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. Author manuscript; available in PMC: 2019 Dec 1.
Published in final edited form as: Environ Int. 2018 Sep 13;121(Pt 1):232–239. doi: 10.1016/j.envint.2018.09.005

Concentrations of Endocrine Disrupting Chemicals in Newborn Blood Spots and Infant Outcomes in the Upstate KIDS Study.

Erin M Bell a, Edwina H Yeung b, Wanli Ma c,d, Kurunthachalam Kannan c, Rajeshwari Sundaram e, Melissa M Smarr f, Germaine M Buck Louis g
PMCID: PMC6376484  NIHMSID: NIHMS1506883  PMID: 30219610

Abstract

Background:

Novel methodologies to quantify infant exposures to endocrine disrupting chemicals (EDCs) for population-based studies are needed.

Objectives:

We used newborn dried blood spots to quantify three EDCs and their associations with infant outcomes in the Upstate KIDS Cohort.

Methods:

We measured bisphenol A (BPA), perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) in 2,071 singleton and 1,040 twin infants born to mothers in New York State. We log transformed concentrations after rescaling by their standard deviations and modeled each in relation to gestational age, birthweight, length, head circumference and Ponderal Index (PI) using linear regression techniques. All models were adjusted for maternal age, body mass index, education, infertility treatment and parity. Generalized estimating equations with robust standard errors were used to assess the associations for twins.

Results:

Chemicals were largely quantified above the limits of detection (>99% for PFOS and PFOA; 90% for BPA). Overall, we observed no significant associations between PFASs and birth size irrespective of plurality of birth. However, among twins, BPA was associated with decreases in gestational age (adjusted β=−0.09 weeks; 95% Confidence Interval (CI): −0.17, −0.02) and birthweight (adjusted β=−32.52 gm; 95% CI: −60.99, −4.05), head circumference (adjusted β=−0.18 cm; 95% CI: −0.38,−0.02) and increased PI in singletons (adjusted β=0.02 cm; 95% CI: 0.004, 0.04).

Conclusion:

We observed negative associations between BPA and birth size in twins. Our findings demonstrate the feasibility of newborn dried blood spots for quantifying neonatal exposure at the population level.

Keywords: endocrine–disrupting chemicals, birth outcomes, newborn bloodspots, bisphenol A, perfluorooctanesulfonic acid, perfluorooctanoic acid

1. Introduction

Previous literature reviews and reports have suggested that chemicals with endocrine disrupting properties may impact reproductive and neurodevelopmental outcomes (Wang et al. 2016; WHO 2013). Two such endocrine disrupting chemicals (EDCs), perfluoroooctane sulfonic acid (PFOS) and perfluoroctanoic acid (PFOA), are persistent organic pollutants whose chemical properties were historically and widely used as repellents and non-stick surfaces in a variety of common household products. Despite recent regulations to decrease their use in manufacturing, PFOS and PFOA remain ubiquitous human exposures given their persistence, with a half-life ranging from 3.5 to 5 years (Negri et al. 2017). PFOS and PFOA are known to cross the placenta and rodent studies have demonstrated decreases in birthweight following in utero exposure, although at exposure levels higher than typically observed in human studies (Bach et al. 2015; Negri et al. 2017; Olsen et al. 2009; Rappazzo et al. 2017). Epidemiologic studies examining PFOS and PFOA measured in maternal sera and cord blood have observed an inverse association with birthweight and birth size and markers of fetal growth (Alkhalawi et al. 2016; Chen et al. 2017; Chen et al. 2012; Darrow et al. 2013; Fei et al. 2007; Lauritzen et al. 2017; Li et al. 2017; Maisonet et al. 2012; Washino et al. 2009; Wu et al. 2012) other studies have shown no such reduction (Apelberg et al. 2007; Chen et al. 2012; Darrow et al. 2013; Fei et al. 2007; Hamm et al. 2010; Lee et al. 2013; Monroy et al. 2008; Shi et al. 2017; Whitworth et al. 2012).

Bisphenol A (BPA), used in the production of plastics, is also considered an ubiquitous human exposure. However, BPA is not considered persistent due to its rapid metabolism (Wang et al. 2016; Woodruff et al. 2011). As with PFOS and PFOA, epidemiologic studies examining fetal exposure to BPA and birth outcomes are limited and inconsistent (Pergialiotis et al. 2017). For example, studies measuring BPA in maternal urine samples during pregnancy have observed a decrease in birthweight with increasing BPA concentrations (Chou et al. 2011; Huo et al. 2015; Snijder et al. 2013), while others have observed no or an increased association with markers of fetal growth (Casas et al. 2016; Lee et al. 2014; Philippat et al. 2012; Smarr et al. 2015).

The equivocal findings for BPA, PFOA and PFOS and infant birth size may reflect differences in exposure profiles across samples, varying biospecimen collection and processing protocols, varying laboratory practices for the quantification or reporting of concentrations, and specification of analytic models among other considerations (Bach et al. 2015; Lee et al. 2014; Lee et al. 2016; Shi et al. 2017). Much of the literature has relied upon maternal urine/blood or cord blood concentrations as a proxy for in utero exposure, with no studies known to us measuring EDCs in neonates. While these measures are critical for quantifying in utero exposures at specified gestational ages, they do not provide a direct measure of infant exposure. Given that twin infants are at increased risk for diminished fetal growth relative to singletons (Grantz et al. 2016), it is important to assess such exposures for this high risk group of infants. However to our knowledge, no study has examined neonatal EDC exposure and birth size in population based birth cohorts inclusive of twin infants.

Previously, we described a method for successfully quantifying these three EDCs in newborn dried bloodspots (DBS)(Ma et al. 2013), which provided support for their use as a noninvasive method for quantifying neonates’ exposures. This avenue of research is unique in that it allows investigators to be inclusive in their choice of sampling framework to ensure representation of potentially vulnerable infant subgroups, such as twins or infants from geographically unique areas. Therefore, we built upon the existing literature (Ma et al. 2013; Spliethoff et al. 2008; Yeung et al. 2016) and empirically assessed the feasibility and utility of using newborn dried blood spots for quantifying PFOS, PFOA and BPA and their associations with selected infant outcomes in the Upstate KIDS birth cohort study.

2. Methods

2.1. Study Population

Primarily designed to examine the long-term impact of infertility treatment on child growth and neurodevelopment through 3 years of age, Upstate KIDS is a prospective cohort study comprising 6,171 infants delivered between 2008–2010 in 57 New York State counties (excluding the 5 New York City boroughs). Briefly, infants conceived with and without infertility treatments were sampled based upon the infertility treatment data field on birth certificates (Buck Louis et al. 2015; Roohan et al. 2003). Infants conceived with infertility treatment were frequency matched to infants without treatment by perinatal region of birth at a ratio of 1 to 3. All mothers of twins were recruited irrespective of treatment status. The cohort comprised 6,171 infants (3,905 singletons, 2,132 twins and 134 higher order multiples) born to 5,034 women. Mothers completed standardized baseline questionnaires about reproductive and medical history and other sociodemographic and environmental data upon enrollment. At the eight-month follow-up, parents were asked to provide consent for use of archived DBS for the quantification of chemicals. Of enrolled families, 3,125 (62%) provided consent to analyze newborn bloodspots with no strong differences identified between consenting and nonconsenting parents (Yeung et al. 2016). After excluding the higher-order multiple infants, 2,071 singletons and 1,040 twins were included in this analysis. Complete details on the study’s methods have previously been published (Buck Louis et al. 2014). The New York State Department of Health and the University of Albany (State University of New York) Institutional Review Boards (NYSDOH IRB #07–097; UAlbany #08–179) approved this study, along with a signed reliance agreement with the National Institutes of Health.

2.2. Quantification of EDCs in Newborn Blood Spot

The New York State Newborn Screening Program (NSP) collects 5 drops of infant whole blood taken from a heel stick and captured onto filter paper cards at 24 hours or more following delivery, but prior to discharge. Within 24 hours, these filter cards are then sent to the Wadsworth Center Laboratory, New York State Department of Health, for genetic and metabolic screening. The remaining DBS are archived in cold storage at 4°C. Among the study infants, DBS were collected from one to four or more days post-delivery, with a mean collection time of two days post-delivery. As previously described, the DBS cards for infants with parental consent were retrieved and the equivalent of one 16-mm diameter punch was used for analyses (Yeung et al. 2016). A liquid-liquid extraction was used to extract the BPA, PFOS and PFOA from the bloodspot samples and high-performance liquid chromatography/tandem mass spectrometry HPLC-MS/MS methods were used for quantification. The method was validated for accuracy, precision, sensitivity, and background contamination as described below and in greater detail in Ma et al (Ma et al. 2013).

While two separate analysis could have improved efficiency, it would have required a higher volume of final extract and available volume was too low for complete analyses. Thus, the final volume was adjusted to 50uL and, with one injection, completed analyses as described. However, parameters were optimized separately for BPA and the perfluorinated chemicals. The ion-pair extraction procedure for BPA used basic conditions with tetrabutyl ammonium hydrogen sulfate. While unlikely in newborn infants, if BPA was conjugated, BPA would have been deconjugated under these basic/alkaline conditions.

13C-labelled internal standards of PFOS, PFOA and BPA were spiked prior to extraction and the quantification was by isotope dilution to compensate for low recovery rates. In checking for a matrix effect, the matrix-matched calibration curve with isotope-dilution and methanol calibration curves with isotope-dilution were compared. The results showed that the matrix suppression for BPA was significant, however for PFOA and PFOS the matrix effect was minimal. Therefore, for recovery review with our method and other applications with real blood spot samples, only the methanol calibration curve with isotope-dilution was used.

Unspotted blank areas of DBS cards were analyzed as field blanks to account for background contamination. One field blank was collected for every 20–30 samples. The comparison of method and field blanks confirmed negligible contamination of filter cards during collection, storage and handling (Ma et al. 2013). Similar to other studies (Adam 2000, Andersen 2014), we assumed volume, using one 16 mm punch equivalent to 50 uL of whole blood, the standard used in previous studies by the New York State Department of Health (Ma et al. 2013; Spliethoff et al. 2008). Further details describing these methods can be found in Ma et al. (2013).

On the basis of background levels found in method blanks, the limits of detection were 0.03, 0.05, and 0.3 ng/mL of whole blood for PFOS, PFOA, and BPA. Instrument derived concentrations were used without substitution to avoid bias when estimating human health outcomes (Schisterman et al. 2006).

2.3. Infant Characteristics and Outcomes

Infant outcomes examined included gestational age (defined as completed weeks gestation), birthweight (gm), birth length (cm), head circumference (cm), and ponderal index (PI, kg/m3). Mothers reported birth length, head circumference, education status, infertility treatment (i.e., use of assisted reproductive technologies or fertility drugs), and maternal race/ethnicity on the baseline questionnaire. Information from birth certificate data included: maternal age, weight and height, parity (number of live births), infant sex, birthweight, gestational age, and admission to neonatal intensive care unit (NICU). Information on birthweight and gestational age was complete. Birth length was reported for 84% of infants while head circumference data were reported for 28% of infants. Infants with available birth length data were more likely to have mothers with graduate school education (33% compared to 23% without length data), mothers who were white (85% compared to 77% without length data) and conceived with infertility treatment (33% compared to 27% of those without birth length data). Availability of head circumference data did not differ by any factor measured (e.g. maternal education, race/ethnicity or infertility treatment).

The Ponderal Index (PI) was calculated [(birthweight (gm)/length (cm3)] x100 to assess infant adiposity (Miller and Hassanein 1971) and further categorized as: asymmetric (< 2.21); normal (2.20–3.00) and symmetric (> 3.00). Preterm birth was defined as < 37 weeks and early preterm as < 32 weeks. Size for gestational age was computed using the United States reference (Koval et al. 2013; Oken et al. 2003). For singletons, large (LGA) and small for gestational age (SGA) were defined as birthweights >90th and <10th percentiles, respectively. Given the absence of references for twins (Yeung et al. 2015), we defined SGA as < 3rd percentile since a third or more of our twins were <10th percentile when using the singleton reference (Yeung et al. 2015). Infants whose birth lengths exceeded the U.S. reference by ±3 centimeters for gestational age were excluded (n=95; <1%).

2.4. Statistical Analysis

After examining the percentage of samples with chemical measurements above the limit of detection (LOD), we examined the median and interquartile range (IQR) overall and by plurality. In the descriptive phase of research after inspecting data completeness, maternal and infant characteristics were compared by median concentrations of chemicals and significance (2-sided p-value) was assessed using the Wilcoxon sample test and Kruskal-Wallis test for dichotomous and polytomous outcomes, respectively and Pearsons Correlation Coefficients were calculated to assess correlation with BPA, PFOS and PFOA. Data for covariates were largely complete with <1% missing for parity. We log transformed (log(BPA + 19); log (PFOA + 1); log (PFOS +1)) concentrations and rescaled by the standard deviations of the log-transformed chemicals to aid interpretation, and modeled each EDC in relation to gestational age, birthweight, length, head circumference, and Ponderal Index (PI) using linear regression techniques for singletons and generalized estimating equations with robust standard errors to account for the lack of independence among twins (Zeger and Liang 1986). The underlying causal model between EDCs, including perfluoroalkyl acids and birth size, have not been empirically demonstrated prompting varying opinions and approaches to model specification. In our approach, each chemical was modeled individually and three models were assessed, to confirm robustness of our findings, with covariates selected a priori (Model 1: adjusting for maternal age (years); Model 2: adjusting for maternal age (years), BMI (<25, 25–30, 30–35, ≥35) and education (high school, college/some college, graduate school) and Model 3: adjusting for maternal age, BMI, education, infertility treatment and Model 4: adjusting for Model 3 covariates and nulliparous (yes/no), given its uncertain causal structure between prenatal EDC concentrations and infant outcomes. Finally, to assess whether observed estimates varied when considering all chemicals jointly, a fourth model was assessed with all chemicals entered simultaneously.

3. Results

3.1. Descriptive Statistics

The cohort comprised mostly singleton (67%) infants born to mothers who were largely white (83%) and college educated (54%). Thirty-two (n=844) percent of infants were conceived with infertility treatment, reflecting our sampling framework. Distribution of other maternal and infant characteristics are reported in Table 1. All chemicals were largely quantified in DBS at concentrations above the LOD (>99% for PFOS and PFOA; 90% for BPA) as presented in Table 2. Concentrations of PFOS and PFOA were somewhat correlated (r = 0.32; p ≤ 0.0001, but neither was correlated with BPA(r = −0.005; p = 0.78 and r = −0.003; p=0.85, respectively). Median concentrations were: 1.69 ng/ml (IQR: 1.12, 2.40) for PFOS, 1.07 ng/ml (IQR:0.67,1.60) for PFOA and 7.88 ng/ml (IQR: 3.39, 14.56) for BPA. Median concentrations of PFOA and PFOS did not differ by length of time from delivery to bloodspot collection in singletons or twins. Among twins, a positive association was observed between median BPA concentrations and interval between birth and collection of the bloodspot (9.68 ng/ml for collection ≥4 versus 6.38 ng/ml for collection ≤2 days post-delivery). A similar pattern was observed among singletons with a median of 8.50 ng/ml for collection ≥4 compared to 7.23 ng/ml for collection ≤ 2 days post-delivery. Overall, the EDC distributions were similar for infants irrespective of their plurality of birth as shown in Table 2.

Table 1.

Infant and Maternal characteristics with archived newborn bloodspot samples in the Upstate KIDS Study, 2008–2010(n = 3111 infants, 2604 mothers) [mean ±SD or n(%)].

Infant and Maternal Characteristics
Gestational age (weeks) 37.8 ±2.44
Birthweight (g) 3095.31 ±700.26
Birth length boys (cm) 49.95 ±3.96
Birth length girls (cm) 48.92 ±3.83
Head circumference boys (cm) 33.62 ±2.62
Head circumference girls (cm) 33.02 ±2.46
Ponderal Index (g/cmA3×100) 2.57 ±0.37
Gestational Length (weeks)
 ≥37 2422 (78)
 <37 689 (22)
Plurality
 Singleton 2071 (67)
 Twin 1040 (33)
Sex
 Male 1567 (50)
 Female 1544 (50)
Maternal Age (years)
 ≤29 1004 (39)
 30–39 1391 (53)
 ≥40 209 (8)
Maternal Education
 High school or equivalent 367 (14)
 College/some college 1408 (54)
 Graduate school 829 (32)
Maternal Prepregnancy Body Mass Index (kg/m2)
 <25 1271 (49)
 25.0–29.9 671 (25)
 30.0–34.9 328 (12)
 ≥35.0 329 (12)
Maternal Parity
 Nulliparous 1186 (46)
 Parous 1395 (54)
Maternal race/ethnicity
 White, non-Hispanic 2180 (84)
 Black, non-Hispanic 90 (3)
 Asian, non-Hispanic 77 (3)
 Hispanic 106 (4)
 Other/multi-race 151 (6)
Maternal Infertility treatment
 No treatment 1760 (68)
 Yes, any treatment 844 (32)
Maternal Infertility Treatment Type
 Ovulation induction/intrauterine insemination 440 (52)
 Assisted reproductive technologies 403 (48)
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ART, Artificial reproductive technology

Birth length boys n= 1314; girls n = 1297

Head circumference boys n = 421; girls n = 441

OI, Ovulation induction; IUI: Intrauterine insemination

Ponderal Index (birthweight in grams/birth length in cm3 ×100)

n = 2611

Table 2.

Concentration of BPA, PFOA and PFOS in newborn blood spots, Upstate KIDS Study, 2008–2010a.

All Singleton Twins
Chemical (ng/ml) LOD
(ng/ml)		 % <LOD Md (IQR) Md (IQR) Md (IQR)
BPA 0.3 10 7.88 (3.39,14.56) 7.57 (3.34,13.90) 8.67 (3.48,16.28)
PFOA 0.05 <1 1.07 (0.67,1.60) 1.10 (0.69,1.63) 1.01 (0.63,1.53)
PFOS 0.03 <1 1.69 (1.12,2.40) 1.72 (1.14,2.44) 1.64 (1.09,2.33)
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BPA, bisphenol A

IQR, interquartile range (25th, 75th percentiles)

LOD, limit of detection

Md, median

ng/ml, nanogram per milli-liter of whole blood

PFOA, perfluorooctanoic acid

PFOS, perfluorooctanesulfonic acid

a

n=2071 singleton infants, n = 1040 twin infants

The distribution of EDCs by infant outcomes are reported in Table 3. Median concentrations of PFOS and PFOA did not differ by gestational age, birthweight, birth length, male head circumference or PI among singletons. Median PFOA and PFOS concentrations were higher in infants classified as SGA (1.17 ng/ml and 1.73 ng/ml, respectively) compared to LGA infants (1.02 ng/ml and 1.65 ng/ml, respectively). Median PFOS was higher for female infants with a head circumference less than or equal to the 50th percentile (1.77 ng/ml) compared to those greater than or equal to the 50th percentile (1.50 ng/ml). Among twins, median PFOA and PFOS concentrations were higher for female than male infants and whose head circumferences were ≥50th percentile.

Table 3.

Median concentrations of BPA, PFOS and PFOA by infant outcomes, Upstate KIDS Study, 2008–2010a.

Singleton infants Twin infants
Infant Outcomes BPA
Md
(IQR)		 PFOA
Md
(IQR)		 PFOS
Md
(IQR)		 BPA
Md
(IQR)		 PFOA
Md
(IQR)		 PFOS
Md
(IQR)
Gestational age (weeks)
 <37 8.22 (4.62, 15.57) 1.07 (0.68, 1.68) 1.72 (1.19, 2.40) 9.00 (3.89, 18.19) 1.02 (0.62, 1.57) 1.66 (1.08, 2.34)
 ≥37 7.48 (3.26, 13.82) 1.10 (0.69, 1.62) 1.72 (1.13, 2.44) 8.36 (3.19, 14.60)* 1.01 (0.64, 1.49) 1.63 (1.10, 2.33)
Birthweight (g)
 <2500 8.31 (4.36, 15.30) 1.09 (0.69, 1.69) 1.74 (1.10, 2.54) 9.00 (4.34, 17.50)* 1.01 (0.62, 1.60) 1.62 (1.08, 2.34)
 ≥2500 7.48 (3.26, 13.85) 1.1 (0.69, 1.62) 1.71 (1.14, 2.44) 8.30 (3.05, 15.00) 1.02 (0.63, 1.49) 1.67 (1.11, 2.31)
Infant Birth Size
SGA 7.64 (3.04,13.87) 1.17 (0.73, 1.67)* 1.73 (1.07, 2.82)* 8.23 (3.63, 15.20) 1.00 (0.58, 1.53) 1.61 (1.03, 2.31)
AGA 7.50 (3.37,13.72) 1.10 (0.7, 1.64) 1.73 (1.15, 2.46) 8.76 (3.43, 16.43) 1.02 (0.63, 1.53) 1.66 (1.09, 2.34)
LGA 7.94 (3.5,15.69) 1.02 (0.62, 1.42) 1.65 (1.07, 2.09) NA NA NA
Birth Length - males
 <50th percentile 8.14 (4.49, 14.91) 1.09 (0.72, 1.68) 1.74 (1.18, 2.51) 8.94 (3.15, 16.68) 0.99 (0.62, 1.56) 1.70 (1.08, 2.36)
 ≥50th percentile 7.42 (3.00, 13.76) 1.13 (0.68, 1.67) 1.77 (1.14, 2.43) 9.61 (5.38, 14.52) 0.99 (0.73, 1.33) 1.68 (1.15, 2.34)
Birth length - females
 <50th percentile 7.08 (3.09, 14.80) 1.07 (0.69, 1.59) 1.66 (1.25, 2.43) 8.32 (3.48, 17.5)* 1.01 (0.62, 1.60) 1.60 (1.04, 2.33)
 ≥50th percentile 7.46 (3.26, 13.21) 1.09 (0.68, 1.62) 1.67 (1.08, 2.51) 5.41 (2.38, 11.52) 1.08 (0.76, 1.49) 1.64 (1.14, 2.28)
Head circumference - male
 <50th percentile 8.37 (4.01, 15.66) 1.15 (0.64, 1.64) 1.79 (1.21, 2.45) 9.32 (2.81, 17.63) 0.90 (0.63, 1.51) 1.56 (1.06, 2.31)
 ≥50th percentile 5.89 (3.11, 10.38) 0.97 (0.66, 1.45) 1.74 (1.14, 2.20) 11.46 (9.44, 13.48) 1.49 (1.47, 1.51) 2.53 (2.38, 2.69)
Head circumference - female
 <50th percentile 7.36 (3.11, 14.4) 1.13 (0.74, 1.58) 1.77 (1.1, 2.66)* 6.31 (2.94, 17.92) 0.97 (0.58, 1.53)* 1.47 (0.94, 2.04)*
 ≥50th percentile 8.16 (3.67, 15.28) 1.02 (0.58, 1.48) 1.50 (0.99, 2.14) 16.91 (5.01, 23.24) 1.85 (0.95, 2.38) 2.29 (1.89, 2.66)
Ponderal Index
 <2.20 7.45 (3.15, 13.22) 1.06 (0.68, 1.68) 1.73 (1.17, 2.60) 7.75 (4.10, 14.23) 0.99 (0.57, 1.65) 1.62 (1.07, 2.48)
 2.20–3.00 7.43 (3.18, 13.90) 1.12 (0.70, 1.66) 1.75 (1.14, 2.46) 8.67 (3.10, 16.77) 1.02 (0.66, 1.54) 1.66 (1.10, 2.31)
 >3.00 7.93 (3.94, 15.13) 0.97 (0.65, 1.46) 1.58 (1.11, 2.27) 9.63 (2.89, 16.71) 0.99 (0.55, 1.52) 1.51 (1.00, 2.24)
Admission NICU
 No 7.52 (3.28,13.88) 1.10 (0.69,1.62) 1.72 (1.14,2.44) 8.20 (3.25,15.05)* 1.03 (0.64,1.52) 1.65 (1.09,2.32)
 Yes 8.43 (4.38,15.16) 1.05 (0.64,1.68) 1.64 (1.02,2.37) 9.36 (4.29,17.93) 1.00 (0.62,1.63) 1.63 (1.09,2.36)
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BPA, bisphenol A

LGA, large for gestational age defined as >90th percentile

Md, Median (ng/ml); IQR, interquartile range

NA, not calculated due to only 1 infant in cell

NICU: Neonatal intensive care unit

PFOA, perfluorooctanoic acid

PFOS, perfluorooctanesulfonic acid

Ponderal Index, birthweight in grams/birth length in cm3 X100

SGA, small for gestational defined <10th percentile,

a

n=2071 singleton infants, n = 1040 twin infants

*

p<0.05 Wilcoxon sample test and Kruskal-Wallis test for dichotomous and polytomous outcomes, respecitvely

Unadjusted BPA concentrations did not vary by any infant outcome for singletons. Among twins, median BPA concentrations were higher for infants delivered <37 weeks gestation in comparison to infants delivered at later gestational ages (9.00 ng/ml and 8.36 ng/ml, respectively), as were BPA concentrations for low birthweight infants in comparison to normal weight infants (9.00 ng/ml and 8.30 ng/ml) and for infants admitted to the neonatal intensive care unit (NICU) or not (9.36 ng/ml and 8.20 ng/ml). Median BPA concentrations were also higher for female twin infants with a birth length <50th percentile compared to those at or above the 50th percentile (Table 3).

3.2. Adjusted associations between BPA, PFOS and PFOA and birth outcomes

In adjusted analyses, results were consistent across all three models and, therefore, only the results for the model including maternal age, BMI, education, infertility treatment and parity are reported here and in Table 4.

Table 4.

Adjusteda associations between log-transformed endocrine disrupting chemical concentrations and infant outcomes by plurality of birth, Upstate KIDS Study, 2008–2010b.

BPA PFOA PFOS
Adjusted β (95% CI) Adjusted β (95% CI) Adjusted β (95% CI)
Gestational Age (weeks) Singletons −0.04 (−0.11, 0.03) 0.01 (−0.07, 0.08) 0.05 (−0.03, 0.13)
Twins −0.09 (−0.16, −0.02) −0.01 (−0.12, 0.11) −0.02 (−0.15, 0.11)
Birthweight (g) Singletons 6.43 (−16.45, 29.31) −11.55 (−35.72, 12.62) −18.32 (−42.41, 5.78)
Twins −32.52 (−60.99, −4.05) 18.48 (−17.18, 54.13) 3.91 (−31.07, 38.89)
Birth Length (cm) Singletons −0.10 (−0.24, 0.04) 0.02 (−0.13, 0.17) −0.04 (−0.19, 0.10)
Twins −0.18 (−0.40, 0.04) 0.21 (−0.11, 0.52) 0.23 (−0.07, 0.53)
Head Circumference (cm) Singletons −0.07(−0.28, 0.14) 0.04 (−0.17, 0.26) 0.03 (−0.19, 0.24)
Twins −0.18 (−0.38, −0.02) 0.12 (−0.22, 0.46) 0.23 (−0.04, 0.49)
Ponderal Index Singletons 0.02 (0.004, 0.04) −0.01 (−0.03, 0.01) −0.01 (−0.03, 0.01)
Twins 0.001 (−0.02, 0.02) −0.01 (−0.04, 0.02) −0.01 (−0.04, 0.01)
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BPA, bisphenol A

PFOA, perfluorooctanoic acid

PFOS, perfluorooctanesulfonic acid

Ponderal Index (birthweight in grams/birth length in cm3 X100)

a

Models are adjusted for continuous maternal age (years), categorical maternal BMI (<25,25–30,30–35,>=35), maternal education (high school, college/some college, graduate school), infertility treatment (yes/no), parity (nulliparous, parous)

b

n = 2071 singleton infants, n = 1040 twin infants; birth length n = 2611; head circumference n = 862

Overall, we observed no significant associations between PFASs and birth size irrespective of plurality of birth. Among singletons, log-transformed PFOS was associated with only minimal reductions in birthweight per one unit increase in PFOS (adjusted β= −18.32 gm; 95% CI: −42.41, 5.78), though the findings failed to achieve significance. Results were similar for log-transformed PFOA. The observed estimates for PFOS and PFOA were attenuated from those observed in Model 3, when parity was not included in the model (adjusted β= −31.27 gm; 95% CI: −54.85, −7.69 and adjusted β= −28.04 gm; 95% CI: −51.20, −4.89, respectively). When not adjusting for parity, no outcomes among twins were associated with PFOS or PFOA. No associations were observed when including PFOS, PFOA and BPA in the same model (Supplemental Table 1).

Among singletons, when adjusting for covariates, the only observed association was for BPA and body adiposity as measured by the PI (adjusted β= 0.02 g/cm3; 95% CI: 0.004, 0.04). Among twins, BPA was associated with decreases in gestational age (adjusted β= −0.09 weeks; 95% CI: −0.17,−0.02); birthweight (adjusted β= −32.52 gm; 95% CI: −60.99,−4.05) and head circumference (β= −0.18 cm; 95% CI: −0.38,−0.02). The observations were robust to additional adjustment for PFOA and PFOS concentrations (Supplemental Table 1).

4. Discussion

4.1. Key Findings

To our knowledge, this is the first study to examine neonatal EDC exposure as measured in newborn bloodspots in relation to neonatal birth size for both singletons and twins. While we observed no associations for persistent EDCs (i.e., PFOS and PFOA) and birth size irrespective of plurality of birth, differing signals emerged for BPA. Specifically, BPA concentrations were inversely associated with birthweight and gestational age among twins, while positively associated with PI among singletons. While the observed absolute impact on birthweight and gestational age are not large, given that twins are biologically vulnerable, our observed associations are notable.

All chemicals were largely quantified above the LOD underscoring fetal exposure. The median concentration of PFOA (1.08 ng/ml) is within the range of measured PFOA concentrations in maternal and cord blood samples reported in previous studies (with median concentrations ranging from 0.88 to 2.6 ng/ml) (Apelberg et al. 2007; Arbuckle et al. 2013; Bach et al. 2015; Lee et al. 2016; Lee et al. 2013; Monroy et al. 2008; Shi et al. 2017). The median concentration of PFOS (1.69 ng/ml) was higher than PFOA (1.07 ng/ml) in the Upstate KIDs study despite the fact that PFOS is less easily transferred through the placental barrier than PFOA (Zhang et al. 2015). This pattern is similar to several studies summarized by Bach et al (Bach et al. 2015; Bach et al. 2016) and Shi et al (Shi et al. 2017) where PFOS concentrations were higher than PFOA concentrations when measured in cord blood. However, the median concentration of PFOS was lower in the Upstate KIDS cohort than most concentrations reported in previous studies that measured PFOS in maternal sera and cord blood (Apelberg et al. 2007; Arbuckle et al. 2013; Bach et al. 2015; Lee et al. 2016; Monroy et al. 2008; Shi et al. 2017). Some variation may be due to differences in geography. For instance, two studies observed different levels of PFOS in cord blood sera from deliveries in two different geographic regions of China. Li and colleagues reported a median (IQR) concentration of 3.0 (1.7, 4.6) ng/ml in the Guangzhou birth cohort study (with births in 2013) (Li et al. 2017), while Shi and colleagues reported a PFOS concentration of 0.974 (0.626, 1.584) ng/ml in samples from Beijing (with births in 2012) (Shi et al. 2017). In addition, PFOS production declined significantly in the United States after 2002 and PFOA followed in the mid-2000s (EPA 2017; Fromme et al. 2009; Fromme et al. 2010). The lower concentrations observed in the Upstate KIDS cohort may reflect the decreased usage overtime of these particular PFAs; however usage of newer PFAs, with unknown effects, are increasing (EPA 2017; Kato et al. 2011).

4.2. Comparison with other studies and interpretations

A direct comparison between our study and others is not possible given our reliance on newborn bloodspots whereas previous literature relied upon maternal or cord blood. However, our lack of an inverse association with PFOS and PFOA and birthweight is consistent with a number of studies observing minimal or no reduction in birthweight and PFOS and PFOA measured in cord serum samples (Li et al. 2017; Shi et al. 2017; Woods et al. 2017).

Similarly, a number of studies using maternal measurement of PFOS and PFOA also observed no association with birthweight for either chemical (Alkhalawi et al. 2016; Bach et al. 2016; Robledo et al. 2015; Shi et al. 2017). A recent study (Alkhalawi et al. 2016) observed reductions in the PI with increasing concentrations of PFOS and PFOA measured in maternal plasma (β =−0.412; 95% CI: −0.788, −0.037 and β =−.355; 95% CI: −.702, −.008, respectively) but no association with birth length.

Previous studies have measured BPA in maternal and cord blood and birthweight (Pergialiotis et al. 2017); however none have measured BPA in newborn bloodspots or examined exposure in twins. In a recent study, (Pinney et al. 2017) measured BPA in amniotic fluid during the second trimester and observed an inverse relationship with birthweight while no association was observed in another study measuring BPA in maternal blood samples at the time of delivery (Padmanabhan et al. 2008). Our observed decreases in gestational age and birthweight with increasing BPA concentrations in twins require corroboration. Recent studies have observed a similar association among singletons (Lee et al. 2014), while others observed an inverse association with BPA concentrations and PI (Ding et al. 2017).

Our reported results for twins and BPA concentrations are novel and require additional investigation. As previously reported, infants requiring medical interventions, as is common in a NICU setting, have greater urinary BPA concentrations compared to infants in the general population (Calafat et al. 2009; Duty et al. 2013). Given that twin infants are more likely to be delivered earlier in gestation and to be admitted to NICUs in comparison to singletons, it is possible that the BPA measured in the archived newborn bloodspots reflects postnatal exposures from plastic-based medical equipment in the NICU. In our study population, BPA concentrations were higher among infants who were preterm, low birth weight and admitted to the NICU and for infants with bloodspot collection more than two days post-delivery (suggesting a longer hospital stay) in comparison to their counterparts, suggesting increased opportunities for exposure to an already vulnerable population of infants.

4.3. Strengths and Limitations

There are several limitations for consideration. As cited in previous publications (Andersen et al. 2014; Ma et al. 2013), while it is standard practice in New York State to use 50 μl as the assumed blood volume for quantifying concentrations from one 16 mm newborn bloodspots, blood volume was not quantified in our samples. However, given our large sample size and the observed associations with BPA and growth in twin infants, a vulnerable population, our findings suggest further exploration of neonatal exposure to BPA in the NICU and the impact on future growth are warranted.

While we observed no association with head circumference and birth length, the small sample size, particularly for head circumference, suggests the need to interpret these findings with caution given the instability of the estimates.

Model specification is another important consideration in weighing our findings in the context of the existing literature. In thinking about our specific findings suggestive of a decrease in birthweight with exposure to PFOS and PFOA, we cannot rule out the possibility that we may have overadjusted when including parity in the model, attenuating our observed estimates for birthweight. While parity may be associated with differences in neonatal anthropometry (Gaillard et al. 2014) especially between the first two births (Hinkle et al. 2014), reasons for such differences are largely unknown but may reflect changes in maternal physiology, behaviors, or weight gain along with changes in paternity (Khong et al. 2003; Miranda et al. 2011; Trogstad et al. 2001; Villamor and Cnattingius 2006). Some of these factors, as well as reproductive history, gravid disease and risky lifestyles were controlled for in the study design phase in light of our lengthy exclusion criteria aimed at identifying pregnant women for optimal fetal growth (Grewal et al. 2018). Moreover, PFASs bind to albumin, and not lipids, resulting in a lower placental transfer than lipophilic EDCs (Fromme et al. 2010; Kim et al. 2011). Even in the context of some transfer across pregnancy, the mean daily uptake of specific PFAS such as PFOS and PFOA is estimated to be approximately 2–3 ng/kg and largely from dietary sources (Fromme et al. 2009). Collectively, these findings have prompted some investigators to characterize changes in PFAS concentrations in pregnant women as being transitory (Tao et al. 2008).

Given the stable nature of the target chemicals and storage at 4°C, degradation of these samples is not likely. However, given that cards were stored for many months prior to sampling for these analyses, variation in sample stability cannot be ruled out. Future analyses should include methodological assessments for variation due to long-term storage.

Finally, it has been previously reported that women are exposed to several EDCs simultaneously in pregnancy (Woodruff et al. 2011). This was suggested in our study with the correlation, although low, between PFOS and PFOA concentrations. Except for PFOA and birthweight, we observed no significant differences in fetal growth and birth outcomes with PFOS and PFOA when considered individually and no associations were observed when assessing all chemicals simultaneously. However, future analyses should include the possibility for additive and synergistic effects of multiple chemicals.

To our knowledge, this is the first study to use archived newborn DBS to measure EDCs relative to birth outcomes in a population-based cohort inclusive of twins. In light of the high incidence of twins in the U.S.(Martin et al. 2017), it is important for environmental research to capture multiples to have a complete understanding of exposures’ impact on all children’s growth and development. Our study is responsive to this need. This method provides an opportunity to measure exposures in prospective studies, particularly for high risk and hard to reach populations such as multiples. For persistent contaminants, such as PFOS and PFOA, measurement at the time of delivery reflects gestational exposure given maternal-infant transfer throughout the gestational period. However, given the short half-life compared to PFOS and PFOA, BPA measurements at the time of delivery may not reflect exposure throughout the gestational period (Braun et al. 2012; Fisher et al. 2015; Koch et al. 2014; Lassen et al. 2013). Therefore, the measured BPA at delivery may reflect very recent exposures around the time of or after delivery and, therefore, may best be used in prospective analyses of child outcomes (rather than newborn).

5. Conclusions

Using novel methods to quantify neonatal EDC concentrations for an inclusive cohort of infants, we observed no association with PFAS concentrations and birth outcomes for either singletons or twins. BPA concentrations were negatively associated with gestational age and birthweight in twins, but positively associated with neonatal adiposity as measured by the ponderal index in singletons. In light of twins being biologically vulnerable, exposures further impacting their gestation and birth size warrant continued investigation. Lastly, our findings support the feasibility and utility of using DBS for quantification of neonatal exposure and offer promise for designing population-based studies that reflect contemporary birth cohorts and the detection of small changes in infants’ birth size.

Supplementary Material

1

Highlights.

  1. Used newborn dried blood spots to quantify BPA, PFOS and PFOA

  2. Observed inverse association between BPA and birth size in twins

  3. No observed association between BPA and birth size in singletons

  4. No observed association with PFOS and PFOA and birth size, regardless of plurality

Acknowledgement:

Tzu-Chun Lin, MS Glotech Inc for contributing to the data analyses.

The authors declare no competing conflicts of interest.

Funding Acknowledgement: Funded by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NICHD; contracts # HHSN267200700019C; HHSN275201200005C).

Abbreviations:

ART

Artificial reproductive technology

BPA

bisphenol A

CI

Confidence Interval

DBS

dried bloodspot

EDC

endocrine disrupting chemical

IQR

interquartile range

IUI

Intrauterine insemination

LGA

large for gestational age

NICU

neonatal intensive care unit

NSP

newborn screening program

OI

Ovulation induction

PFOA

perfluorooctanoic acid

PI

Ponderal Index

PFOS

perfluorooctanesulfonic acid

SGA

small for gestational age

Footnotes

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