-like PCB intake in the 4th quartile and birth weight, compared witdioxin-like PCBs per quartile of seafood intake was 0.40 pg TEQ/kg bw/day (IQR = 0.22), 0TEQ/kg bw/day (IQR = 0.51), respectively.

milk (Fein et al., 1984; Hertz-Picciotto et al., 2005; Nishijo et al., 2008;Tan et al., 2009). Our findings of head circumference related to dioxinsand PCBs are interpreted in the context of a reduction in overall birthsize and not as evidence of neurotoxicity. Further follow-up of thesechildren may focus on low-level organochlorine exposure throughmaternal diet and neurodevelopment.

Dioxins and dioxin-like PCBs share common sources of exposure andare highly correlatedwith non-dioxin-like PCBs, hence it is hard to attri-bute the estimated negative effects to one of the compound groups.Studies indicate that dioxins and dioxin-like PCBs are more readilytransferred from maternal blood to the placenta and cord bloodthan non-dioxin-like PCBs (Tsukimori et al., 2013). This procedure ismediated through the affinity of dioxins and dioxin-like PCBs for thearylhydrocarbon (Ah) receptor which is also the mediator for the man-ifest of their toxic effects (Tsukimori et al., 2013; Van den Berg et al.,2006). AhR-ligand activation induces the expression of placental xeno-biotic metabolizing enzymes and might lead to an unfavorable intra-uterine environment and finally to disruption of normal fetal growth(Bustamante et al., 2012; Suter et al., 2010). However, other pathwayshave been suggested as potential mechanisms for the effect of prenataldioxin and PCB exposures on child's health, illustrating the complexityof the mechanism.

The present study has strengths and limitations. A main strength isthe large sample size, including participants from both urban andrural regions representing all age and socioeconomic groups. We haveused an extensive FFQ which has been thoroughly validated andallowed us to estimate dietary intakes of dioxins and PCBs from thewhole diet. However, all dietary assessment tools have uncertaintiesand imprecisionswhichmight lead to underestimation of the true effectof the PCB and dioxin exposure on fetal growth (Grandjean and Budtz-Jorgensen, 2007; MacMahon et al., 1990). As described by Caspersenet al. (2013) and Kvalem et al. (2009), the food contamination levelsare a compilation of available concentrations of dioxins and PCB in Nor-wegian foods from 2000 to 2006. However, 19.6% of women in ourstudy gave birth from 2007 to 2008 and the food contamination levels

-116.9

-107.7

-91.0

-78.4

-65.0

-49.1

40-60 g seafood/day

highest quartile (>0.77 pg TEQs/kg bw/day)est quartile (<0.39 pg TEQs/kg bw/day)

>60 g seafood/day

d dioxin-like PCBs and birth weight, compared to low intake (1st quartile) of dioxins andpresents the regression coefficient and line edges represent the 95% CI for the associationh dioxin and dioxin-like PCB intake in the 1st quartile. The median intake of dioxins and.51 pg TEQ/kg bw/day (IQR = 0.26), 0.61 pg TEQ/kg bw/day (IQR = 0.31) and 0.80 pg

215E. Papadopoulou et al. / Environment International 60 (2013) 209–216

might not be representative for them. Nevertheless, the association be-tween dietary intake of dioxins and PCBs with birth size was negativewhen we restricted our analysis to deliveries from 2007 to2008. More-over, adjustment of our analysis for the year of birth provided similarassociations. In line to a recent publication by Verner et al., on the im-portance of gestational weight gain as a confounder in the associationsbetween maternal blood levels of lipophilic contaminants and birthweight, we have included weight gain during pregnancy in all ouradjusted models (Verner et al., 2013). The authors suggested that asso-ciations between prenatal PCB levels and birth weight, not adjusted forgestation weight gain, may be biased away from the null. Hence, eventhough our exposure assessment included dietary intakes of dioxinsand PCBs rather than blood measurements, we consider that our effectestimates were not confounded by gestational weight gain.

We acknowledge that the body burden and toxicity of dioxins andPCBs depend on their bioaccumulation resulting from long-term expo-sure and are not directly linked with the amount consumed at a giventime. However, there are several reports on the positive relationshipbetween dietary intake and blood levels of dioxins and PCBs, eitherassessed as calculated intakes of dioxins and PCBs, like in our study(Huisman et al., 1995; Knutsen et al., 2011; Kvalem et al., 2009) or asfood consumption (Gasull et al., 2011) concluding on the importanceof dietary intake as a significant predictor of the body burden. Giventhe main exposure pathway to dioxins and PCBs through diet andtheir long half-lives, long-term dietary intake can reflect the bodyburden and are used as a proxy of human exposure to dioxins andPCBs and to rank individuals in the population (Bilau et al., 2008;Huisman et al., 1995; Kvalem et al., 2012). Several lifestyle factors,along with diet, can influence the body burden of dioxins and PCBs, in-cluding age, parity, BMI and breastfeeding history (Knutsen et al., 2011).In our study maternal diet was assessed during the 1st trimester, hencepregnancy-related dietary changes might have influenced our calcula-tions and provided non-representative estimates of long-term dietaryintake of dioxins and PCBs. However, changes in diet and intake ofdioxins and PCBs due to pregnancy are considered small (Chan-Hon-Tong et al., 2013; Crozier et al., 2009).

5. Conclusions

In conclusion, within a large population-based mother and childstudy, we found that dietary intakes of dioxins and PCBs during preg-nancymight adversely affect fetal growth. This is thefirst report relatingmaternal dietary dioxin and PCB intakes with fetal growth. Our findingssupport the hypothesis that prenatal exposure to environmental con-taminants, through maternal diet, can negatively affect fetal size, evenat low dietary intakes. Maternal diet might affect fetal growth, since itis contributing to maternal and fetal body burden of contaminants andcan influence the intra-uterine environment. Therefore, reduction ofmaternal body burden long before pregnancy can reduce prenatal expo-sure to environmental toxicants and consequently avoid impaired fetalgrowth.

Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.envint.2013.08.017.

Acknowledgments

The Norwegian Mother and Child Cohort Study is supported by theNorwegianMinistry of Health and the NorwegianMinistry of Educationand Research, NIH/NIEHS (contract no. NO-ES-75558), NIH/NINDS(grant no. 1 UO1 NS 047537-01) and the Norwegian Research Council/FUGE (grant no. 151918/S10). EP holds the Yggdrasil grant (Yggdrasilmobility program 2012–2013) awarded by the Research Council ofNorway (219671/F11). The authors would like to thank all study partic-ipants for their generous collaboration.

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