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American Journal of Epidemiology Advance Access originally published online on May 5, 2008
American Journal of Epidemiology 2008 168(1):66-72; doi:10.1093/aje/kwn095
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American Journal of Epidemiology © The Author 2008. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

ORIGINAL CONTRIBUTIONS

Fetal Growth Indicators and Perfluorinated Chemicals: A Study in the Danish National Birth Cohort

Chunyuan Fei1, Joseph K. McLaughlin2,3, Robert E. Tarone2,3 and Jørn Olsen1,4

1 Department of Epidemiology, School of Public Health, University of California, Los Angeles, Los Angeles, CA
2 International Epidemiology Institute, Rockville, MD
3 Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN
4 Institute of Public Health, University of Aarhus, Aarhus, Denmark

Correspondence to Dr. Chunyuan Fei, Box 951772, Department of Epidemiology, School of Public Health, University of California, Los Angeles, 650 Charles E. Young Drive, Los Angeles, CA 90095-1772 (e-mail: cfei{at}ucla.edu).

Received for publication November 8, 2007. Accepted for publication March 19, 2008.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS) are widespread persistent organic pollutants that have been associated with reduced birth weight at doses expected in many pregnant populations. The authors randomly selected 1,400 pregnant women and their newborns from the Danish National Birth Cohort (1996–2002) to investigate whether these compounds reduce organ growth. PFOS and PFOA were measured in maternal blood samples taken early in pregnancy. Placental weight, birth length, and head and abdominal circumferences were measured shortly after birth by trained midwives or nurses. Maternal PFOA levels in early pregnancy were associated with smaller abdominal circumference and birth length. For each ng/ml increase in PFOA, birth length decreased by 0.069 cm (95% confidence interval: 0.024, 0.113) and abdominal circumference decreased by 0.059 cm (95% confidence interval: 0.012, 0.106). An inverse association was also observed between PFOA and placental weight and head circumference, and a positive association was observed with newborn ponderal index, but none of these associations was statistically significant. Maternal PFOS levels were not associated with any of the five fetal growth indicators. These findings suggest that fetal exposure to PFOA but not PFOS during organ development may affect the growth of organs and the skeleton.

birth weight; fetal development; perfluorooctanoic acid; perfluorooctane sulfonic acid; prenatal exposure delayed effects

Abbreviations: CI, confidence interval; PFOA, perfluorooctanoate; PFOS, perfluorooctanesulfonate


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) are synthetic compounds or metabolites of other perfluorinated chemicals (1, 2). They have been used worldwide in a variety of consumer products, such as nonstick pans, carpets, furniture, and household cleaners, and manufacturing processes for more than 50 years. They are now among the most widespread persistent environmental contaminants, with half-lives in humans of approximately 4 years for PFOA and 5 years for PFOS. The 3M Company (St. Paul, Minnesota) stopped the production of PFOS, PFOA, and related compounds in 2000 (1, 3), and the use of PFOA is being phased out in the United States after eight companies accepted an agreement with the Environmental Protection Agency in 2006 (4). These actions have led to a decline in PFOA and PFOS concentrations in US populations (5), but past and continued exposures may still be of public health concern.

In animal studies, decreased birth weight, shorter gestational length, congenital malformations, and neonatal mortality have been associated with exposure to both PFOS and PFOA at doses several orders of magnitude higher than any reported human exposure (6–14). Only a few human studies have examined possible effects of prenatal exposure to these perfluorinated chemicals at population levels (15–17). In a small (n = 293) hospital-based study, Apelberg et al. (15) reported inverse associations between both PFOS and PFOA in umbilical cord blood and birth weight, head circumference, and newborn ponderal index but no significant association with birth length. Using data from the Danish National Birth Cohort, we previously found PFOA but not PFOS to be associated with reduced birth weight (17). Neither PFOA nor PFOS increased the risk of being born small for gestational age.

Birth weight or birth weight for gestational age is a combined measure that does not entail differentiation in the growth of organs, the skeleton, or fat tissue. In this paper, we present data on indicators related to liver size at birth (abdominal circumference), the skeleton (length), the brain (head circumference), and the placenta (placental weight). We further examine associations between perfluorinated chemical exposure and fat tissue by using the ponderal index.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Study subjects
We used data from the Danish National Birth Cohort, which was created in 1996–2002 for a nationwide study of pregnant women and their offspring (17, 18). Briefly, all pregnant women who spoke Danish well enough and intended to carry the pregnancy to term were invited to join the cohort if their general practitioners (approximately 50 percent of all general practitioners in Denmark) participated in the study, and about 60 percent of invited women gave written informed consent (n = 91,827). Women took part in four computer-assisted telephone interviews at approximately 12 and 30 weeks of gestation and approximately 6 and 18 months after birth. A food frequency questionnaire was filled out at home around week 25 of gestation. The women also provided two blood samples, the first of which was taken during routine screening at the first antenatal care visit between gestational weeks 4 and 14 (median, 8 weeks) and which was used for this analysis. In the present study, we randomly selected 1,400 pregnant women among 43,045 women who provided the first blood sample, gave birth to a single liveborn child without congenital malformations, and completed all four telephone interviews.

Exposure assessment
Each blood sample was sent by mail to the State Serum Institute in Copenhagen. Blood was then separated and stored in freezers or in liquid nitrogen. Plasma concentrations of PFOS and PFOA were measured blindly at the 3M Toxicology Laboratory (St. Paul, Minnesota) using high performance liquid chromatography-tandem mass spectrometry based on the methods described by Ehresman et al. (19). The lower limit of quantitation in this study was 1.0 ng/ml. All values were above the lower limit of quantitation, except one PFOA value that was assigned a value of half the lower limit of quantitation. Twelve frozen whole blood samples were measured with regard to the plasma component, and these were multiplied by 2 to make them comparable to plasma measurements (19).

Outcomes and potential confounders
Growth measurements used in this study included placental weight (grams), birth length (centimeters), head and abdominal circumferences (centimeters), and ponderal index at birth (birth weight (kg) divided by cubed birth length (m3)). These data were collected by trained midwives according to standard protocols and were extracted from the National Hospital Discharge Register.

Data on gestational age were also extracted from the National Hospital Discharge Register as recorded by the midwives and were usually based on early ultrasound estimates. If data were missing or out of the expected range (n = 10), we used the expected date of delivery provided by the pregnant woman at the second interview (after the ultrasound examination). Data on the following determinants of fetal growth were reported by the mothers in the telephone-based interviews: infant sex (male or female), maternal age (<25, 25–29, 30–34, or ≥35 years), parity (0, 1, 2, or ≥3), socio-occupational status (high, middle, or low), prepregnancy body mass index (weight (kg)/squared height (m2); <18.5, 18.5–24.9, 25.0–29.9, or ≥30.0), smoking during the pregnancy (none, stopped smoking during pregnancy, smoked 1–9 cigarettes/day, or smoked ≥10 cigarettes/day), and alcohol drinking during the pregnancy (nondrinker, 0.5 drinks/week, 1–1.5 drinks/week, or ≥2 drinks/week). Dietary factors, such as intakes of fish, protein, fat, carbohydrate, and energy, were obtained from the food frequency questionnaire that was filled out by nearly 80 percent of women in the sample.

Data analyses
We categorized PFOA and PFOS levels into quartiles, using the lowest quartile as the reference group, and we also analyzed exposure data as continuous variables (ng/ml). Placental weight, birth length, head and abdominal circumferences, and ponderal index were analyzed as continuous variables. Analysis of covariance and linear regression were used to assess the associations between the growth indicators and maternal plasma PFOS and PFOA levels as measured between gestational weeks 4 and 14. Both log-transformed and untransformed blood perfluorinated chemical levels were used in the analyses, and both measures gave similar results. We present results only for untransformed data.

Covariates included gestational age, infant sex, maternal age, parity, socio-occupational status, prepregnancy body mass index, smoking during pregnancy, gestational week at blood drawing, alcohol drinking, nutritional factors (intakes of fish, protein, fat, carbohydrate, and energy), weight gain during pregnancy, hypertension and diabetes during pregnancy, and mode of delivery. We did not adjust for the last six factors in the final models because they changed the estimates less than 5 percent when taken out of the full model. Only results without this further adjustment are presented in the tables. Gestational age at birth, measured in days, was entered as both a linear term and a quadratic term into all of the models to capture the expected departure from linear fetal growth during the last few weeks of gestation. All covariates but gestational age at birth and gestational week at blood drawing were introduced into the models as indicator variables. We also evaluated possible effect-measure modifications between PFOA and PFOS levels and other determinants of fetal growth (length of gestation, parity, sex, prepregnancy body mass index) by including cross-product terms in the multiple linear regression models and by performing stratified analyses.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Maternal plasma levels of both PFOA and PFOS were in the ranges found in other non-occupationally exposed human populations in various countries, such as the United States, Canada, and Germany (5, 20, 21). The mean PFOS level was 35.3 ng/ml (range, 6.4–106.7 ng/ml), and the mean PFOA level was 5.6 ng/ml (range, less than lower limit of quantitation to 41.5 ng/ml). Concentrations of perfluorinated chemicals in plasma samples decreased markedly with increasing parity, with differences of 1.9 ng/ml and 4.3 ng/ml between nulliparous and multiparous women for PFOA and PFOS, respectively. The examined fetal growth indicators were all higher in parous women than in nulliparous women. Higher levels of PFOA and PFOS were observed in overweight and obese women (prepregnancy body mass index ≥ 25.0) and in younger women. Almost half of the women were having their first babies; mean maternal age was 28.7 years for nulliparous women and 32.2 years for parous women. One third of women were overweight or obese. Further descriptive details about the study groups have been presented elsewhere (17).

In analyses of PFOA, although average placental weight, birth length, and head and abdominal circumferences in the higher exposure quartiles were all lower than those in the lowest quartiles (table 1), the dose-response relation was not strong. After adjustment for potential confounders, only birth lengths in the second and fourth quartiles of PFOA exposure were statistically significantly lower than that in the first quartile; the difference between the highest and lowest quartiles was 0.49 cm (95 percent confidence interval (CI): 0.16, 0.81; p = 0.003). There was no significant difference in any of the five fetal growth indicators between the lowest quartile and higher quartiles of PFOS level (table 1).


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  		TABLE 1. Mean values and differences (from the lowest exposure category) for placental weight, birth length, and head and abdominal circumference, according to maternal levels of perfluorooctanoate and perfluorooctanesulfonate (in quartiles) during pregnancy, Danish National Birth Cohort, 1996–2002

 
Table 2 shows crude and adjusted regression coefficients for PFOA and PFOS as continuous variables in relation to the fetal growth indicators. PFOA levels were associated with placental weight, birth length, and head and abdominal circumference in the crude analyses, but after adjustments, all PFOA regression coefficients were attenuated, and only the associations with abdominal circumference and birth length remained statistically significant. For each ng/ml increase in maternal PFOA level, birth length decreased on average by 0.069 cm (95 percent CI: 0.024, 0.113) and abdominal circumference decreased by 0.059 cm (95 percent CI: 0.012, 0.106). A nonsignificant positive association was observed between PFOA levels and ponderal index. Maternal PFOS levels were not associated with any of the five fetal growth indicators.


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  		TABLE 2. Crude and adjusted regression coefficients (β) for four fetal growth indicators according to maternal levels of perfluorooctanoate and perfluorooctanesulfonate (ng/ml) during pregnancy, Danish National Birth Cohort, 1996–2002

 
There was a significant positive association between ponderal index and PFOA levels among nulliparous women but a nonsignificant inverse association for multiparous women, suggesting effect-measure modification by parity (p for interaction = 0.059) (table 3). Among obese women, we found a positive association between ponderal index and PFOA levels (β = 0.189, 95 percent CI: 0.024, 0.354) (table 3). When results were stratified by length of gestation, the associations between PFOA and birth length and placental weight were more pronounced in preterm (n = 53) and postterm (n = 139) babies, but the tests for interaction were not statistically significant. The estimates for PFOA levels in relation to any fetal growth indicators did not differ markedly by infant sex. In the stratified analyses of PFOS, we found an inverse association between birth length and maternal PFOS levels in postterm and preterm infants, but the association was not statistically significant for preterm birth. PFOS levels were associated with ponderal index inversely among multiparous women but positively among nulliparous women (p for interaction = 0.021), although none of the associations was statistically significant.


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  		TABLE 3. Mean values, differences (from the lowest exposure category), and regression coefficients (β) for ponderal index* according to maternal perfluorooctanoate level during pregnancy, by parity and prepregnancy body mass index{dagger}, Danish National Birth Cohort, 1996–2002{ddagger}

 
Besides the covariates included in our final model, we checked for possible confounding by alcohol drinking, dietary variables (intakes of fish, protein, fat, carbohydrate, and energy), and other factors potentially associated with fetal growth, such as gestational weight gain, hypertension, and diabetes during pregnancy. None of these factors materially changed the estimates, nor did adjustment for delivery mode in the analyses of head circumference (vaginal birth vs. cesarean section) or for mother's height in analyses of any fetal growth indicator. As expected, ponderal index was positively associated with abdominal circumference, but the coefficient for the regression of PFOA on abdominal circumference shifted slightly away from the null value after adjustment for ponderal index (β = –0.066, 95 percent CI: –0.110, –0.023).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
In our study, maternal plasma PFOA levels were inversely associated with birth length and abdominal circumference. We observed a dose-response pattern for abdominal circumference but not for birth length. An inverse association was also seen for placental weight and head circumference. The small decreases in some growth measures (birth length and abdominal circumference) and the positive association with ponderal index could suggest that growth restriction is not limited to a reduction of fat tissue. We observed no association between maternal PFOS level and the fetal growth indicators examined in this study.

Fetal growth impairment may correlate with diseases with a much later onset (22, 23); for example, head circumference is related to cognitive and neurologic development in children, and abdominal circumference at birth reflects liver size as well as abdominal fat and may affect the risk of heart disease later in life. Therefore, not only birth weight but also these indicators of fetal organ growth play an important role in the possible link between intrauterine growth and long-term health. It is not known whether fetal exposure to perfluorinated chemicals and the decreases in fetal growth measurements observed in this study and our previous study (17) have any long-term health effects, but this should be further explored.

The one previously published study (15) of these fetal growth indicators was based on umbilical cord blood samples taken after delivery, and that study had a smaller sample size of 293. Apelberg et al. (15) reported that umbilical cord levels of both PFOS and PFOA were significantly inversely associated with ponderal index and head circumference. In the present study, we did not observe an inverse association with ponderal index for either chemical. We observed a nonsignificant inverse association between PFOA and head circumference but no association with PFOS. Both studies suggested a decreased birth length with increasing PFOA levels, although the association was not statistically significant in the smaller study by Apelberg et al. PFOS did not appear to affect the size of newborns in our study, whereas Apelberg et al. found decreases of similar magnitudes for both PFOA and PFOS (15). Different types of blood samples (i.e., maternal blood vs. cord blood) and different laboratories were used in the two studies, but these differences are unlikely to account entirely for the inconsistency of the findings. Differences in confounder adjustment or chance could be an alternative explanation. Apelberg et al. adjusted for weight gain, hypertension, and diabetes during pregnancy, but our regression coefficients changed little when we adjusted for these variables. Our study had the strength of being larger and based on exposure data collected while women were pregnant.

If PFOA impairs fetal growth, the mechanism is unclear. Disruption of the action of thyroid hormone observed in animal studies (24) may be a possible mechanism, although there is no consistent evidence of a causal link between these perfluorinated chemicals and thyroid metabolism disorders in humans (25–28). Recent studies have further suggested that alterations in thyroid hormones in animal studies may be an artifact of analog assay methods (10, 29). Repeat-dose studies in rodents and monkeys have identified the liver as the primary target organ of PFOA, and exposure to PFOA can result in significant increases in liver weight (12, 24, 30). In contrast, we found a reduced abdominal circumference related to PFOA exposure that may reflect a smaller liver size, which is inconsistent with findings in animals. Determining the role of perfluorinated chemical exposure in fetal liver growth probably requires more precise organ-growth data. Ponderal index is a measure of proportionality of birth size, and the positive association between ponderal index and PFOA, although not statistically significant, does not indicate that PFOA affects a reduction of fat tissue. We have no obvious explanation for why we found no influence of PFOS on these fetal growth indicators while Apelberg et al. (15) did.

Limitations of our study should be noted, including unavoidable measurement errors in outcomes and exposures, although most of the midwives who measured the fetal growth indicators recorded in the National Hospital Discharge Register went through standardized training at one of three midwife schools in Denmark and PFOA and PFOS concentrations are rather stable throughout pregnancy (17). These measurement errors are likely to be random in nature and usually lead to attenuated measures of association. Unlike the more lipophilic persistent organic pollutants, PFOS and PFOA do not typically accumulate in the lipid tissues because of their oil-repellent properties (31). Since these compounds are primarily retained in blood and in the liver, PFOS and PFOA would not be expected to be associated with body mass index. Our data did, however, demonstrate higher plasma levels of PFOS and PFOA among overweight or obese women, and the regression coefficients increased slightly after adjustment for prepregnancy body mass index. Similarly to our previous study (17), adjustment for parity also led to marked attenuation of the regression coefficient for all outcomes, perhaps because giving birth to a child eliminates some maternal exposure, through fetal uptake and lactation (32), and newborns are usually smaller in the first pregnancy than in subsequent pregnancies. It is, of course, possible that the reported regression coefficients are still confounded by unmeasured confounders or incomplete statistical adjustment for measured confounders. Other environmental pollutants, such as polychlorinated biphenyls and dichlorodiphenyltrichloroethane, have been linked to adverse birth outcomes (33–35), but they are probably not related to PFOA exposure because of differences in sources of exposure.

In conclusion, our data showed that maternal blood PFOA levels in early pregnancy were associated with small decreases in birth length and abdominal circumference, but no association was found between PFOS exposure and any measure of fetal growth. In view of inconsistencies in the limited amount of available literature for the general population, more extensive research is needed to elucidate any potential effects of PFOA, PFOS, and related chemicals on fetal growth and development.


   ACKNOWLEDGMENTS
 
This study was supported by the International Epidemiology Institute, which received funding from the 3M Company. The 3M Toxicology Laboratory performed all laboratory analyses.

The authors appreciate the work of Dr. David J. Ehresman and his team members in the analysis of PFOS/PFOA in plasma.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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C. R. Stein, D. A. Savitz, and M. Dougan
Serum Levels of Perfluorooctanoic Acid and Perfluorooctane Sulfonate and Pregnancy Outcome
Am. J. Epidemiol., October 1, 2009; 170(7): 837 - 846.
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