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. Author manuscript; available in PMC: 2017 Oct 1.
Published in final edited form as: Reprod Toxicol. 2016 Jul 10;65:76–86. doi: 10.1016/j.reprotox.2016.07.002

Maternal exposure to di-2-ethylhexylphthalate and adverse delivery outcomes: a systematic review

Lusine Yaghjyan a, Gabriela L Ghita b, Marilyn Dumont-Driscoll c, Richard A Yost d, Su-Hsin Chang e
PMCID: PMC5067201  NIHMSID: NIHMS803885  PMID: 27412369

Abstract

Adverse pregnancy outcomes, including preterm delivery, short gestational age, and abnormal birth weight, remain a public health concern. The evidence on the association of the most common phthalate, di-2-ethylhexyl phthalate (DEHP) with adverse pregnancy outcomes remains equivocal. This systematic review summarizes published studies that investigated the association of DEHP with preterm delivery, gestational age, and birthweight. A comprehensive literature search found 15 relevant studies, most of which evaluated more than one outcome (four studies for preterm delivery, nine studies for gestational age, and ten studies for birthweight). Studies varied greatly with respect to study design, exposure assessment, analytical methods, and direction of the associations. We identified important methodological concerns which could have resulted in selection bias and exposure misclassification and contributed to null findings and biased associations. Given limitations of the previous studies discussed in this review, more thorough investigation of these associations is warranted to advance our scientific knowledge.

Keywords: preterm delivery, birthweight, phthalate exposure, gestational age

1. Introduction

Phthalates are industrial chemicals extensively used in a variety of consumer products, including plastic food containers, cosmetics/beauty products, toys, and certain medical products such as blood bags and pharmaceutical coatings [1]. Because of their wide-spread use and biological effects in animals, phthalates were included in the list of regulated (priority) pollutants by the US Environmental Protection Agency and the European Union [2]. Humans are exposed to phthalates through ingestion, inhalation, and dermal contact as well as via parenteral route when using medical devices [1]. Phthalates have short biological half-lives (6-12 hours), metabolize quickly, do not bioaccumulate, and are primarily excreted in urine [1, 3]. Secondary phthalate metabolites are detected in 100% of the samples from general US population with wide variation [4, 5]. Further, higher levels of phthalates in younger women as compared to men of the same age have been also reported possibly reflective of their potential exposure from cosmetic products [6].

Di-2-ethylhexyl phthalate (DEHP) is the most common phthalate that the general population is exposed to ubiquitously mainly through ingestion [7, 8]. DEHP is rapidly hydrolyzed in the intestine to the corresponding monoesters (mono-(2-ethyl-hexyl) phthalate, MEHP) [7, 9, 10]. These monoesters are considered the biologically active metabolites and their use as biomarkers of DEHP exposure minimizes accidental contamination from parent compound [11-13]. In addition, urinary concentrations integrate exposures from multiple routes thus accounting for the total exposure [14]. Upon absorption, these monoesters undergo further hydroxylation and oxidation (Figure 1) [7]. A greater proportion of the dose of DEHP is represented by the more downstream metabolites, including mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP) [15, 16]. In addition, it has been previously shown that a higher ratio of MEHP to MEHHP or MEHP to MEOHP is associated with potentially greater endocrine disrupting capacity [7].

Figure 1. Di-2-ethylhexyl phthalate (DEHP) metabolism.

Figure 1

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DEHP is rapidly hydrolyzed in the intestine to MEHP, which undergoes further hydroxylation and oxidation. A greater proportion of the dose of DEHP is represented by the more downstream metabolites, including MEHHP, MEOHP, and MECPP. MEHP, MEHHP, MEOHP, and MECPP are used as biomarkers of exposure to DEHP.

Abbreviations: MBP - monobutyl phthalate; MBzP - Mono-benzyl phthalate; MEHP - Mono-2-ethylhexyl phthalate; MEP - Mono-ethyl phthalate; MEHHP -Mono-(2-ethyl-5- hydroxyhexyl) phthalate; MEOHP - Mono-(2-ethyl-5-oxohexyl) phthalate; MECPP - Mono- (2-ethyl-5-carboxypentyl) phthalate; MOEHP - Mono-2-(1-oxoethyl)hexyl-d4 phthalate; MCMHP - mono(2-carboxymethylhexyl) phthalate; MHEHP – mono-2-(hydrohyethyl)hexyl phthalate, MHECPP – mono-e-(1-hydroxyethyl)-5-carboxypentyl phthalate, MEHCPP – mono-(2-ethyl-4-hydroxy-5-carboxypentyl) phthalate, MEOCPP -mono-(2-ethyl-4-oxo-5- carboxypentyl) phthalate; MECBP – mono-(2-ehtyl-4-carboxybutyl) phthalate, MHECBP – mono-2-(1-hydroxyethyl)-4-carboxybutyl phthalate, MECPrP - Mono(2-ethyl-3- carboxypropyl) phthalate

Animal studies have found a variety of adverse effects from exposure to phthalates, including DEHP. Most severe of these effects were noted for reproductive system and normal development. In animal studies, reduction in testosterone levels following administration of DEHP in male animals resulted in underdevelopment of various androgen-dependent tissues and testicular abnormalities including reduced anogenital distance, agenesis of the gubernacular cords and sex accessory tissues, undescended testis, epididymal agenesis, testicular atrophy, and others [13, 17, 18]. Some of these effects resemble testicular dysgenesis syndrome in humans [14]. In female animals, reproductive effects from phthalates included altered serum estradiol levels, advanced or delayed onset of puberty, increased ovarian and uterine weights, and deficits in growing follicles and corpora lutea [14]. Other effects observed in one or more animal species included changes in hepatic structure and function, including liver cancer, changes in kidney function, and disruption of thyroid signaling, immune functions, and metabolic homeostasis [13, 14, 19-25].

The evidence on the association of phthalates with adverse effects in humans is limited. Previous studies suggested an association of exposure to phthalates with the risk of premature thelarche [26, 27], higher risk of endometriosis [14, 28, 29], low sperm quality [11, 30, 31], reduced testosterone levels [32-34], obesity, diabetes, and possibly breast cancer [12, 35-41]. Given the variety of these effects and ubiquitous exposure, phthalates were included on the list of endocrine-disrupting compounds with high exposure concern, evidence of endocrine disruption, and highest priority for research [42]. Moreover, phthalates have been recently classified by the International Agency for Research on Cancer as possible carcinogens to humans [43].

Several biological mechanisms were suggested for reproductive and developmental toxicity of DEHP. The primary metabolite of DEHP, MEHP, is a well-known ligand for the peroxisome proliferator-activated receptor (PPAR) family [14, 44], is a mitochondrial toxicant and disruptor of lipid and glucose metabolism [14, 44-46], and is the most potent DEHP metabolite in its toxicity [14, 47, 48]. Even though some studies suggested differences in susceptibility to the toxic effects of peroxisome proliferators across species with lower potential in humans, the basis for species differences in peroxisome proliferation and carcinogenesis by phthalate esters has not been fully described [13, 48]. In addition, phthalates were also found to reduce the expression of insulin-like factor 3 (insl3) gene involved in the initial stages of testicular descent [14]. In females, DEHP-induced activation of PPAR resulted in dysregulation of aromatase activity and decreased estradiol production in rat granulosa cells [14]. Finally, a growing body of evidence suggests that, in addition to endocrine-disrupting effects on reproductive system, DEHP exhibits pro-inflammatory properties [49-53] and is associated with thyroid dysfunction [54-57]. Importantly, inflammation, oxidative stress, and hypothyroidism, all have been associated with adverse pregnancy outcomes in previous studies in humans [58-61].

The role of prenatal exposures with endocrine disrupting potential, including phthalates, on pregnancy outcomes is poorly understood. Adverse pregnancy outcomes, including preterm delivery, short gestational age, and abnormal birth weight, remain a public health concern [62, 63]. These outcomes are associated with an increased risk of morbidity and mortality in the first year of life [64] as well as long-term health consequences in childhood and adulthood, such as neurodevelopmental disability, an increased risk of behavioral problems, hypertension, type 2 diabetes, cardiovascular disease, obesity, psychiatric disorders, and cancer [65-70].

The purpose of this systematic review was to summarize published studies on the association of exposure to DEHP, the most common phthalate, with preterm delivery, gestational age, and birthweight in humans and to identify methodological gaps that need to be addressed in future studies.

2. Materials and Methods

2.1 Literature search, study selection, and data extraction

An electronic search was performed using PubMed Central (U.S. National Institutes of Health [NIH]), BioMed Central, and Toxnet with the cutoff date of July 31, 2015. Bibliographies of the articles identified in the electronic searches were then searched manually for additional relevant references. We used any combination of the key words/terms “DEHP” ‘MEHP’, ‘MEHHP’, ‘MEOHP, ‘MECPP’, ‘DEHP metabolites’ with “gestational age”, “preterm delivery”, “birth weight”, and “birthweight” to identify relevant publications.

Study selection was accomplished by first applying the following inclusion criteria: (1) accessible in full-text manuscript and (2) published in English. We then excluded studies that did not measure DEHP metabolites in biological specimens to objectively characterize the exposure (referred to as exposure biomarkers or direct exposure assessment method). Our search yielded 117 manuscripts, from which 17 studies were relevant to the topic and met the eligibility criteria (Figure 2). Two studies were further excluded due to the absence of objective exposure assessment (biomarkers of exposure) [71, 72]. Two articles reported the results on the exactly same study population [73, 74] and thus only one was included in the review [73]. From each selected article, we extracted the data on epidemiologic design features including study type, sample size, characteristics of the study population, exposure assessment approaches (type and timing of biological specimen, measured DEHP metabolites), outcome assessment method, statistical analysis methods, and results for each of the studies outcomes. We examined the evidence of the association between DEHP exposure and the birth outcomes across the studies while grouping them by the type of the outcome and phthalate analyte.

Figure 2. Flow diagram of literature search.

Figure 2

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3. Results

In Table 1, we summarize the key characteristics of the 15 studies included in this review. Most of the studies were prospective cohorts (9 studies or 56%), three studies utilized a nested case-control design, one study was case-control, and two studies were cross-sectional. Most of the studies simultaneously evaluated more than one adverse outcome, totaling 4 studies for preterm delivery, 9 studies for gestational age, and 10 studies for birthweight. The mean sample size across the studies was 307 with a median of 283 women. Five of the studies included racially/ethnically diverse study populations and the remaining 10 studies were limited to a single race/ethnicity (5 Asian, 3 Caucasian, and 2 Hispanic). Most of the studies (13 out of 15) used medical records to verify the pregnancy outcomes. All of the studies, except one, measured one or more DEHP metabolite in a biological sample; one study assessed parent DEHP concentrations only [75]. Selected studies additionally assessed associations of the birth outcomes with sum of DEHP metabolites (MEHP, MEHHP, MEOHP, and MECCP) or % MEHP (ratio of MEHP to the sum of MEHHP, MEOHP, and MECCP). Most of the studies (11 out of 15) measured phthalates in urine (spot urine or repeated samples). Other types of biological specimens included umbilical cord blood, maternal blood, meconium, and placental tissue. The details of the study designs and methods are summarized in Table 2.

Table 1. Summary Characteristics of the Studies on Association of DEHP Exposure With Preterm Delivery, Gestational Age, and Birthweight.

Study characteristic Preterm delivery (n=4) Gestational age (n=9) Birthweight (n=10)
N (%) Study sample range N (%) Study sample range N (%) Study sample range
Study design
 Nested case-control 2 (50%) 60-482 0 N/A 1 (10%) 119-201
 Prospective cohort 1 (25%) 283 7 (78%) 65-404 6 (60%) 65-1250
 Case-control 0 NA 0 NA 1 (10%) 201
 Cross-sectional 1 (25%) 207 2 (22%) 84-207 2 (20%) 84-207
Racial/ethnical composition
 Caucasian only 0 NA 1(11%) 84 3 (30%) 84-1250
 Hispanic only 1 (25%) 60 2 (22%) 72-390 1 (10%) 390
 Asian only 1 (25%) 207 3 (33%) 65-207 5 (50%) 65-207
 Racially diverse 2 (50%) 283-482 3 (33%) 283-404 1 (10%) 404
Sample type
 Spot urine 2 (50%) 60-283 6 (67%) 65-404 5 (50) 65-404
 Repeated urine 1 (25%) 482 1(11%) 390 1(10%) 390
 Umbilical cord blood 1 (25%) 207 2 (22%) 84-207 3 (30%) 84-207
 Maternal blood 0 NA 0 NA 2 (20%) 201-1250
 Meconium 0 NA 0 NA 1 (10%) 201
 Placental tissue 0 NA 0 NA 1 (10%) 119
DEHP metabolites measured
 MEHP 3 (75%) 60-482 8 (89%) 65-404 7 (70%) 65-404
 MEHHP 3 (75%) 60-482 6 (67%) 72-404 6 (60%) 119-1250
 MEOHP 3 (75%) 60-482 6 (67%) 72-404 6 (60%) 119-1250
 MECPP 2 (50%) 60-482 3 (33%) 331-404 3 (30%) 287-404
 DEHP 1 (25%) 207 2 (22%) 84-207 3 (30%) 84-390
 All metabolites 2 (50%) 60-482 3 (33%) 331-404 2 (20%) 404
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Abbreviations: DEHP, di-(2-ethylhexyl)phthalate; MEHP, mono - (2-ethylhexyl)phthalate; MEHHP, mono-(2-ethyl-5-hydroxyhexyl)phthalate; MEOHP, mono-(2-ethyl-5-oxohexyl)phthalate; MECPP, mono-(2-ethyl-5-carboxypentyl)phthalate

Table 2. Key Design Features of the Studies on Association Between DEHP Exposure and Birth Outcomes.

Reference,
country		 Study
Design		 Sample
Size a 		Outcome
assessed		 Outcome
assessment
method		 Phthalates
measured		 Sample type and
timing		 Urine
Dilution
Correction		 Confounders adjusted
for
Lanini et al. 2003, Itali [79] Cross-sectional 84 Gestational age Birthweight Not reported DEHP, MEHP Umbilical cord blood collected immediately after delivery N/A Not reported
Wolff et al. 2008, US [114] Cohort 404 Gestational age Birthweight Calculated from LMP Medical records MEHP, MEHHP, MEOHP, MECPP, ΣDEHP Spot urine sample, 3rd trimester Creatinine Race/ethnicity, infant sex, prenatal smoking, maternal pre-pregnancy BMI, education, and marital status, gestation age (for birthweight)
Adibi et al. 2009, US [76] Cohort 283 Gestational age Gestational age >41 weeks Preterm birth (<37 weeks) Sonography MEHP, MEHHP, MEOHP, % MEHPb Spot urine sample, 3rd trimester Creatinine Race, geographic site, mother's education, age, employment status during pregnancy, timing of urine sample, parity, history of miscarriage, infant sex, maternal and paternal smoking, job-related stress, mother's pre-pregnancy health
Zhang et al. 2009, China [81] Case-control 88//113 Birthweight Medical records MEHP, DEHP Umbilical vein blood collected immediately after delivery; Maternal blood samples collected post-delivery Meconium: within 48 hours post-delivery N/A Gestational age, smoking at home, socioeconomic status, and pre-pregnancy BMI
Whyatt et al., US 2009 [115] Cohort 331 Gestational age Sonography, LMP MEHP, MEHHP, MEOHP, MECPP, ΣDEHP Spot urine sample, 3rd trimester Specific gravity Maternal ethnicity age, maternal pre-pregnancy weight and height, smoking during pregnancy, prenatal asthma, diabetes, and hypertension (yes or no), planned cesarean section (yes or no), and premature rupture of membranes (yes or no)
Meeker et al. 2009, Mexico [34] Nested case-control 30//30 Preterm birth (<37 weeks) Calculated from LMP MEHP, MEHHP, MEOHP, MECPP, ΣDEHP Spot urine sample, 3rd trimester Creatinine, specific gravity Marital status, maternal education, infant sex, and gestational age at time of urine sample
Huang et al. 2009, China [78] Cohort 65 Gestational age Birthweight Measurements taken by pediatrician MEHP Spot urine samples, 15-20 minutes before amniocentesis (1st trimester) Amniotic fluid collected at the beginning of amniocentesis Creatinine Not reported
Suzuki et al. 2010, Japan [77] Cohort 149 Gestational age Birthweight Calculated from LMP Measured at delivery MEHP, MEHHP, MEOHP Spot urine sample, 9th to 40th week of gestation Creatinine Infant sex, parity, maternal age, BMI and gestational age (for birthweight).
Philippat et al. 2012, France [84] Cohort 287 Birthweight Medical records MEHP, MEHHP, MEOHP, MECPP Spot urine sample, collected at 6- 30 gestational weeks Creatinine Gestational age, maternal pre-pregnancy weight and height, maternal smoking, education, parity, recruitment center
Ferguson et al., 2013, US [73] Nested case-control 130/352 Preterm birth (<37 weeks) Sonography MEHP, MEHHP, MEOHP, MECPP, ΣDEHP Repeated urine samples (1-3) throughout pregnancy Specific gravity Maternal age at first visit, race/ethnicity, education
Weinberger et al. 2014, US [116] Cohort 72 Gestational age Medical records MEHP, MEHHP, MEOHP Spot urine sample, last clinic visit prior to delivery Specific gravity Parity and maternal race
Huang et al. 2014, China [75] Cross-sectional 207 Gestational age Preterm birth (<37 weeks) Birthweight Calculated from LMP Hospital records DEHP Cord blood collected within 10 minutes of delivery N/A Maternal age, BMI, frequency of prenatal examination, pregnancy history, gestational age (for birthweight)
Lenters et al. 2015, Greenland, Poland, and Ukraine [80] Cohort 1250 Birthweight Hospital records MEHHP, MEOHP, MECPP Non-fasting venous blood sample at enrollment, varied timing N/A Maternal education, smoking during pregnancy, parity, birth season, and urinary cotinine levels during pregnancy
Casas et al. 2015, Spain [117] Cohort 390 Birthweight Gestational age MEHP, MEHHP, MEOHP, MECPP, ΣDEHP Repeated urine samples, 1st and 3rd trimesters (12 and 32 weeks of gestation) Creatinine Site, maternal age, pre-pregnancy BMI, parity, gestational age (for birthweight), infant sex, maternal height, alcohol consumption before conception, maternal serum cotinine and serum vitamin D
Zhao et al. 2015, China [82] Nested case-control 55/64 Fetal Growth Restricted Birth (birth weight <2,500 g and GA≥37 weeks Sonography MEHP, MEHHP, MEOHP Spot urine sample, 3rd semester Placental tissue samples collected immediately after delivery Specific gravity Infant sex, gestational age, environmental tobacco smoke during pregnancy
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Abbreviations: BMI, Body Mass Index; DEHP, di-(2-ethylhexyl)phthalate; GA, gestational age; LMP, last menstrual period; MEHP, mono - (2-ethylhexyl)phthalate; MEHHP, mono-(2-ethyl-5-hydroxyhexyl)phthalate; MEOHP, mono-(2-ethyl-5-oxohexyl)phthalate; MECPP, mono-(2-ethyl-5-carboxypentyl)phthalate; ΣDEHP, sum of DEHP metabolites (MEHP, MEHHP, MEOHP, MECCP); N/A, not applicable

a

Total number for cohort studies, n of cases/n of controls for case-control studies

b

Ratio of MEHP concentration to the sum of the secondary DEHP metabolite concentrations (MEHHP, MEOHP, and MECPP)

Preterm delivery was defined as <37 weeks of gestation across all the studies. The results of these studies by the type of DEHP biomarker are presented in Figure 3. Across four studies that evaluated the association of DEHP with preterm delivery, one study [76] reported significant inverse associations with MEHP, MEHHP, and MEOHP, and three studies reported significant positive associations with MEHP, MECPP, and parent DEHP concentrations [34, 73, 75].

Figure 3. Associations of phthalate metabolites with preterm delivery across the studies.

Figure 3

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Individual study results are presented by DEHP metabolites. Vertical lines represent odds ratios and corresponding 95% Confidence Intervals. as follows: per log unit change (*); per one quartile change (#), or for > vs. < median (‡) metabolite concentration. Abidi (2009) reported significant inverse associations with MEHP, MEHHP, and MEOHP, and Ferguson (2014), Meeker (2009), and Huang (2014) reported significant positive associations with MEHP, MECPP, and parent DEHP concentrations.

Abbreviations: MEHP-Mono-2-ethylhexyl phthalate; MEHHP-Mono-(2-ethyl-5- hydroxyhexyl) phthalate; MEOHP - Mono-(2-ethyl-5-oxohexyl) phthalate; MECPP - Mono- (2-ethyl-5-carboxypentyl) phthalate, ΣDEHP-sum of metabolites

Figure 4 summarizes the results of the studies on the association of gestational age with DEHP. Four of the nine studies found inverse associations of all individual metabolites, ΣDEHP, and parent DEHP with gestational age and two studies reported positive associations with MEHP, MEHHP, and MEOHP.

Figure 4. Association of phthalate metabolites with gestation age (weeks) across the studies.

Figure 4

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Individual study results are presented by DEHP metabolites. Note: does not include study by Lanini et al that reported ORs (for MEHP=1.50, 95% CI 1.01-2.21; does not include studies by Suzuku et al and Huang et al (2009) as the risk estimates are not reported. Vertical lines represent regression coefficients and corresponding 95% Confidence Intervals as follows: per log unit increase (*); per inter-quartile range increase (**), or per doubling of log2-transformed exposure levels (†). Four studies found inverse associations of all individual metabolites, ΣDEHP, and parent DEHP with gestational age and two studies reported positive associations with MEHP, MEHHP, and MEOHP.

Abbreviations: MEHP-Mono-2-ethylhexyl phthalate; MEHHP-Mono-(2-ethyl-5- hydroxyhexyl) phthalate; MEOHP - Mono-(2-ethyl-5-oxohexyl) phthalate; MECPP - Mono- (2-ethyl-5-carboxypentyl) phthalate, ΣDEHP-sum of metabolites

The results of the studies on the association of birthweight with phthalates are presented in Figure 5a (findings reported as regression coefficients) and 5b (findings reported as odds ratios), with the exception of three studies that did not report risk estimates [77-79]. Among ten studies, two reported significant inverse associations of MEHHP or DEHP with birthweight [75, 80] and two studies found positive associations with MEHP, MEHHP, and MEOHP [81, 82].

Figure 5a. Associations of DEHP metabolites with birthweight (studies reporting regression coefficients).

Figure 5a

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Individual study results are presented by DEHP metabolites. Note: does not include study by Lanini et al., Suzuku et al., and Huang et al. (2009) as the risk estimates are not reported. Vertical lines represent regression coefficients and corresponding 95% Confidence Intervals as follows: per log unit increase (*); per 1.70 ng/mL increment increase in ln(MEHHP) (**), or per doubling of log2-transformed exposure levels (†). Huang (2014) and Lenters (2003) reported significant inverse associations of MEHHP or DEHP with birthweight.

Abbreviations: MEHP-Mono-2-ethylhexyl phthalate; MEHHP-Mono-(2-ethyl-5- hydroxyhexyl) phthalate; MEOHP - Mono-(2-ethyl-5-oxohexyl) phthalate; MECPP - Mono- (2-ethyl-5-carboxypentyl) phthalate, ΣDEHP-sum of metabolites

Figure 5b. Associations of DEHP metabolites with birthweight (studies reporting odds ratios).

Figure 5b

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Individual study results are presented by DEHP metabolites. Vertical lines represent odds ratios and corresponding 95% Confidence Intervals per log unit change (*). Zhang (2009) and Zao (2015) found positive associations with MEHP, MEHHP, and MEOHP.

Abbreviations: MEHP-Mono-2-ethylhexyl phthalate; MEHHP-Mono-(2-ethyl-5- hydroxyhexyl) phthalate; MEOHP - Mono-(2-ethyl-5-oxohexyl) phthalate; ΣDEHP-sum of metabolites

4. Discussion

The evidence on the association of phthalates with adverse birth outcomes remains inconsistent. We systematically reviewed 15 published studies that investigated the association of the most common phthalate, DEHP, with preterm delivery, gestational age, and birthweight. We identified important methodological concerns (discussed below) related to different aspects of study design which could have resulted in selection bias and exposure misclassification and contributed to null findings and biased associations in the identified studies. We further discussed their implications and suggested some strategies for the future studies.

4.1 Study population and sample size

The median sample size across the studies was relatively small (283 women) and given that the relative increase in the risk associated with environmental exposures is usually low, typically below 1.5 [83], these studies were likely underpowered to detect significant associations. In addition, some of the studies were focused on high-risk populations thus limiting generalizability of their findings. For example, Philippat et al. included pregnant women who gave birth to infants with malformations and their matched controls [84]. Another study by Huang et al. included women who had indication for amniocentesis due to advanced maternal age and abnormal screening [78]. This study subsequently reported a significant inverse association of DEHP with birthweight and gestational age and a higher risk of preterm delivery in women with higher DEHP levels, which should be interpreted with caution.

The majority of the identified studies were limited to a single race/ethnicity. Previous studies show disparities in distribution of selected phthalates among reproductive aged and pregnant women [85, 86] with higher levels noted in non-Hispanic Black and Hispanic women, though the ethnic disparities in DEHP or other high molecular weight phthalates among women are inconsistent with most studies reporting no differences and a few reporting higher levels in Caucasians [87]. Further, a recent study showed that non-Hispanic Blacks and Hispanic individuals had higher levels of %MEHP (the ratio of MEHP to the sum of the secondary metabolites), reflective of a slower MEHP conversion rate and possibly, higher potential for adverse effects from DEHP exposure [88]. Previous studies also demonstrated pronounced racial disparities in occurrence of adverse pregnancy outcomes including preterm birth and low birthweight [89, 90]. Finally, racial/ethnic differences in the associations of phthalates with adverse health outcomes such as diabetes have been also reported [91]. The above listed disparities make it important to examine these associations in racially diverse populations and to identify population subgroups that might be more susceptible to adverse effects of phthalates on pregnancy outcomes.

4.2 Exposure assessment

The studies varied with respect to the different aspects of exposure assessment, including the type of biological specimen, timing of sample collection, and the number of samples per woman.

Use of urine samples is the standard approach for biomonitoring of phthalates, including DEHP. Urine samples offer several advantages as compared to other types of biospecimens, including ease of sample collection, higher metabolite concentrations, and reduced potential for contamination by the parent compound and its subsequent conversion into metabolites as the result of post-collection enzymatic activity in the blood samples leading to hydrolysis of extraneous phthalate diesters to their monoesters and, subsequently, exposure misclassification [1, 7, 8, 11, 16, 92]. In the studies measuring concentrations in umbilical cord blood, contamination by DEHP in the sampling and analytic equipment cannot be excluded [93]. Furthermore, previous studies suggest that cord blood samples may not be reflective of maternal exposure levels during pregnancy (correlation between maternal and cord blood levels ranging between 0.1 and 0.5) [16]. Whenever possible, the use of urinary samples for exposure assessment should be preferred.

Even though DEHP is rapidly metabolized within hours (half-life 6-12 hours) [1, 3], previous studies suggest that a single urine sample can accurately reflect phthalate exposure over the previous 3 months [14, 94, 95]. However, previous reports suggest that metabolite concentrations have equivocal reproducibility in pregnant women, especially during the last 6 weeks of pregnancy (intraclass correlation for DEHP metabolites ranging from 0.30 to 0.36; for ΣDEHP =0.08) [96, 97]. Thus, the use of a single sample in the studies assessing the exposure during the 3rd trimester (majority of the studies) could result in significant exposure misclassification. Collection of repeated samples (one per pregnancy trimester) to account for intra-individual variation in DEHP biomarker levels is strongly recommended. Further, standardization for the time of day may be needed to account for within-individual variability [11, 16]. Finally, it was previously reported that urinary creatinine excretion may be affected by individual characteristics, including age, muscle mass, and race, as well as lifestyle factors, such as diet and physical activity [16]. Creatinine excretion may vary during the course of pregnancy and specific gravity may be more effective in correcting for urine dilution later in pregnancy as it is not influenced by individual factors, thus reducing the chances for exposure misclassification [16, 97, 98].

It remains unclear which window of susceptibility during pregnancy would be more relevant for the potential effect of phthalates on adverse birth outcomes. A recent report indicates that both early and late exposures during pregnancy could have implications for preterm birth [74]. Previous studies on the associations of other environmental exposures with birth outcomes suggest that exposures during the 2nd and 3rd trimester could have greater impact on birth outcomes, as the result of more rapid fetal weight gain in the 3rd trimester as well as disrupting effects of DEHP on parturition [76, 99, 100]. In some of the included studies, the samples were collected in the 1st trimester while others have varied sample collection timing [77, 78, 80, 84]. In addition, some of the effects of phthalates on selected outcomes, such as birthweight, could potentially result from “fetal programming” earlier in pregnancy leading to long-term effects on structure, physiology and metabolism [101-103]. For example, undernutrition in the 1st trimester of pregnancy has been linked to increased birth weight [102] suggesting possible importance of this crucial period for metabolic programming. Thus, exposure assessment during different windows of susceptibility is warranted for better understanding of the effects of DEHP exposure on birth outcomes.

It has been previously shown that a higher ratio of MEHP to MEHHP or MEHP to MEOHP is associated with a greater physiologic effect and potentially greater endocrine disrupting capacity as compared to individual metabolites [7]. It was also suggested that MEHP, but not other metabolites, can disturb energy metabolism of fat cells [104], a mechanism which could potentially lead to changes in birthweight. Only one study attempted to account for individual differences in phthalate metabolism by examining the ratio of MEHP concentration to the sum of MEHHP, MEOHP, and MECPP (% MEHP). Using the ratios of metabolites rather than individual metabolite concentrations in future studies could help to account better for different metabolic patterns. Finally, even though the evidence from animal studies suggests transplacental transfer of MEHP [105], findings from the studies in humans have been conflicting [14, 106]. Thus, the results of the studies on maternal MEHP concentrations and birthweight should be interpreted with caution.

4.3 Important confounders

Previous studies suggest that several maternal factors and environmental exposures can affect birthweight and duration of pregnancy. Maternal weight gain during the 2nd and 3rd trimester, history of diabetes and gestational diabetes, and maternal smoking and alcohol use increase the risk of adverse birth outcomes [107-113]. However, only a few of the studies in this review accounted for possible confounding effect of these risk factors and some of the findings could be explained in part by the residual confounding effects. Adjustment for these risk factors in future studies is warranted.

5. Conclusions

We found no consistent evidence of the association of phthalates with preterm delivery, gestational age, and birthweight across the studies included in this review, which might be explained by the heterogeneity of the studies. Given the aforementioned methodological gaps that likely contributed to the findings, addressing these concerns in more thorough investigation of these associations is warranted to advance our scientific knowledge on the potential effects of DEHP exposure on birth outcomes.

Highlights.

  • The evidence on association of DEHP with adverse pregnancy outcomes is inconsistent

  • Heterogeneity of the included studies precludes a direct comparison of the findings

  • Some of the findings should be interpreted with caution due to design limitations

  • Future studies should address methodological concerns identified in this review

Acknowledgments

This work was supported by the Agency for Healthcare Research and Quality (K01 HS022330); the Foundation for Barnes-Jewish Hospital; and the National Institutes of Health (U54 CA155496).

Financial support: This work was supported by the Agency for Healthcare Research and Quality (K01 HS022330 to S-H.C.); the Foundation for Barnes-Jewish Hospital; and the National Institutes of Health (U54 CA155496 to S-H.C.).

Footnotes

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Contributor Information

Gabriela L. Ghita, Email: glghita0429@ufl.edu.

Marilyn Dumont-Driscoll, Email: dumonmd@peds.ufl.edu.

Richard A. Yost, Email: ryost@chem.ufl.edu.

Su-Hsin Chang, Email: changsh@wudosis.wustl.edu.

References

  • 1.Diamanti-Kandarakis E, Bourguignon JP, Giudice LC, Hauser R, Prins GS, Soto AM, et al. Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr Rev. 2009;30:293–342. doi: 10.1210/er.2009-0002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Olujimi OO, Fatoki OS, Odendaal JP, Okonkwo JO. Endocrine disrupting chemicals (phenol and phthalates) in the South African environment: a need for more monitoring. Water SA. 2010;36:671–682. [Google Scholar]
  • 3.Duty SM, Ackerman RM, Calafat AM, Hauser R. Personal care product use predicts urinary concentrations of some phthalate monoesters. Environ Health Perspect. 2005;113:1530–5. doi: 10.1289/ehp.8083. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Kato K, Silva MJ, Needham LL, Calafat AM. Determination of 16 phthalate metabolites in urine using automated sample preparation and on-line preconcentration/high-performance liquid chromatography/tandem mass spectrometry. Anal Chem. 2005;77:2985–91. doi: 10.1021/ac0481248. [DOI] [PubMed] [Google Scholar]
  • 5.CDC. Center for Disease Control and Prevention. Fourth National Report on Human Exposure to Environmental Chemicals. 2009 [Google Scholar]
  • 6.Wittassek M, Koch HM, Angerer J, Bruning T. Assessing exposure to phthalates - the human biomonitoring approach. Mol Nutr Food Res. 2011;55:7–31. doi: 10.1002/mnfr.201000121. [DOI] [PubMed] [Google Scholar]
  • 7.Frederiksen H, Skakkebaek NE, Andersson AM. Metabolism of phthalates in humans. Molecular Nutrition & Food Research. 2007;51:899–911. doi: 10.1002/mnfr.200600243. [DOI] [PubMed] [Google Scholar]
  • 8.Koch HM, Preuss R, Angerer J. Di(2-ethylhexyl)phthalate (DEHP): human metabolism and internal exposure-- an update and latest results. Int J Androl. 2006;29:155–65. doi: 10.1111/j.1365-2605.2005.00607.x. discussion 181-5. [DOI] [PubMed] [Google Scholar]
  • 9.Albro PW, Corbett JT, Schroeder JL, Jordan S, Matthews HB. Pharmacokinetics, interactions with macromolecules and species differences in metabolism of DEHP. Environ Health Perspect. 1982;45:19–25. doi: 10.1289/ehp.824519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Albro PW, Lavenhar SR. Metabolism of di(2-ethylhexyl)phthalate. Drug Metab Rev. 1989;21:13–34. doi: 10.3109/03602538909029953. [DOI] [PubMed] [Google Scholar]
  • 11.Hauser R, Calafat AM. Phthalates and human health. Occup Environ Med. 2005;62:806–18. doi: 10.1136/oem.2004.017590. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Meeker JD, Sathyanarayana S, Swan SH. Phthalates and other additives in plastics: human exposure and associated health outcomes. Philos Trans R Soc Lond B Biol Sci. 2009;364:2097–113. doi: 10.1098/rstb.2008.0268. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Talsness CE, Andrade AJ, Kuriyama SN, Taylor JA, vom Saal FS. Components of plastic: experimental studies in animals and relevance for human health. Philos Trans R Soc Lond B Biol Sci. 2009;364:2079–96. doi: 10.1098/rstb.2008.0281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Lyche JL, Gutleb AC, Bergman A, Eriksen GS, Murk AJ, Ropstad E, et al. Reproductive and developmental toxicity of phthalates. J Toxicol Environ Health B Crit Rev. 2009;12:225–49. doi: 10.1080/10937400903094091. [DOI] [PubMed] [Google Scholar]
  • 15.Koch HM, Rossbach B, Drexler H, Angerer J. Internal exposure of the general population to DEHP and other phthalates--determination of secondary and primary phthalate monoester metabolites in urine. Environ Res. 2003;93:177–85. doi: 10.1016/s0013-9351(03)00083-5. [DOI] [PubMed] [Google Scholar]
  • 16.Johns LE, Cooper GS, Galizia A, Meeker JD. Exposure assessment issues in epidemiology studies of phthalates. Environment International. 2015;85:27–39. doi: 10.1016/j.envint.2015.08.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Gray LE, Jr, Wilson VS, Stoker T, Lambright C, Furr J, Noriega N, et al. Adverse effects of environmental antiandrogens and androgens on reproductive development in mammals. Int J Androl. 2006;29:96–104. doi: 10.1111/j.1365-2605.2005.00636.x. discussion 105-8. [DOI] [PubMed] [Google Scholar]
  • 18.Gray LE, Ostby J, Furr J, Wolf CJ, Lambright C, Parks L, et al. Effects of environmental antiandrogens on reproductive development in experimental animals. Hum Reprod Update. 2001;7:248–64. doi: 10.1093/humupd/7.3.248. [DOI] [PubMed] [Google Scholar]
  • 19.Shehata A, Mohamed Z, El-Haleem M, Samak M. J Clin Toxicol. 2013;3:169–178. [Google Scholar]
  • 20.Rusyn I, Peters JM, Cunningham ML. Effects of DEHP in the Liver: Modes of Action and Species-Specific Differences. Critical reviews in toxicology. 2006;36:459–479. doi: 10.1080/10408440600779065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Wei Z, Song L, Wei J, Chen T, Chen J, Lin Y, et al. Maternal exposure to di-(2-ethylhexyl)phthalate alters kidney development through the renin–angiotensin system in offspring. Toxicology Letters. 2012;212:212–221. doi: 10.1016/j.toxlet.2012.05.023. [DOI] [PubMed] [Google Scholar]
  • 22.Kluwe WM, Huff JE, Matthews HB, Irwin R, Haseman JK. Comparative chronic toxicities and carcinogenic potentials of 2-ethylhexyl-containing compounds in rats and mice. Carcinogenesis. 1985;6:1577–1583. doi: 10.1093/carcin/6.11.1577. [DOI] [PubMed] [Google Scholar]
  • 23.Kluwe WM, McConnell EE, Huff JE, Haseman JK, Douglas JF, Hartwell WV. Carcinogenicity testing of phthalate esters and related compounds by the National Toxicology Program and the National Cancer Institute. Environmental Health Perspectives. 1982;45:129–133. doi: 10.1289/ehp.8245129. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Ito Y, Yamanoshita O, Asaeda N, Tagawa Y, Lee CH, Aoyama T, et al. Di(2-ethylhexyl)phthalate Induces Hepatic Tumorigenesis through a Peroxisome Proliferator-activated Receptor α-independent Pathway. Journal of Occupational Health. 2007;49:172–182. doi: 10.1539/joh.49.172. [DOI] [PubMed] [Google Scholar]
  • 25.Crocker JF, Safe SH, Acott P. Effects of chronic phthalate exposure on the kidney. J Toxicol Environ Health. 1988;23:433–44. doi: 10.1080/15287398809531126. [DOI] [PubMed] [Google Scholar]
  • 26.Colon I, Caro D, Bourdony CJ, Rosario O. Identification of phthalate esters in the serum of young Puerto Rican girls with premature breast development. Environ Health Perspect. 2000;108:895–900. doi: 10.1289/ehp.108-2556932. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Buck Louis GM, Gray LE, Jr, Marcus M, Ojeda SR, Pescovitz OH, Witchel SF, et al. Environmental factors and puberty timing: expert panel research needs. Pediatrics. 2008;(3):121. S192–207. doi: 10.1542/peds.1813E. [DOI] [PubMed] [Google Scholar]
  • 28.Cobellis L, Latini G, De Felice C, Razzi S, Paris I, Ruggieri F, et al. High plasma concentrations of di-(2-ethylhexyl)-phthalate in women with endometriosis. Hum Reprod. 2003;18:1512–5. doi: 10.1093/humrep/deg254. [DOI] [PubMed] [Google Scholar]
  • 29.Reddy BS, Rozati R, Reddy BV, Raman NV. Association of phthalate esters with endometriosis in Indian women. BJOG. 2006;113:515–20. doi: 10.1111/j.1471-0528.2006.00925.x. [DOI] [PubMed] [Google Scholar]
  • 30.Duty SM, Silva MJ, Barr DB, Brock JW, Ryan L, Chen Z, et al. Phthalate exposure and human semen parameters. Epidemiology. 2003;14:269–77. [PubMed] [Google Scholar]
  • 31.Hauser R, Meeker JD, Duty S, Silva MJ, Calafat AM. Altered semen quality in relation to urinary concentrations of phthalate monoester and oxidative metabolites. Epidemiology. 2006;17:682–91. doi: 10.1097/01.ede.0000235996.89953.d7. [DOI] [PubMed] [Google Scholar]
  • 32.Joensen UN, Frederiksen H, Jensen MB, Lauritsen MP, Olesen IA, Lassen TH, et al. Phthalate excretion pattern and testicular function: a study of 881 healthy Danish men. Environ Health Perspect. 2012;120:1397–403. doi: 10.1289/ehp.1205113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Swan SH. Environmental phthalate exposure in relation to reproductive outcomes and other health endpoints in humans. Environ Res. 2008;108:177–84. doi: 10.1016/j.envres.2008.08.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Meeker JD, Hu H, Cantonwine DE, Lamadrid-Figueroa H, Calafat AM, Ettinger AS, et al. Urinary phthalate metabolites in relation to preterm birth in Mexico city. Environ Health Perspect. 2009;117:1587–92. doi: 10.1289/ehp.0800522. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.James-Todd T, Stahlhut R, Meeker JD, Powell SG, Hauser R, Huang T, et al. Urinary Phthalate Metabolite Concentrations and Diabetes among Women in the National Health and Nutrition Examination Survey (NHANES) 2001-2008. Environ Health Perspect. 2012;120:1307–13. doi: 10.1289/ehp.1104717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Stahlhut RW, van Wijngaarden E, Dye TD, Cook S, Swan SH. Concentrations of urinary phthalate metabolites are associated with increased waist circumference and insulin resistance in adult U.S. males. Environ Health Perspect. 2007;115:876–82. doi: 10.1289/ehp.9882. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Lind PM, Zethelius B, Lind L. Circulating levels of phthalate metabolites are associated with prevalent diabetes in the elderly. Diabetes Care. 2012;35:1519–24. doi: 10.2337/dc11-2396. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Svensson K, Hernandez-Ramirez RU, Burguete-Garcia A, Cebrian ME, Calafat AM, Needham LL, et al. Phthalate exposure associated with self-reported diabetes among Mexican women. Environ Res. 2011;111:792–6. doi: 10.1016/j.envres.2011.05.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Lopez-Carrillo L, Hernandez-Ramirez RU, Calafat AM, Torres-Sanchez L, Galvan-Portillo M, Needham LL, et al. Exposure to phthalates and breast cancer risk in northern Mexico. Environ Health Perspect. 2010;118:539–44. doi: 10.1289/ehp.0901091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Yaghjyan L, Sites S, Ruan Y, Chang SH. Associations of urinary phthalates with body mass index, waist circumference and serum lipids among females: National Health and Nutrition Examination Survey 1999-2004. Int J Obes (Lond) 2015 doi: 10.1038/ijo.2015.8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Meeker J, Ferguson K. Phthalates: Human Exposure and Related Health Effects. In: Schecter A, editor. Dioxins and Health. 3rd. Hoboken, NJ: John Wiley & Sons; 2012. [Google Scholar]
  • 42.Beyerlein A, Lack N, von Kries R. Within-population average ranges compared with Institute of Medicine recommendations for gestational weight gain. Obstet Gynecol. 2010;116:1111–8. doi: 10.1097/AOG.0b013e3181f1ad8b. [DOI] [PubMed] [Google Scholar]
  • 43.International Agency for Research on Cancer. Di(2-ethylhexyl)phthalate; Sup 7, 77, 101. Lion, France: 2013. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. [PMC free article] [PubMed] [Google Scholar]
  • 44.Campioli E, Batarseh A, Li J, Papadopoulos V. The Endocrine Disruptor Mono-(2-Ethylhexyl) Phthalate Affects the Differentiation of Human Liposarcoma Cells (SW 872) PLoS One. 2011;6:e28750. doi: 10.1371/journal.pone.0028750. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Dees JH, Gazouli M, Papadopoulos V. Effect of mono-ethylhexyl phthalate on MA-10 Leydig tumor cells. Reproductive Toxicology. 2001;15:171–187. doi: 10.1016/s0890-6238(01)00110-1. [DOI] [PubMed] [Google Scholar]
  • 46.Martinez-Arguelles DB, Papadopoulos V. Mechanisms Mediating Environmental Chemical-Induced Endocrine Disruption in the Adrenal Gland. Frontiers in Endocrinology. 2015;6:29. doi: 10.3389/fendo.2015.00029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Huber WW, Grasl-Kraupp B, Schulte-Hermann R. Hepatocarcinogenic potential of di(2-ethylhexyl)phthalate in rodents and its implications on human risk. Crit Rev Toxicol. 1996;26:365–481. doi: 10.3109/10408449609048302. [DOI] [PubMed] [Google Scholar]
  • 48.Lapinskas PJ, Brown S, Leesnitzer LM, Blanchard S, Swanson C, Cattley RC, et al. Role of PPARα in mediating the effects of phthalates and metabolites in the liver. Toxicology. 2005;207:149–163. doi: 10.1016/j.tox.2004.09.008. [DOI] [PubMed] [Google Scholar]
  • 49.Ferguson KK, McElrath TF, Chen YH, Mukherjee B, Meeker JD. Urinary phthalate metabolites and biomarkers of oxidative stress in pregnant women: a repeated measures analysis. Environ Health Perspect. 2015;123:210–6. doi: 10.1289/ehp.1307996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Ajjan RA, Watson PF, Weetman AP. Cytokines and thyroid function. Adv Neuroimmunol. 1996;6:359–86. doi: 10.1016/s0960-5428(97)00027-7. [DOI] [PubMed] [Google Scholar]
  • 51.Ferguson KK, Cantonwine DE, Rivera-Gonzalez LO, Loch-Caruso R, Mukherjee B, Anzalota Del Toro LV, et al. Urinary phthalate metabolite associations with biomarkers of inflammation and oxidative stress across pregnancy in Puerto Rico. Environ Sci Technol. 2014;48:7018–25. doi: 10.1021/es502076j. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Ferguson KK, Loch-Caruso R, Meeker JD. Exploration of oxidative stress and inflammatory markers in relation to urinary phthalate metabolites: NHANES 1999-2006. Environ Sci Technol. 2012;46:477–85. doi: 10.1021/es202340b. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Vetrano AM, Laskin DL, Archer F, Syed K, Gray JP, Laskin JD, et al. Inflammatory effects of phthalates in neonatal neutrophils. Pediatr Res. 2010;68:134–9. doi: 10.1203/PDR.0b013e3181e5c1f7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Meeker JD, Calafat AM, Hauser R. Di(2-ethylhexyl) phthalate metabolites may alter thyroid hormone levels in men. Environ Health Perspect. 2007;115:1029–34. doi: 10.1289/ehp.9852. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Meeker JD, Ferguson KK. Relationship between urinary phthalate and bisphenol A concentrations and serum thyroid measures in U.S. adults and adolescents from the National Health and Nutrition Examination Survey (NHANES) 2007-2008. Environ Health Perspect. 2011;119:1396–402. doi: 10.1289/ehp.1103582. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Boas M, Main KM, Feldt-Rasmussen U. Environmental chemicals and thyroid function: an update. Curr Opin Endocrinol Diabetes Obes. 2009;16:385–91. doi: 10.1097/MED.0b013e3283305af7. [DOI] [PubMed] [Google Scholar]
  • 57.Boas M, Frederiksen H, Feldt-Rasmussen U, Skakkebaek NE, Hegedus L, Hilsted L, et al. Childhood exposure to phthalates: associations with thyroid function, insulin-like growth factor I, and growth. Environ Health Perspect. 2010;118:1458–64. doi: 10.1289/ehp.0901331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Stagnaro-Green A. Maternal thyroid disease and preterm delivery. J Clin Endocrinol Metab. 2009;94:21–5. doi: 10.1210/jc.2008-1288. [DOI] [PubMed] [Google Scholar]
  • 59.López M, Figueras F, Coll O, Goncé A, Hernández S, Loncá M, et al. Inflammatory Markers Related to Microbial Translocation Among HIV-Infected Pregnant Women: A Risk Factor of Preterm Delivery. Journal of Infectious Diseases. 2015 doi: 10.1093/infdis/jiv416. [DOI] [PubMed] [Google Scholar]
  • 60.Ferguson KK, McElrath TF, Chen YH, Loch-Caruso R, Mukherjee B, Meeker JD. Repeated measures of urinary oxidative stress biomarkers during pregnancy and preterm birth. Am J Obstet Gynecol. 2015;212:208 e1–8. doi: 10.1016/j.ajog.2014.08.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Menon R. Oxidative stress damage as a detrimental factor in preterm birth pathology. Frontiers in Immunology. 2014;5 doi: 10.3389/fimmu.2014.00567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Mattison DR, Damus K, Fiore E, Petrini J, Alter C. Preterm delivery: a public health perspective. Paediatr Perinat Epidemiol. 2001;15(2):7–16. doi: 10.1046/j.1365-3016.2001.00004.x. [DOI] [PubMed] [Google Scholar]
  • 63.McCormick MC, Litt JS, Smith VC, Zupancic JA. Prematurity: an overview and public health implications. Annu Rev Public Health. 2011;32:367–79. doi: 10.1146/annurev-publhealth-090810-182459. [DOI] [PubMed] [Google Scholar]
  • 64.Parets SE, Bedient CE, Menon R, Smith AK. Preterm birth and its long-term effects: methylation to mechanisms. Biology (Basel) 2014;3:498–513. doi: 10.3390/biology3030498. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Sutherland MR, Bertagnolli M, Lukaszewski MA, Huyard F, Yzydorczyk C, Luu TM, et al. Preterm birth and hypertension risk: the oxidative stress paradigm. Hypertension. 2014;63:12–8. doi: 10.1161/HYPERTENSIONAHA.113.01276. [DOI] [PubMed] [Google Scholar]
  • 66.Gunay F, Alpay H, Gokce I, Bilgen H. Is late-preterm birth a risk factor for hypertension in childhood? Eur J Pediatr. 2014;173:751–6. doi: 10.1007/s00431-013-2242-x. [DOI] [PubMed] [Google Scholar]
  • 67.Leong NM, Mignone LI, Newcomb PA, Titus-Ernstoff L, Baron JA, Trentham-Dietz A, et al. Early life risk factors in cancer: the relation of birth weight to adult obesity. Int J Cancer. 2003;103:789–91. doi: 10.1002/ijc.10886. [DOI] [PubMed] [Google Scholar]
  • 68.Tamimi RM, Lagiou P, Czene K, Liu J, Ekbom A, Hsieh CC, et al. Birth weight, breast cancer susceptibility loci, and breast cancer risk. Cancer Causes Control. 2010;21:689–96. doi: 10.1007/s10552-009-9496-7. [DOI] [PubMed] [Google Scholar]
  • 69.Park SK, Kang D, McGlynn KA, Garcia-Closas M, Kim Y, Yoo KY, et al. Intrauterine environments and breast cancer risk: meta-analysis and systematic review. Breast Cancer Res. 2008;10:R8. doi: 10.1186/bcr1850. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Xue F, Michels KB. Intrauterine factors and risk of breast cancer: a systematic review and meta-analysis of current evidence. Lancet Oncol. 2007;8:1088–100. doi: 10.1016/S1470-2045(07)70377-7. [DOI] [PubMed] [Google Scholar]
  • 71.Snijder CA, Roeleveld N, Te Velde E, Steegers EA, Raat H, Hofman A, et al. Occupational exposure to chemicals and fetal growth: the Generation R Study. Hum Reprod. 2012;27:910–20. doi: 10.1093/humrep/der437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72.Burdorf A, Brand T, Jaddoe VW, Hofman A, Mackenbach JP, Steegers EAP. The effects of work-related maternal risk factors on time to pregnancy, preterm birth and birth weight: the Generation R Study. Occupational and Environmental Medicine. 2011;68:197–204. doi: 10.1136/oem.2009.046516. [DOI] [PubMed] [Google Scholar]
  • 73.Ferguson KK, McElrath TF, Meeker JD. Environmental phthalate exposure and preterm birth. JAMA Pediatr. 2014;168:61–7. doi: 10.1001/jamapediatrics.2013.3699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Ferguson KK, McElrath TF, Ko YA, Mukherjee B, Meeker JD. Variability in urinary phthalate metabolite levels across pregnancy and sensitive windows of exposure for the risk of preterm birth. Environ Int. 2014;70:118–24. doi: 10.1016/j.envint.2014.05.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Huang Y, Li J, Garcia JM, Lin H, Wang Y, Yan P, et al. Phthalate levels in cord blood are associated with preterm delivery and fetal growth parameters in Chinese women. PLoS One. 2014;9:e87430. doi: 10.1371/journal.pone.0087430. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76.Adibi JJ, Hauser R, Williams PL, Whyatt RM, Calafat AM, Nelson H, et al. Maternal urinary metabolites of Di-(2-Ethylhexyl) phthalate in relation to the timing of labor in a US multicenter pregnancy cohort study. Am J Epidemiol. 2009;169:1015–24. doi: 10.1093/aje/kwp001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Suzuki Y, Niwa M, Yoshinaga J, Mizumoto Y, Serizawa S, Shiraishi H. Prenatal exposure to phthalate esters and PAHs and birth outcomes. Environ Int. 2010;36:699–704. doi: 10.1016/j.envint.2010.05.003. [DOI] [PubMed] [Google Scholar]
  • 78.Huang PC, Kuo PL, Chou YY, Lin SJ, Lee CC. Association between prenatal exposure to phthalates and the health of newborns. Environment International. 2009;35:14–20. doi: 10.1016/j.envint.2008.05.012. [DOI] [PubMed] [Google Scholar]
  • 79.Latini G, De Felice C, Presta G, Del Vecchio A, Paris I, Ruggieri F, et al. In utero exposure to di-(2-ethylhexyl)phthalate and duration of human pregnancy. Environ Health Perspect. 2003;111:1783–5. doi: 10.1289/ehp.6202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Lenters V, Portengen L, Rignell-Hydbom A, Jonsson BA, Lindh CH, Piersma AH, et al. Prenatal Phthalate, Perfluoroalkyl Acid, and Organochlorine Exposures and Term Birth Weight in Three Birth Cohorts: Multi-Pollutant Models Based on Elastic Net Regression. Environ Health Perspect. 2015 doi: 10.1289/ehp.1408933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.Zhang Y, Lin L, Cao Y, Chen B, Zheng L, Ge RS. Phthalate levels and low birth weight: a nested case-control study of Chinese newborns. J Pediatr. 2009;155:500–4. doi: 10.1016/j.jpeds.2009.04.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82.Zhao Y, Shi HJ, Xie CM, Chen J, Laue H, Zhang YH. Prenatal phthalate exposure, infant growth, and global DNA methylation of human placenta. Environ Mol Mutagen. 2015;56:286–92. doi: 10.1002/em.21916. [DOI] [PubMed] [Google Scholar]
  • 83.Steenland K, Savitz D. Future trends in environmental epidemiology. In: Steenland K, Savitz DA, editors. Topic in Environmental Epidemiology. New York: Oxford University Press; 1997. pp. 350–357. [Google Scholar]
  • 84.Philippat C, Mortamais M, Chevrier C, Petit C, Calafat AM, Ye X, et al. Exposure to phthalates and phenols during pregnancy and offspring size at birth. Environ Health Perspect. 2012;120:464–70. doi: 10.1289/ehp.1103634. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85.James-Todd TM, Meeker JD, Huang T, Hauser R, Seely EW, Ferguson KK, et al. Racial and ethnic variations in phthalate metabolite concentration changes across full-term pregnancies. J Expos Sci Environ Epidemiol. 2016 doi: 10.1038/jes.2016.2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86.Zota A, Woodruff T. Abstracts of the 2011 Conference of the International Society of Environmental Epidemiology (ISEE) Abstract 979. Research Triangle Park, NC: Environmental Health Perspectives; 2011. http://dx.doi.org/10.1289/ehp.isee2011. [Google Scholar]
  • 87.James-Todd TM, Chiu YH, Zota AR. Racial/Ethnic Disparities in Environmental Endocrine Disrupting Chemicals and Women's Reproductive Health Outcomes: Epidemiological Examples Across the Life Course. Current Epidemiology Reports. 2016;3:161–180. doi: 10.1007/s40471-016-0073-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88.Yaghjyan L, Carlsson NP, Ghita GL, Chang SH. Associations of individual characteristics and lifestyle factors with metabolism of di-2-ethylhexyl phthalate in NHANES 2001–2012. Environmental Research. 2016;149:23–31. doi: 10.1016/j.envres.2016.05.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89.Burris HH, Collins JW, Wright RO. Racial/ethnic disparities in preterm birth: clues from environmental exposures. Current opinion in pediatrics. 2011;23:227–232. doi: 10.1097/MOP.0b013e328344568f. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90.Bryant AS, Worjoloh A, Caughey AB, Washington AE. Racial/Ethnic Disparities in Obstetrical Outcomes and Care: Prevalence and Determinants. American journal of obstetrics and gynecology. 2010;202:335–343. doi: 10.1016/j.ajog.2009.10.864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 91.Huang T, Saxena AR, Isganaitis E, James-Todd T. Gender and racial/ethnic differences in the associations of urinary phthalate metabolites with markers of diabetes risk: national health and nutrition examination survey 2001–2008. Environmental Health. 2014;13:1–10. doi: 10.1186/1476-069X-13-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 92.Genuis SJ, Beesoon S, Lobo RA, Birkholz D. Human elimination of phthalate compounds: blood, urine, and sweat (BUS) study. ScientificWorldJournal. 2012;2012:615068. doi: 10.1100/2012/615068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 93.Calafat AM, Needham LL. Factors affecting the evaluation of biomonitoring data for human exposure assessment. International Journal of Andrology. 2008;31:139–143. doi: 10.1111/j.1365-2605.2007.00826.x. [DOI] [PubMed] [Google Scholar]
  • 94.Hauser R, Meeker JD, Park S, Silva MJ, Calafat AM. Temporal variability of urinary phthalate metabolite levels in men of reproductive age. Environ Health Perspect. 2004;112:1734–40. doi: 10.1289/ehp.7212. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 95.Hoppin JA, Brock JW, Davis BJ, Baird DD. Reproducibility of urinary phthalate metabolites in first morning urine samples. Environ Health Perspect. 2002;110:515–8. doi: 10.1289/ehp.02110515. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 96.Braun JM, Smith KW, Williams PL, Calafat AM, Berry K, Ehrlich S, et al. Variability of urinary phthalate metabolite and bisphenol A concentrations before and during pregnancy. Environ Health Perspect. 2012;120:739–45. doi: 10.1289/ehp.1104139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 97.Adibi JJ, Whyatt RM, Williams PL, Calafat AM, Camann D, Herrick R, et al. Characterization of Phthalate Exposure among Pregnant Women Assessed by Repeat Air and Urine Samples. Environmental Health Perspectives. 2008;116:467–473. doi: 10.1289/ehp.10749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 98.Davison JM, Dunlop W, Ezimokhai M. 24-hour creatinine clearance during the third trimester of normal pregnancy. Br J Obstet Gynaecol. 1980;87:106–9. doi: 10.1111/j.1471-0528.1980.tb04501.x. [DOI] [PubMed] [Google Scholar]
  • 99.van den Hooven EH, Pierik FH, de Kluizenaar Y, Willemsen SP, Hofman A, van Ratingen SW, et al. Air pollution exposure during pregnancy, ultrasound measures of fetal growth, and adverse birth outcomes: a prospective cohort study. Environ Health Perspect. 2012;120:150–6. doi: 10.1289/ehp.1003316. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 100.England LJ, Kendrick JS, Wilson HG, Merritt RK, Gargiullo PM, Zahniser SC. Effects of smoking reduction during pregnancy on the birth weight of term infants. Am J Epidemiol. 2001;154:694–701. doi: 10.1093/aje/154.8.694. [DOI] [PubMed] [Google Scholar]
  • 101.Godfrey KM, Barker DJ. Fetal programming and adult health. Public Health Nutr. 2001;4:611–24. doi: 10.1079/phn2001145. [DOI] [PubMed] [Google Scholar]
  • 102.Langley-Evans SC. Developmental programming of health and disease. Proc Nutr Soc. 2006;65:97–105. doi: 10.1079/pns2005478. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 103.Barker DJP. The malnourished baby and infant: Relationship with Type 2 diabetes. British Medical Bulletin. 2001;60:69–88. doi: 10.1093/bmb/60.1.69. [DOI] [PubMed] [Google Scholar]
  • 104.Chiang HC, Kuo YT, Shen CC, Lin YH, Wang SL, Tsou TC. Mono(2-ethylhexyl)phthalate accumulation disturbs energy metabolism of fat cells. Arch Toxicol. 2014 doi: 10.1007/s00204-014-1446-9. [DOI] [PubMed] [Google Scholar]
  • 105.U.S. Department of Health and Human Services. Public Health Service Agency for Toxic Substances and Disease Registry. Toxicological profile for Di(2-ethylhexyl)phthalate. 2002 [PubMed] [Google Scholar]
  • 106.Mose T, Knudsen LE, Hedegaard M, Mortensen GK. Transplacental transfer of monomethyl phthalate and mono(2-ethylhexyl) phthalate in a human placenta perfusion system. Int J Toxicol. 2007;26:221–9. doi: 10.1080/10915810701352721. [DOI] [PubMed] [Google Scholar]
  • 107.Ludwig DS, Currie J. The association between pregnancy weight gain and birthweight: a within-family comparison. The Lancet. 376:984–990. doi: 10.1016/S0140-6736(10)60751-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 108.Frederick I, Williams M, Sales A, Martin D, Killien M. Pre-pregnancy Body Mass Index, Gestational Weight Gain, and Other Maternal Characteristics in Relation to Infant Birth Weight. Maternal and Child Health Journal. 2008:12, 557–567. doi: 10.1007/s10995-007-0276-2. [DOI] [PubMed] [Google Scholar]
  • 109.Chiolero A, Bovet P, Paccaud F. Association between maternal smoking and low birth weight in Switzerland: the EDEN study. Swiss Med Wkly. 2005;135:525–30. doi: 10.4414/smw.2005.11122. [DOI] [PubMed] [Google Scholar]
  • 110.Bernstein IM, Mongeon JA, Badger GJ, Solomon L, Heil SH, Higgins ST. Maternal smoking and its association with birth weight. Obstet Gynecol. 2005;106:986–91. doi: 10.1097/01.AOG.0000182580.78402.d2. [DOI] [PubMed] [Google Scholar]
  • 111.Mills JL, Graubard BI, Harley EE, Rhoads GG, Berendes HW. Maternal alcohol consumption and birth weight: How much drinking during pregnancy is safe? JAMA. 1984;252:1875–1879. [PubMed] [Google Scholar]
  • 112.Nykjaer C, Alwan NA, Greenwood DC, Simpson NAB, Hay AWM, White KLM, et al. Maternal alcohol intake prior to and during pregnancy and risk of adverse birth outcomes: evidence from a British cohort. Journal of Epidemiology and Community Health. 2014 doi: 10.1136/jech-2013-202934. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 113.Ray JG, Vermeulen MJ, Shapiro JL, Kenshole AB. Maternal and neonatal outcomes in pregestational and gestational diabetes mellitus, and the influence of maternal obesity and weight gain: the DEPOSIT study. Diabetes Endocrine Pregnancy Outcome Study in Toronto. QJM. 2001;94:347–56. doi: 10.1093/qjmed/94.7.347. [DOI] [PubMed] [Google Scholar]
  • 114.Wolff MS, Engel SM, Berkowitz GS, Ye X, Silva MJ, Zhu C, et al. Prenatal phenol and phthalate exposures and birth outcomes. Environ Health Perspect. 2008;116:1092–7. doi: 10.1289/ehp.11007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 115.Whyatt RM, Adibi JJ, Calafat AM, Camann DE, Rauh V, Bhat HK, et al. Prenatal Di(2-ethylhexyl)Phthalate Exposure and Length of Gestation Among an Inner-City Cohort. Pediatrics. 2009;124:e1213–e1220. doi: 10.1542/peds.2009-0325. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 116.Weinberger B, Vetrano AM, Archer FE, Marcella SW, Buckley B, Wartenberg D, et al. Effects of maternal exposure to phthalates and bisphenol A during pregnancy on gestational age. J Matern Fetal Neonatal Med. 2014;27:323–7. doi: 10.3109/14767058.2013.815718. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 117.Casas M, Valvi D, Ballesteros-Gomez A, Gascon M, Fernandez MF, Garcia-Esteban R, et al. Exposure to Bisphenol A and Phthalates during Pregnancy and Ultrasound Measures of Fetal Growth in the INMA-Sabadell Cohort. Environ Health Perspect. 2015 doi: 10.1289/ehp.1409190. [DOI] [PMC free article] [PubMed] [Google Scholar]

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