Environment International 157 (2021) 106854

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Environment International
journal homepage: www.elsevier.com/locate/envint

Gestational triclosan exposure and infant birth weight: A systematic review

and meta-analysis
Marisa A. Patti a, *, Noelle B. Henderson a, Priya Gajjar a, Melissa Eliot a, Medina Jackson-
Browne b, Joseph M. Braun a
a
Brown University School of Public Health, 121 S. Main Street, Providence, RI 02912, United States
b
University of Delaware, 210 South College Ave, Newark, DE 19716, United States

A R T I C L E I N F O A B S T R A C T

Handling Editor: Hanna Boogaard Background: Exposure to triclosan, an antimicrobial chemical used in some personal care and cleaning products,
has been associated with reduced birth weight in some, but not all epidemiological studies.
Keywords: Objectives: We conducted a systematic review and meta-analysis to characterize the relation of gestational tri­
Birth weight closan exposure with infant birth weight and identify sources of heterogeneity between studies.
Birthweight
Methods: We identified original studies measuring urinary triclosan concentrations during pregnancy and
Prenatal
reporting their association with infant birth weight, gestational age (GA) adjusted birth weight (g), or GA-
Triclosan
standardized birth weight z-scores. Using a random effects model, we estimated differences in these outcomes
per 10-fold increase in triclosan concentrations and considered triclosan levels and infant sex as sources of
heterogeneity. Using Navigation Guide Methods, we evaluated risk of bias within individual studies and across
the body of evidence.
Results: Among thirteen studies, median triclosan concentrations varied by almost 2-orders of magnitude (0.6–29
ng/mL), with higher concentrations in North American and some European studies compared to Asian ones.
Associations between triclosan and birth weight (β:-20 g; 95% CI:-65, 26; n = 6) were stronger than those for GA-
adjusted birth weight (β:-12 g; 95% CI:-29, 5; n = 9). Triclosan was not associated with GA-standardized birth
weight z-scores (β:-0.04; 95% CI:-0.16, 0.07; n = 5). The association between triclosan and GA-adjusted birth
weight was stronger in studies with median triclosan values ≥10 ng/mL compared to studies with median values
< 10 ng/mL (β:-27 g; 95% CI:-61, 7; n = 4 vs. β:6g; 95% CI:-20, 31; n = 5). With a limited number of studies, we
observed suggestive evidence that inverse associations were more apparent in studies with ≥ 2 prospective
triclosan measures compared to those with one measure.
Discussion: Available evidence, with “low” risk of bias, provides limited evidence that triclosan exposure and
reduces infant birth weight. We observed stronger inverse associations between triclosan concentrations and
birth weight in populations with higher triclosan exposure.

1. Introduction exposed through routine use of triclosan containing products. Up to 75%

Triclosan is a man-made antimicrobial chemical used in some per­
sonal care and cleaning products (Dann and Hontela 2011; Geer et al.
2017), including some toothpastes, mouthwashes, soaps, and lotions.
Human exposure occurs primarily through dermal or oral routes
(Rodricks et al. 2010). Triclosan is non-persistent in the body with a
biological half-life of ~21 h (Sandborgh-Englund et al. 2006). While
triclosan has a short biological half-life, individuals can be chronically
of the United States (US) population has detectable urinary triclosan
concentrations, and generally higher concentrations of triclosan are
detected in women, and those with higher education and income
(Arbuckle et al. 2015; Calafat et al. 2010; Han et al. 2016). There is
concern over the potential health effects of triclosan because it has been
found to adversely affect the hypothalamic-pituitary-thyroid axis in
both experimental studies using rodents and observational studies of
humans (Braun et al. 2018; Brucker-Davis 1998; Johnson et al. 2016;

* Corresponding author at: School of Public Health, Brown University, 121 S. Main Street, Box G-S121-3, Providence, RIc 02912, United States.
E-mail addresses: marisa_patti@brown.edu (M.A. Patti), noelle_henderson@alumni.brown.edu (N.B. Henderson), priya_gajjar@brown.edu (P. Gajjar), Melissa_
Eliot@brown.edu (M. Eliot), mjbrowne@udel.edu (M. Jackson-Browne), joseph_braun_1@brown.edu (J.M. Braun).

https://doi.org/10.1016/j.envint.2021.106854
Received 21 January 2021; Received in revised form 2 August 2021; Accepted 30 August 2021
Available online 21 September 2021
0160-4120/© 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
M.A. Patti et al.
Skarha et al. 2019).
Adequate thyroid hormone concentrations are essential during fetal
development and failure for the mother or developing fetus to maintain
sufficient thyroid hormone concentrations during gestation has been
associated with adverse fetal growth trajectories including reduced birth
length and head circumference (Bigsby et al. 1999; de Escobar et al.
2004; Lassen et al. 2016; Philippat et al. 2014; Wolff et al. 2008).
Maternal hypothyroidism has been previously associated with lower
birth weight (Derakhshan et al. 2020; Korevaar et al. 2017; Monen et al.
2015). Evidence for triclosan to alter maternal thyroid hormone con­
centrations have been found in both animal (Axelstad et al. 2013; Paul
et al. 2010; Rodríguez and Sanchez 2010) and human literature (John­
son et al. 2016; Braun et al. 2018p. 201; Wang et al. 2017).
Indeed, some, but not all, epidemiological studies report that
gestational urinary triclosan concentrations during pregnancy are
associated with decreased birth weight and neonatal anthropometry
(Calkins and Devaskar 2011; Gishti et al. 2014, 2015; Toemen et al.
2016). The heterogeneity in findings across the epidemiologic literature
warrants further investigation in order to better understand the under­
lying reasons which may be contributing to these disparate findings in
order to ultimately determine if triclosan adversely impacts fetal
growth.
Thus, we evaluated the relation between gestational urinary triclo­
san and infant birth weight by conducting a systematic review and meta-
analysis of human studies examining maternal exposure to triclosan
during gestation and infant birth weight. In addition to applying The
Navigation Guide criteria to these studies to assess risk of bias, we
evaluated several potential sources of heterogeneity, including different
birth weight outcomes, child sex, and median triclosan levels.
2. Methods
2.1. Systematic review methodology
We followed PRISMA guidelines as a reporting standard for our
systematic literature review (Moher et al. 2009). Systematic review
methodology has been previously used and validated in clinical sciences,
such as the Cochrane Collaboration and Grading of Recommendations
Assessment Development and Evaluation (Guyatt et al. 2008; Higgins
and Green 2011; Woodruff et al. 2011); however, such protocols for
conducting systematic reviews may not be applicable in the context of
environmental health (Johnson et al. 2014, 2016; Koustas et al. 2014;
Lam et al. 2014). For this reason, we used the Navigation Guide in
conjunction with PRISMA reporting guidelines. The Navigation Guide
differs from PRISMA in that it is a methodological framework for con­
ducting environmental health systematic reviews, (Johnson et al. 2014,
2016; Koustas et al. 2014; Lam et al. 2014, 2016; Vesterinen et al. 2015;
Woodruff et al. 2011) while the PRISMA guidelines are standards for
reporting how a systematic reviews and meta-analyses was conducted.
We developed our protocol for our systematic review prior to beginning
our initial literature search, and registered it in PROSPERO, registration
number: CRD42019147431 (Patti et al. 2019).
2.2. Study question
Our objective was to estimate the effect of gestational exposure to
triclosan on infant birth weight in the context of describing the dos­
e–response relation for risk characterization. Thus, we sought to answer
the question: “Among infants, what is the effect of a 10-fold increase in
maternal urinary concentrations of triclosan during gestation on infant
birth weight?” The “Participants”, “Exposure”, “Comparator” and
“Outcomes” (PECO) statement is outlined below (Morgan et al. 2018).
• Participants: Mothers and their newborn infants, the population was
human.
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Environment International 157 (2021) 106854
• Exposure: Maternal exposure to triclosan during the gestational
period assessed via urinary triclosan concentrations. Exposure to log-
10 transformed maternal urinary triclosan concentrations during
gestation.
• Comparator: Mother-infant dyads exposed to lower concentrations
of triclosan during gestation compared to those with higher con­
centrations of triclosan during gestation. An incremental increase of
log-10 transformed maternal urinary triclosan concentrations during
gestation on infant birth weight.
• Outcomes: Our primary outcome of interest was infant birthweight, a
marker of fetal growth. To make our review as comprehensive as
possible, we included all measures of birth weight reported across,
and within included studies. We considered infant birth weight
measured in three different ways: birth weight measured in grams
(g), birth weight measured in grams with multivariable adjustment
for gestational age (GA), and GA-standardized z-scores of birth
weight.
2.3. Data sources
We searched PubMed and Medline on May 29th, 2019, with search
terms identified within the supplement (Supplemental Table S1). The
Medical Subject Headings (MeSH) database was used to compile our
search terms used for triclosan and birth weight. Our search was limited
to studies published in English. While we did not limit our search based
on publication date, it is worth noting that triclosan did not enter the
consumer market until the 1970s (FDA 2016 Decision and History). We
updated our search on March 9, 2020, to identify any new studies. We
also used several databases to identify synonyms for triclosan, and
combined “triclosan” with all identified synonyms using the “OR”
statement. To identify synonyms for triclosan, we used PubChem,
Sigma-Aldrich, and ChemSpider (https://pubchem.ncbi.nlm.nih.
gov/#query=triclosan; https://www.sigmaaldrich.com/catalog/search
?term=triclosan&interface=All&N=0&mode=match%20partialma
x&lang=en&region=US&focus=product; http://www.chemspider.com
/Chemical-Structure.5363.html). Finally, we supplemented these re­
sults by hand-searching references of included studies in order to iden­
tify any additional publications not previously recognized.
2.4. Study selection
Original studies were included if they quantified the association
between maternal gestational triclosan, measured in urine samples, and
reported associations with at least 1 of the 3 birth weight outcomes of
interest (grams (g), grams plus adjustment for GA, GA-standardized
birth weight z-scores). References compiled from both search engines
were screened for duplicates. Two of 3 reviewers (M.P., N.H., P.G.)
independently screened the remaining articles at the title and abstract
level to determine eligibility for full text screening. At least 2 reviewers
independently screened the remaining articles through full text review.
Studies were excluded if they met any of the following criteria. 1) they
did not report original data; 2) the study was performed on animal
subjects; 3) maternal triclosan exposure was not quantitatively
measured in any biological sample; 4) infant birth weight was not
quantitatively measured as outcome; 5) the study was not available in
English.
2.5. Data extraction
At least 1 of 3 authors (M.P., N.H., P.G.) independently extracted
data related to study characteristics, exposure measures, outcome in­
formation, effect measures, and secondary analyses from all included
articles. A second author reviewed all extracted information. All 3 re­
viewers assessed and discussed discrepancies to ensure accuracy
amongst all 3 reviewers. We extracted relevant estimates of association
reporting the relation between maternal triclosan exposure and infant
M.A. Patti et al.
birth weight from the main text or any supplemental material.
For the meta-analysis, we extracted the fully adjusted, linear effect
estimate and 95% confidence interval. It should be noted that amongst
those studies that were considered meta-analyzable, exposures were
transformed and scaled differently across studies. In order to address
these discrepancies, we re-scaled all exposure-outcome effect estimates
to represent a change in outcome per 10-fold increase in triclosan, when
possible. We were unable to include studies that did not report contin­
uous associations between prenatal triclosan concentrations and infant
birth weight. Additionally, we contacted 5 of 14 corresponding study
authors to request additional results that were not present in their
published articles, resulting in usable data from 4 of the 5 studies who’s
authors we contacted.
2.6. Risk of bias in individual studies
We evaluated risk of bias across multiple domains described in other
applications of the Navigation Guide for each of the included studies
(Higgins and Green 2011; Viswanathan et al. 2008). Briefly, we
considered the following domains: recruitment strategy, blinding, con­
founding, exposure assessment, outcome assessment, incomplete
outcome data, selective outcome reporting, and conflicts of interest.
Within each domain, authors assigned articles a rating of low,
probably low, probably high, or high risk of bias based on specific in­
structions (Supplemental Table S2). For example, we identified a list of
important confounders within our protocol based on subject matter
expertise and use of a directed acyclic graph (DAG) (Supplemental
Fig. S1, Supplemental Table S3). We identified maternal age, pre-
pregnancy body mass index (BMI), a measure of socioeconomic status,
and maternal smoking as important confounders. We also considered
adjustment for race/ethnicity in cohorts within the United States. We
included child sex and GA as precision variables. Note, this was only
considered in cases where z-scores were not used, as z-scores are stan­
dardized by GA and infant sex. Two of 3 possible review authors (M.P.,
N.H., P.G.) independently recorded risk-of-bias determinations for each
included study. All reviewers collectively determined the final risk of
bias rating for all studies.
2.7. Quality of evidence across studies
Considering the full body of evidence across all included studies, we
rated the quality of evidence as “low quality”, “moderate quality”, or
“high quality” (Supplemental Table S4). Since we only considered
human observational studies, the initial rating of quality of evidence was
“moderate” as based on previously defined methodologies (Johnson
et al. 2014; Koustas et al. 2014; Vesterinen et al. 2015; Woodruff and
Sutton 2014). Next, based on previously established methods (Balshem
et al. 2011), we considered several “downgrade” or “upgrade” factors in
adjusting our overall rating (Table 1). Downgrade factors included risk
of bias, indirectness, inconsistency, imprecision, and publication bias.
Upgrade factors consisted of large magnitude of effect, dose response,
and if confounding would minimize the overall effect. For each item
downgrade or upgrade factors ratings ranged from − 2 to 2 as integers
with a rating of 0 indicating no change from the initial quality of rating.
Review authors (M.P., N.H., P.G.) independently evaluated the quality
of evidence across studies, and as a group determined the final decision.
2.8. Strength of evidence across studies
To determine the rating of the overall strength of evidence, we
considered 4 items. First, the previously determined rating for the
overall quality of evidence. Second, we considered the direction of effect
across studies. Third, our confidence in the effect based on the likelihood
that a new study would provide new insights or change the conclusions.
Fourth, we considered any other factors within the data that could in­
fluence certainty (NTP (National Toxicology Program) 2015). Based on
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Environment International 157 (2021) 106854
Table 1
Summary of rating quality and strength of the body of evidence for association
between maternal urinary triclosan concentration and infant birth weight
outcomes.
Category Summary of Criteria for Downgrades
Risk of Bias Evidence streams were rated down if most of the relevant
evidence came from studies that had high risk of bias. Rate
down only if you judged that there was a substantial risk of
bias in the body of available evidence.
Indirectness Evidence streams were rated down if substantial
differences existed between the study population,
exposure, comparator, or outcome measured relevant to
our study question. Potential sources of indirectness
included a study population or intervention/exposure that
was so different from that of interest that there was a
compelling reason to think that the magnitude of effect
would differ substantially, or studies that reported on
surrogate end points instead of the outcome of interest.
Inconsistency Evidence streams were rated down if studies conducted in
similar human populations had widely different estimates
of effect (unexplained heterogeneity or variability in
results). To indicate potential inconsistency: a) point
estimates varied widely across studies b) confidence
intervals (CIs) showed minimal or no overlap for similar
studies of comparable size c) the statistical test for
heterogeneity had a low p-value (p < 0.05) d) the I2 was
large (>50%, based on the Cochrane’s guide to
interpretation of I2). Studies that were inconsistent with
respect to the magnitude of an effect (but not in terms of
direction of effect estimates) would not be rated down.
Imprecision Evidence streams were rated down if most studies had
small sample sizes and few events, thus leading to wide
confidence intervals.
Publication Bias Evidence steams were rated down if we thought that
studies were missing from the body of evidence that might
result in an overestimate or underestimate of true
exposure effects. We used considerations from GRADE
guidance for evaluating publication bias, with
modifications to reflect the Navigation Guide’s primary
concern with underestimating the true effects of existing
chemical exposure. Considerations for evaluating
publication bias included the following: a) the body of
evidence was dominated by early studies with negative
results, particularly studies that were small in size b)
studies were uniformly small (particularly when
sponsored or funded by industry) c) empirical examination
of patterns of results (e.g., funnel plots) suggested
publication bias d) we were able to obtain results of
unpublished studies that demonstrated results different
from those of published studies e) a comprehensive search
of the literature was not performed.
Category Summary of Criteria for Upgrades
Large Magnitude of GRADE (Guyatt et al., 2011) recommends rating the
Effect evidence stream up by one category (e.g., from “low” to
“moderate”) if there were associations with a relative risk
(RR) > 2, and up by two categories (for instance, from
“low” to “high”) for those with RR > 5. However, there are
limitations to using RR to determine magnitude of effect
because RR relies on dichotomous exposure scales and
outcomes. Although there is no established cutoff for the
continuous scales, we evaluated the evidence judiciously
to assess whether the magnitude of effect from the human
evidence was compelling enough to justify upgrading the
evidence.
Dose Response The evidence stream was rated up if there were consistent
dose–response gradients within one or more studies and/
or evidence of dose response across the studies in the
overall body of evidence.
Confounding The evidence stream was rated up if consideration of
Minimizes Effect plausible residual confounders or biases would only
reduce the magnitude of the observed effect, or would
suggest a spurious effect when results show no effect.
a
Instructions and definitions on how to apply these criteria were derived from
(Lam et al. 2014).
M.A. Patti et al.
previously established categories and rationale, the overall strength of
evidence across the body of evidence could be rated as having “Suffi­
cient”, “Limited”, or “Inadequate” evidence of toxicity or “Evidence of
lack of toxicity” (Supplemental Table S4). (IARC (International Agency
for Research on Cancer) 2006; Sawaya et al., 2007; U.S. EPA. 1996; U.S.
EPA (U.S. Environmental Protection Agency) 1991). The authors (M.P.,
N.H., P.G., J.B.) independently evaluated the strength of the evidence
across studies and compared judgments before determining the final
rating as a group.
2.9. Statistical analysis
The primary outcome was infant birth weight. Upon examining the
evidence included in this systematic review, we observed variation in
the ways that studies accounted for GA in their assessment of birth
weight (i.e., infant birth weight (g), GA adjusted birth weight (g), and
GA-standardized birth weight z-scores). Because infant birth weight is
strongly related to GA, we chose to conduct separate meta-analyses, one
for each of the three different measures of infant birth weight identified
among included studies. (Storms and Van Howe 2004).
There were some studies that only reported categorical outcomes,
and thus were not included in meta-analyses. These studies were
Fig. 1. Flowchart describing literature search and screening process for studies relevant to triclosan exposure and infant birth weight outcomes.
4
Environment International 157 (2021) 106854
considered in final ratings for risk of bias, quality, and strength of evi­
dence ratings. If an included article reported results for more than one of
the pre-specified birth weight outcomes, we considered all reported
results. We first considered results obtained from the full study sample in
our primary meta-analyses. If results were only reported by child sex,
values from each sex were included.
Next, we conducted two meta-regressions. First, we conducted the
meta-analyses stratified by child sex. This was only done for the outcome
GA adjusted birth weight (g), as this outcome had a larger pool of results
to consider, and GA-standardized z-scores already account for child sex.
Second, we conducted a third meta-analysis where we separated studies
based on the median triclosan concentrations reported in the sample.
Studies with median triclosan concentrations <10 ng/mL were identi­
fied as “low” triclosan exposure, and those with median concentrations
≥10 ng/mL were considered to have “high” triclosan exposure.
We performed random effects meta-analyses using the inverse-
variance method to estimate differences in each birth weight outcome
per 10-fold increase in triclosan concentrations. We also performed
meta-regression analyses using random effects meta-analysis, adjusting
for median triclosan concentration (low: <10 ng/mL, high: ≥10 ng/mL)
and child sex. To evaluate statistical heterogeneity across study esti­
mates, we calculated Cochran’s Q statistic (p≤0.05 for statistical
M.A. Patti et al.
significance) and I2 values (Higgins and Green, 2011; Johnson et al.
2014; Koustas et al. 2014; Lam et al. 2014). To evaluate publication bias,
we considered funnel plots for each birth weight outcome. However,
these results should be interpreted with caution given that <10 studies
were included, and it is possible that test power is too low to charac­
terize bias (Sterne et al. 2011). We also explored differences in reported
associations based on the number and timing of triclosan exposures
assessed. We did not perform meta-regression for this analysis due to the
small sample size. We completed all statistical analyses in R Studio
(version 4.0.3) and used R Studio packages metaphor and forestplot (R
Core Team 2015).
3. Results
3.1. Data sources
Our search retrieved 37 unique records, 15 of which met inclusion
criteria (Fig. 1). Of 15 included studies, 8 were based in North America
(Aker et al. 2019; Etzel et al. 2017; Ferguson et al. 2018; Geer et al.
2017; Goodrich et al. 2019; Lester et al. 2018; Messerlian et al. 2018;
Wolff et al. 2008), 3 were from Europe (Lassen et al. 2016; Philippat
et al. 2012, 2014), and the remaining 4 were from Asia (Ding et al. 2017;
Huo et al. 2018; Ouyang et al. 2018; Wu et al. 2018). Included studies
were published from 2008 to 2019 and involved 34–1822 study par­
ticipants (Table 2). All studies measured triclosan exposure in maternal
urine, while 1 study also assessed exposure from maternal plasma bio­
markers (Geer et al. 2017). We only considered results from triclosan
measured via maternal urine biospecimens collected before delivery
Table 3..
3.2. Study characteristics
A third (n = 5) of included studies only reported outcomes for infant
birth weight (g),(Ding et al. 2017; Geer et al. 2017; Lester et al. 2018;
Messerlian et al. 2018; Philippat et al. 2014) and 20% (n = 3) only re­
ported GA-standardized birth weight z-scores (Aker et al. 2019; Fergu­
son et al. 2018; Wu et al. 2018). The remaining studies reported 2 of the
birth weight outcomes of interest (Huo et al. 2018; Lassen et al. 2016;
Ouyang et al. 2018; Wolff et al. 2008; Goodrich et al. 2019; Philippat
et al. 2012), while only 1 reported results for all 3 (Etzel et al. 2017).
Half of the studies collected multiple urine samples throughout the
gestational period (Aker et al. 2019; Etzel et al. 2017; Ferguson et al.
2018; Messerlian et al. 2018; Philippat et al. 2014; Wu et al. 2018),
while the remaining 6 obtained 1 urine sample during gestation (Geer
et al. 2017; Goodrich et al. 2019; Lassen et al. 2016; Lester et al. 2018;
Philippat et al. 2012; Wolff et al. 2008). Among these, collections
occurred during the first 20 weeks gestation in 2 studies (Goodrich et al.
2019; Lester et al. 2018), in the latter 20 weeks of gestation in 5 studies
(Geer et al. 2017; Lassen et al. 2016; Philippat et al. 2012, 2014; Wolff
et al. 2008), and throughout the gestational period in the other 5 studies
(Aker et al. 2019; Etzel et al. 2017; Ferguson et al. 2018; Messerlian et al.
2018; Wu et al. 2018). There were 3 studies that collected maternal
urine samples at the time of delivery (Ding et al. 2017; Huo et al. 2018;
Ouyang et al. 2018).
3.3. Range of triclosan exposure
Median triclosan values varied by approximately 2 orders of
magnitude (0.6–20 ng/mL), most markedly by geographic location
(Fig. 2). The lowest medians were in Asian cohorts, with higher values in
North American cohorts.
3.4. Risk of bias in individual studies
Included studies were consistently rated as “low” or “probably low”
risk of bias across all domains (Fig. 3, Supplemental Table S5a-S5n).
5
Environment International 157 (2021) 106854
Judgments of “probably high” risk of bias were given to 7 studies due to
concerns for recruitment strategy, confounding, exposure assessment,
and selective outcome reporting. Only 1 study received a judgment of
“high” risk of bias due to concerns over residual confounding (Geer et al.
2017). Risk of bias ratings across studies did not differ based on year of
publication, geographic location (Asia, North America, Europe), number
of triclosan exposure measures ascertained (at birth, only 1, >1), types
of outcomes reported (all birth weight outcomes, infant birth weight (g)
and GA adjusted birth weight (g), or range of exposure (low: median
level < 10 ng/mL, high ≥10 ng/mL).
3.5. Triclosan and birth weight meta-analyses
Of the 15 studies included, 14 presented results that could be
included in the meta-analyses. One study only reported results based on
categorical triclosan concentrations (Ding et al. 2017) which are sum­
marized along with other categorical results reported from 5 included
studies (Fig. 4) (Etzel et al. 2017; Huo et al. 2018; Lassen et al. 2016;
Ouyang et al. 2018; Philippat et al. 2012). Two studies reported out­
comes for GA and child sex standardized birth weight z-scores (Goodrich
et al. 2019; Philippat et al. 2012). Note that referenced data for birth­
weight z-scores were different amongst the studies, but specific to the
geographic location where the study took place (Cantonwine et al. 2016;
Fenton and Kim 2013; Oken et al. 2003; Villar et al. 2014).
3.5.1. Gestational age standardized birth weight Z-scores
Among 5 studies reporting data on GA-standardized birth weight z-
scores, each 10-fold increase in maternal urinary triclosan concentration
was associated with a 0.04 (95% CI: − 0.16, 0.07; p = 0.23) decrease in
GA-standardized birth weight z-score (Fig. 5a) (Etzel et al. 2017; Fer­
guson et al. 2018; Wu et al. 2018; Goodrich et al. 2019; Aker et al. 2019).
Similar to studies of birth weight adjusted for GA, there was minimal
evidence to suggest heterogeneity (I2 = 32.03% and Cochrane’s Q =
5.61; p=0.23).
3.5.2. Birth weight (g)
Of 6 studies that reported infant birth weight in grams (g) (Etzel et al.
2017; Geer et al. 2017; Lester et al. 2018; Messerlian et al. 2018; Phil­
ippat et al. 2012, 2014), each 10-fold increase in maternal urinary tri­
closan concentration was associated with decreased birth weight (β =
− 20; 95% CI: − 65, 26; p = 0.40). The value of I2 (76.09%) and
Cochrane’s Q (Q = 15.29; p=0.009) indicate heterogeneity amongst
these studies (Fig. 5b).
3.5.3. Gestational age-adjusted birth weight (g)
Among 7 studies examining associations between maternal urinary
triclosan concentrations with GA adjusted birth weight measured in
grams, each 10-fold increase in maternal urinary triclosan concentration
was associated with more modest decreases in birth weight compared to
studies not adjusting for GA (β = − 12; 95% CI: − 29, 4; p = 0.15) (Etzel
et al. 2017; Goodrich et al. 2019; Huo et al. 2018; Philippat et al. 2012;
Wolff et al. 2008; Lassen et al. 2016; Ouyang et al. 2018). The I2 value
was small (0%) and Cochrane’s test for heterogeneity was not significant
(Q = 3.21; p=0.92) (Fig. 5c).
3.5.4. Low vs. high levels of triclosan exposure
To maximize the number of included studies, we conducted sec­
ondary analyses amongst those studies that reported results for the
outcome of GAadjusted birth weight (g). Amongst studies with low
levels of triclosan exposure (<10 ng/mL, n = 5) (Huo et al. 2018; Lassen
et al. 2016; Ouyang et al. 2018), there was no association between tri­
closan and infant birth weight (β = 6; 95% CI: − 20, 31; p = 0.66), Fig. 6.
When considering studies with high levels of triclosan exposure (≥10
ng/mL, n = 4) (Etzel et al. 2017; Goodrich et al. 2019; Philippat et al.
2012; Wolff et al. 2008), we observed a modest, inverse association
between gestational urinary triclosan concentrations and infant birth
M.A. Patti et al. Environment International 157 (2021) 106854

Table 2
Summary of study characteristics on studies examining associations between maternal urinary triclosan concentrations and infant birth weight.
Source Location Study Study Births Birth Weight Covariates Adjusted for Exposure Measurement Concentration
period Design (n) Measures measures timing (range)
(n)

Ding et al., China 2010–2013 Cross- 496 Grams Maternal age, pre-pregnancy 1 Birth Median (25th,
2017 sectional BMI, pregnancy weight gain, 75th percentile)
parity, passive smoking, 0.5 ug/g
household monthly income, creatinine (<0.1a
infant sex , 2.4)
Huo et al., China 2012–2014 Cross- 1006 Grams Maternal age, pre-pregnancy 1 Birth Median (25th,
2018 sectional adjusted for BMI, parity, maternal 75th percentile)
gestational education, passive smoking, 0.6 ng/mL b (0.2,
age infant sex, gestational age, 2.6)
delivery mode,
Ouyang Shanghai, 2012–2013 Cross- 620 Grams Maternal age, pre-pregnancy 1 Birth Median (min,
et al., China sectional adjusted for BMI, parity, maternal height, max) ng/mL
2018 gestational maternal education, passive Low: 0.8 (<0.1 a,
age smoking, gestational age, 1.4)
gestational diabetes mellitus, Medium: 2.7
creatinine (1.5, 5.0)
High:13.3 (5.0,
95.2)
Wu et al., Wuhan, 2014–2015 Cohort 850 Z-score Maternal age, pre-pregnancy 3 13, 23.6, and Median (25th,
2018 China BMI, pregnancy weight gain, 35.9 weeks 75th percentile)
parity, maternal height, 0.7 ng/mL b
maternal education, infant (<0.1 a, 2.5)
sex, paternal height
Wolff et al., New York 1998–2002 Cohort 367 Grams Pre-pregnancy BMI, 1 25 – 40 weeks Median (25th,
2008 City, NY adjusted for maternal education, 75th percentile)
(USA) gestational maternal smoking, race, 11.0 ug/L (2.9,
age marital status, infant sex, 42.0)
gestational age, creatinine
Etzel et al., Cincinnati, 2003–2006 Cohort 387 Grams, Grams Maternal age, pre-pregnancy 2 16, 26 weeks Median (min,
2017 OH (USA) adjusted for BMI, maternal education, max)
gestational maternal serum cotinine 16.0 ng/mL
age, Z-score concentrations, income, (<2.3 a, 1501.0)
maternal race, marital status,
prenatal vitamin use, Beck
Depression Inventory score
Geer et al., Brooklyn, 2007–2009 Cohort 185 Grams Infant sex 1 3rd trimester Median (25th,
2017 NY (USA) 75th percentile)
9.1 ug/L (2.7,
42.9)
Goodrich Michigan 2012–2015 Cohort 56 Grams Infant sex, gestational age, 1 8 –14 weeks Median (25th,
et al., (USA) adjusted for specific gravity 75th percentile)
2019 gestational 15.4 ug/L (5.6,
age, Z-score 73.3)
Messerlian Boston, MA 2012–2016 Cohort 213 Grams, Maternal age, pre-pregnancy 3 6, 21, and 35 Median (25th,
et al., (USA) BMI, maternal education, weeks 75th percentile)
2018 maternal smoking, in-vitro 9.7 ng/mL b (3.6,
fertilization (IVF) based vs. 33.1)
Non-IVF based treatment,
season
Ferguson Boston, MA 2006–2008 Cohort 476 Z-score Maternal age, pre-pregnancy 3 18, 26 and 35 Median (25th,
et al., (USA) BMI, race/ethnicity, health weeks 75th percentile)
2018 insurance provider 13.5 ug/L b (4.4,
50.3)

Lester et al., Canada 2008–2011 Cohort 1822 Grams, Maternal age, pre-pregnancy 1(MIREC), 6 – 13 weeks Median (25th,
2018 (MIREC), BMI, parity, maternal 1 (P4) (MIREC), 75th percentile)
68 (P4) education, maternal Before 20 weeks 14.4 ug/L (2.9,
smoking, income, place of (P4) 121.2)
birth, concentrations were
standardized for time of day,
time since last void, specific
gravity
Aker et al., Puerto Rico 2011–2017 Cohort 867 Z-score Maternal age, passive 3 16–20, Median (25th,
2019 smoking, alcohol use, 20–24, and 75th percentile)
insurance type, specific 24–28 weeks 15.8 ug/L b (3.6,
gravity 139.3)
Philippat France 2002–2006 Cohort 191 Grams, Grams Pre-pregnancy weight and 1 24 – 30 weeks Median: (5th,
et al., adjusted for height, parity, maternal 95th percentile)
2012 gestational smoking, maternal 24.1 ug/L (1.6,
age education, gestational age, 634.0)
recruitment center,
creatinine, concentrations
(continued on next page)

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M.A. Patti et al. Environment International 157 (2021) 106854

Table 2 (continued )
Source Location Study Study Births Birth Weight Covariates Adjusted for Exposure Measurement Concentration
period Design (n) Measures measures timing (range)
(n)

were standardized for hour

of sampling, time elapsed
between sample collection
and freezing, season and day
of sampling, and gestational
age at collection
Philippat France 2003–2006 Cohort 520 Grams Pre-pregnancy weight, 1 22 and 29 Median (5th,
et al., parity, maternal height, weeks 95th percentile)
2014 maternal smoking, passive 29.0 ug/L (<2.3
a
smoking, maternal , 732.0)
education, recruitment 30.0 ug/L (<2.3
a
center, paternal height, , 755.0)
creatinine, concentrations
were standardized for hour
of sampling, time elapsed
between sample collection
and freezing, gestational age
at collection,
Lassen Denmark 2010–2012 Cohort 514 Grams Pre-pregnancy BMI, parity, 1 28 weeks Median (5th,
et al., adjusted for maternal smoking, 95th percentile)
2016 gestational gestational age Girls: 1.0 ng/mL
age (<0.1 a, 536.0)
Boys: 1.0 (<0.1 a,
335.0)

BMI: Body Mass Index, IVF: in-vitro fertilization, USA: United States of America, MIREC: Maternal-Infant Research on Environmental Chemicals Study, P4: Plastics and
Personal-Care Products use in Pregnancy (P4)
a
Limit of Detection
b
Adjusted for specific-gravity
c
Studies that reported birth weight outcomes are z-scores referenced: Wu et al., 2018 and Aker et al., 2019 (Villar et al. 2014), Etzel et al., 2017 (Oken et al. 2003),
Goodrich et al., 2019 (Fenton et al. 2013), Ferguson et al., 2018 (Cantonwine et al. 2016)
d
Note that the study design is reflective of the analysis conducted for each included article, which may differ from the larger cohort from which the data were derived.

weight (β = − 26; 95% CI: − 59, 7; p=0.13). Results from the meta-
regression approached significance when comparing associations in
low vs. high level exposure studies, (difference in associationsβ = 14;
95% CI: − 62, 91; p = 0.08).
This suggests that a potential inverse association between gestational
urinary triclosan concentrations and infant birth weight in more highly
exposed populations, as effect size varies depending on the source
population level of triclosan.
3.5.5. Modification by child sex
Next, we conducted meta-regressions to evaluate if the association
between gestational triclosan exposure was modified by child sex (n = 4
studies). Again, we only considered results reported for the outcome of
GA adjusted birth weight (g). There was not strong evidence that the
association between triclosan levels and GA adjusted birth weight (g)
differed in males (n = 4) (β = − 7; 95% CI: − 31, 17; p = 0.60) compared
to female infants (n = 3) (β = 1; 95% CI: − 11, 13;p = 0.51), (difference
in associationsβ = − 7; 95% CI: − 102, 88; p = 0.25) (Supplemental
Fig. S2). However, given the small sample size of eligible included
studies for this secondary analysis, these results should be interpreted
with caution.
3.5.6. Timing and number of triclosan exposure assessments
The number and timing of maternal urine samples used to assess
triclosan exposure varied across included studies. Studies with only one
urine sample collected this sample either at the time of delivery (n = 2),
or during the gestational period (n = 7). The remaining studies (n = 5)
collected ≥ 2 urine samples throughout pregnancy and before delivery,
averaging repeated urine triclosan concentrations. While we were un­
derpowered to conduct a meta-regression, we observed that studies with
two or more prospectively collected triclosan measures reported inverse
associations, while those studies with one sample collected prospec­
tively or at the time of delivery reported null, or positive associations. It
should be noted that among studies with one sample at the time of
delivery, median triclosan exposure levels were among the lowest of all
included studies.
3.6. Quality and strength of evidence across studies
We rated the quality of evidence to be “moderate”. This was based on
3 downgrades (− 1) for indirectness, inconsistency, and publication bias,
and 2 upgrades (+1) for dose response, and confounding minimizes the
effect. We downgraded the evidence stream (− 1) for indirectness
because across studies, birth weight as the main outcome of interest was
not reported consistently. We also downgraded (− 1) the evidence
stream for inconsistency because of geographic variation in effect esti­
mates and triclosan concentrations. Further, results from Cochrane’s Q
statistic of heterogeneity indicated significant heterogeneity (p < 0.05)
and the I2 value was large (>50%) for the birth weight (g) outcome.
However, it should be noted that we were limited in our ability to
perform formal statistical tests to evaluate publication bias given the
reduced sample size of studies based on the 3 birth weight outcomes
considered when examining potential publication bias (Supplemental
Fig. S3).
We upgraded the overall body of evidence based on evidence for dose
response for 2 reasons. First, among studies with low triclosan exposure
(median value < 10 ng/mL), associations were generally null, compared
to studies with higher triclosan exposure (median value ≥10 ng/mL),
which reported inverse associations. Second, within several studies, we
found evidence for a dose–response relationship by observing mono­
tonic associations across categories of triclosan concentrations (Fig. 4).
Etzel et al. (2017) reported a decrease in GA-standardizedbirth weight z-
scores across quartiles of triclosan exposure. Similarly, Ding et al (2017),
Huo et al (2018), and Philippat et al. (2012) also reported an inverse
trend, such that birth weight (g) decreased with increasing categories of
urinary triclosan concentration. However, this was not observed in all
studies (Lassen et al. 2016; Ouyang et al. 2018). We judged these col­
lective findings to be consistent of enough evidence to upgrade the

7
M.A. Patti et al.
Table 3
Ratings and rationale of the quality and strength of the body of evidence for
association between maternal urinary triclosan concentration and infant birth
weight outcomes.
Criteria for Downgrades
Category Final Rationale
Rating
Risk of Bias 0 When considering the risk of bias across the
studies, we concluded that there was not
substantial bias across the body of evidence.
Indirectness − 1 Our outcome of interest is birth weight and the
studies included assessed this in a number of
different ways. Thus, we had to downgrade for
indirectness given that we had to assess three
different outcomes (grams, grams +
gestational age, z-scores). Additionally, there
were substantial differences regarding
exposure levels across geographic levels.
Inconsistency − 1 When assessing the I2 values, we are able to
determine that the studies that assessed grams
as their outcome of interest had considerable
heterogeneity, especially compared to the
other outcomes (grams + gestational age and z-
scores).
Imprecision 0 The majority of studies had moderate to large
sample sizes and thus the reported results were
fairly precise.
Publication Bias − 1 The body of evidence was not dominated by
early studies with null results, as all studies
were completed around the same time, with
relatively comparable sample sizes. The studies
were not uniformly small, nor were they
sponsored by industry. A comprehensive
search was completed of the literature. The
funnel plots do suggest that there may be some
cases of bias, such that at the base of the plot
there is less symmetry than toward the tip of
the plot, and for grams outcome some studies
fall outside the funnel itself. Note that results
from funnel plots should be evaluated with
caution, as we did not have enough studies
(>10) to include in analyses. We were also not
able to obtain results from unpublished studies
that demonstrated different results than the
published studies that were included.
Criteria for Upgrades
Category Final Rationale
Rating
Large Magnitude of 0 The magnitudes of effect estimates from the
Effect included studies are modest.
Dose Response +1 While there is not clear evidence for a dose
response relation within studies, there is
certainly a dose response effect across all
studies (consider our analysis comparing the <
10 triclosan to ≥10 triclosan exposure levels).
Within studies that included categorical
analyses, we observed evidence for a
dose–response effect, such that birth weight
decreased with increasing concentrations of
urinary triclosan exposure.
Confounding +1 In order to assess the impact of adjusting for
Minimizes Effect confounding, we would need to compare the
crude and adjusted results which only 6 of the
15 studies provided. Of these 6, we generally
see that the effect of adjustment on the
magnitude of effect is downward in 3 studies,
and the magnitude of effect is attenuated in 1
study, but is strengthened in another. When we
consider studies that adjusted for grams + GA
(compared to just grams), we do see that the
averaged summed magnitude of effect is
attenuated, suggesting that a more optimal
approach to addressing birth weight, but
adjusting got GA, an important predictor, does
in fact attenuate the magnitude of the results,
this is further attenuated when considering the
magnitude of effect from z-scores compared to
grams + gestational age adjustment.
8
Environment International 157 (2021) 106854
overall quality of evidence for dose response (+1), although not strong
enough to upgrade the overall quality of evidence by +2.
We also upgraded the evidence because there was no evidence that
residual confounding would minimizes the effect of gestational triclosan
exposure on birth weight. For example, in Etzel et al., the association
between triclosan and birth weight was stronger after adjusting for po­
tential confounders (i.e., negative confounding). The evidence stream
was rated up (+1) when considering the attenuation of the magnitude of
effect across birth weight outcomes. For example, we observed a larger
effect estimate for decreased infant birth weight measured in grams
compared to GA adjusted birth weight. It is noteworthy that the results
from the meta-analysis for GA adjusted birth weight were attenuated,
relative to infant birth weight measured in grams, suggesting that the
association between gestational triclosan concentrations and infant
birth weight are confounded by GA. Further, results from GA and child
sex standardized birth weight z-score analysis also show a reduction in
the magnitude of effect. These findings suggest that the association be­
tween gestational triclosan exposure and infant birth weight are
potentially mediated by GA. Indeed, some studies observed inverse as­
sociations between triclosan levels and duration of gestation (Aker et al.
2019; Etzel et al. 2017).
We rated the overall strength of the evidence as “limited”. This was
collectively based on our judgment of “moderate” quality of the body of
evidence, as our confidence in the relation between gestational triclosan
exposure and birth weight is constrained due to inconsistencies of
findings across individual studies. However, the majority of studies were
found to be of “low” or “probably low” risk of bias, increasing our
confidence in the findings overall. The direction of the association
suggests an inverse association between gestational urinary triclosan
concentrations with infant birth weight in the meta-analyses conducted,
although some studies report null associations. Moreover, when
comparing the results of studies with low triclosan exposure, to those
with higher exposure, we observed stronger inverse associations with
birth weight among those studies with higher median levels of triclosan.
4. Discussion
Overall, we identified limited evidence of toxicity with regard to
triclosan exposure and infant birth weight after systematically reviewing
and meta-analyzing fifteen studies examining the association of gesta­
tional triclosan exposure and infant birth weight. Across these studies,
we observed “low” risk of bias across domains that may affect study
results. However, we observed modest heterogeneity in the association
between triclosan concentrations and birth weight outcomes, which are
suggestive of stronger inverse associations among studies with higher
median triclosan concentrations.
Two previous systematic reviews and meta-analyses came to con­
tradictory conclusions regarding the association between gestational
triclosan exposure and birth weight. (Zhong et al. 2020; Khoshhali et al.
2020) One concluded no association, while the other concluded that
gestational triclosan exposure was associated with greater birth weight.
However, neither study applied the Navigation Guide criteria to their
evaluation (Zhong et al. 2020; Zhong et al. 2020; Khoshhali et al. 2020),
which is the recommended methodology for evaluating evidence
streams within environmental health (Johnson et al. 2014, 2016;
Koustas et al. 2014; Lam et al. 2014, 2016; Vesterinen et al. 2015;
Woodruff et al. 2011). Applying the Navigation Guide, we systemati­
cally evaluated the risk of bias in individual studies, as well as the
quality of evidence across studies using previously established methods.
This additional analysis of included studies was unique to our meta-
analysis and could contribute to some of the differences in our conclu­
sions relative to the prior meta-analyses. Additionally, consistent with
the methodology outlined in the Navigation Guide, we also registered
our systematic review protocol in PROSPERO (Patti et al. 2019). At the
time when our proposal was registered with PROSPERO, no other sys­
tematic reviews or meta-analyses investigating the relation between
M.A. Patti et al. Environment International 157 (2021) 106854

Fig. 2. Median maternal urinary triclosan concentrations by geographic location in studies examining association between triclosan exposure and infant birth
weight outcomes.

Fig. 3. Summary of risk of bias domains for individual studies examining associations between triclosan exposure and infant birth weight outcomes.

triclosan and birth weight were registered.
There are a number of reasons that could contribute to the difference
in our conclusions. These include differences in outcome definitions,
attention to residual confounding, and recognition of differences in the
range of triclosan exposure across studies. This is particularly relevant
given that we report that the triclosan and birth weight association
differed in studies with low (<10 ng/mL) vs. high (>10 ng/mL) urinary
triclosan concentrations. Moreover, median urinary triclosan concen­
trations varied across studies by nearly 2-orders of magnitude (see
Fig. 2). Our findings suggest of a potential inverse association between
gestational urinary triclosan concentrations and infant birth weight in
more highly exposed populations, though the effect size varied
depending on the source population level of triclosan. Future studies
should be conducted in samples with higher levels of triclosan exposure,
as the current state of the literature may not have enough of an exposure
contrast to identify stronger associations, if they truly exist. In addition,
the discrepancies in how birth weight was assessed within and across
studies (i.e., grams, grams adjusting for gestational age, and z-scores)
limited our ability to conduct meta-analyses with all included studies (n
= 15). Future studies should consider reporting birth weight using
multiple definitions.
While previous meta-analysis using a similar groups of studies

9
M.A. Patti et al.
(Zhong et al. 2020) also found that there was substantial heterogeneity
in terms of demographic characteristics of study subjects, timing of
exposure measurement (i.e., trimester when urine samples were ascer­
tained), and exposure detection methods in their included studies, our
review is unique in that we explored heterogeneity in triclosan exposure
range based on geographic location.
Another reason our conclusions may differ from those of prior meta-
analyses is how we defined birth weight as an outcome. We considered
birth weight measured in grams (g), GA adjusted birth weight, and GA-
standardized birth weight z-scores (also standardized by child sex). Both
prior meta-analyses did not differentiate birth weight (g) from GA
adjusted birth weight, nor did they consider GA-standardized birth
weight z-scores (Zhong et al. 2020; Khoshhali et al. 2020). This is an
important distinction that may increase the validity of our outcome
definition, as infant birth weight is highly dependent on GA (Storms and
Van Howe 2004). Future studies should use GA-standardized birth
weight z-scores as not to erroneously adjust for a mediator and enhance
comparisons across studies (Schisterman et al. 2009) given that triclosan
exposure during pregnancy has been previously associated with reduced
GA (Aker et al. 2019; Etzel et al. 2017).
Infants born as low birth weight are at an increased risk for a wide
range of health outcomes throughout the life course including learning
disabilities, as well as attention-deficit disorder or attention-deficit/
hyperactivity disorder (Stein et al. 2006). Indeed, some of these same
outcomes have been previously associated with prenatal urinary tri­
closan concentrations (Jackson-Browne et al. 2018, 2019a, 2019b).
While the prevalence of low birth weight in the United States is stable
(~8% from 2014 to 2019), low birth weight affects a sizable portion of
infants and incurs substantial financial costs to the healthcare system.
(Calkins and Devaskar 2011). Given that that low birth weight is pre­
ventable (Bailey and Byrom 2007), it is imperative that we identify
modifiable risk factors, such as reductions in triclosan use, in order to
10
Environment International 157 (2021) 106854
Fig. 4. Associations Between Categories of Maternal
Urinary Triclosan Concentrations and Infant Birth
Weight Ratio of change in infant birth weight rela­
tive to the lowest category of maternal triclosan
concentrations (reference group). Lines represent
the dose response for each independent study. Sin­
gle points represent the effect for studies and are
plotted at the midpoint of each category of triclosan
concentration. a Birth weight measured in grams b
Birth weight measured in grams, adjusted for
gestational age c Gestational age and child sex
standardized birth weight z-scores, transformed to
grams.
have the largest impact at the population level. In the US (U.S. Food &
Drug Administration 2017) and Europe (Andriukaitis, 2016), triclosan
has been phased out of many consumer products due to the recognition
of triclosan causing unacceptable risks to the environment as a known
harmful endocrine disrupting chemical (Andriukaitis, 2016). However,
triclosan is still used and sold in China (National Health Commission
2019) and Canada, although with restrictions (Health Canada 2016).
Given that triclosan has been replaced with benzalkonium chloride,
benzethonium chloride, or chloroxylenol in some products (Food and
Drug Administration 2016a, 2016b, 2016c), it is critical to ensure that
these substitutes do not confer any additional adverse health effects.
The cohorts included in our review represent geographically and
socioeconomically diverse populations with a wide range of exposure to
triclosan during pregnancy. It is possible, that as more studies becomes
available, particularly those evaluating associations at higher levels of
triclosan exposure, our confidence in the inverse association of birth
weight with triclosan will change. While the magnitude of the associa­
tions we observed were modest, they have important population-health
implications. Given that birth weight is a strong indicator for a number
of health outcomes throughout the life course (Mathews and Driscoll
2017), including neurodevelopment, growth, and overall health (Stein
et al. 2006), even minor decreases in individual birth weight can result
in major consequences at the societal level, emphasizing that docu­
mented decreases in fetal growth are of major public health concern.
Our systematic review and meta-analysis has several strengths and
limitations that should be considered. First, our systematic review and
meta-analysis followed the Navigation Guide, which has been optimized
for conducting systematic reviews in environmental health (Johnson
et al. 2014; Koustas et al. 2014; Lam et al. 2014). This addition to our
analysis was unique relative to other systematic reviews that also
investigated triclosan and birth outcomes (Khoshhali et al. 2020; Zhong
et al. 2020). A key strength of our review is that we included results from
M.A. Patti et al. Environment International 157 (2021) 106854

Fig. 5. Meta-analyses for associations of urinary triclosan concentrations during gestation and infant birth weight outcomes *Boys only, **Girls only All values
represent change in birth weight per 10-fold increase in urinary triclosan concentrations. Error bars indicate 95% confidence intervals.

all outcomes reported from included studies. Thus, we were able to
independently assess each outcome, demonstrating which measures
may capture our outcome of interest best and whether GA acts as a
mediator. This approach also differed from that of previous meta-
analyses, and identified potential reasons for discrepancies across
these prior reviews.
One limitation is that we were unable to account for all potential
sources of heterogeneity. We speculate that the heterogeneity in results
across studies could be attributed to residual confounding, exposure
measurement error, or methods to adjust for urine dilution. While most
studies were rated low and probably low risk of bias for confounding,
there was a lack of consistency in regard to which covariates were
included in analyses. Differences in exposure measurement, including
the number and timing of urinary triclosan concentrations during
pregnancy varied across studies. This is particularly important given
that triclosan has a relatively short half-life (Sandborgh-Englund et al.
2006), which results in moderate within-person variability that would
be expected to attenuate associations towards the null if exposure is non-
differentially misclassified (Stacy et al. 2017). Thus, studies with only 1
measure of triclosan would be subject to greater exposure misclassifi­
cation than studies with more than 1 measure of triclosan (Perrier et al.
2016; Whitehead et al. 2012). Moreover, samples collected at birth may
not be representative of triclosan exposure during the gestational period,
which was of primary interest for the purpose of this review. While the
number of available studies limited our ability to conduct secondary
analyses based on timing of triclosan exposure on infant birth weight,

11
M.A. Patti et al. Environment International 157 (2021) 106854

Fig. 6. Meta-analyses for associations of urinary triclosan concentrations during gestation and infant birth weight in grams adjusted for gestational age by level of
exposure *Boys only, **Girls only All values represent change in birth weight per 10-fold increase in urinary triclosan concentrations. Error bars indicate 95%
confidence intervals.

we qualitatively evaluated this (Fig. 7) and observed some evidence to
suggest that inverse associations were more apparent in studies with at
least two prospective triclosan exposure measures. Furthermore,
different methods of adjustment for urine dilution could contribute to
exposure misclassification discrepancies across studies since some
accounted for urine dilution using creatinine, specific gravity, or urine
osmolality.
is associated with reductions in infant birth weight. Our results indicate
that observed differences in this association across studies are related to
the level of triclosan exposure in source populations. Future work should
consider evaluating associations between triclosan and birth weight at
higher levels of triclosan exposure and evaluate potential sources of
heterogeneity such as gestational age, child sex, and geographic
location.

5. Conclusions Funding

The available epidemiological evidence of moderate quality and low This work was supported by the National Institutes of Health grant
risk of bias provides limited evidence that gestational triclosan exposure numbers R01 ES024381, R01 ES026903, and U01AI126615-05S1.

12
M.A. Patti et al. Environment International 157 (2021) 106854

Fig. 7. Associations between number and timing of maternal urinary triclosan concentrations and infant birth weight *Boys only, **Girls only All values represent
change in birth weight per 10-fold increase in urinary triclosan concentrations. Error bars indicate 95% confidence intervals.

CRediT authorship contribution statement
Marisa A. Patti: Conceptualization, Methodology, Software, Vali­
dation, Formal analysis, Investigation, Data curation, Writing – original
draft, Visualization, Project administration. Noelle B. Henderson:
Validation, Investigation, Writing – original draft. Priya Gajjar: Vali­
dation, Investigation, Writing – original draft. Melissa Eliot: Method­
ology, Software, Data curation, Writing – review & editing. Medina
Jackson-Browne: Writing – review & editing, Supervision, Funding
acquisition. Joseph M. Braun: Conceptualization, Methodology,

13
M.A. Patti et al.
Writing – review & editing, Supervision, Project administration, Fund­
ing acquisition.
Declaration of Competing Interest
The authors declare the following financial interests/personal re­
lationships which may be considered as potential competing interests:
JMB was financially compensated for serving as an expert witness for
plaintiffs in litigation related to tobacco smoke exposures and received
an honoraria for serving on an advisory panel to Quest Diagnostics. The
funders had no role in the design of the study; in the collection, analyses,
or interpretation of data; in the writing of the manuscript, or in the
decision to publish the results.
Acknowledgements
We would like to thank Dr. George Papandonatos for his assistance
and statistical guidance in conducting meta-analyses. We would also like
to thank the authors of included studies for their willingness to collab­
orate and provide additional information, without which this work
would not be possible.
Appendix A. Supplementary material
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.envint.2021.106854.
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