Before the beginning: environmental

exposures and reproductive and

obstetrical outcomes
Thalia R. Segal, M.D. and Linda C. Giudice, M.D., Ph.D.
Center for Reproductive Health, University of California, San Francisco, California

There is growing consensus that preconception exposure to environmental toxins can adversely affect fertility, pregnancy, and fetal
development, which may persist into the neonatal and adult periods and potentially have multigenerational effects. Here we review
current data on preconception and prenatal exposure to several chemicals, including heavy metals, endocrine-disrupting chemicals,
pesticides, and air pollution, and their associated obstetrical and reproductive health effects. Reproductive endocrinologists and affil-
iated health care providers have a unique opportunity to counsel patients before they get pregnant to minimize exposure to hazardous
chemicals with the goal to improve reproductive outcomes and assure a healthy lifestyle overall. We provide practical tools and some
publicly available resources for reproductive health professionals to assess a patient's risks and ways to reduce chemical and air pollu-
tion exposures during the critical preconception and prenatal periods. (Fertil SterilÒ 2019;112:613–21. Ó2019 by American Society for
Reproductive Medicine.)
Key Words: Pregnancy, preconception, environmental toxins, endocrine disrupting chemicals, air pollution, heavy metals

Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-
and-sterility/posts/49575-28391

REPRODUCTION AND THE stressors, these time periods offer op- during the first half of pregnancy were
ENVIRONMENT portunities to minimize harm and more likely to be obese, and those
maximize health and developmental exposed during the third trimester
There are more than 80,000 registered
potential. were born small and had low rates of
chemicals registered in the United
Epidemiologic research has demon- obesity throughout adulthood (8). This
States (1). These chemicals are ubiqui-
strated that prenatal exposure to envi- study was one of the first to introduce
tous and environmental contamination
ronmental toxicants contributes to the concept of environmental stressors
can result as they degrade and persist in
adult onset of disease, especially during the prenatal period and fetal
air, soil, drinking water, consumer
obesity, type 2 diabetes, and coronary development as the origins of adult
products, food, and household dust.
artery disease (4). This hypothesis, first disease.
Detectable levels of various chemical
proposed in the 1990s by British epide- Within the past 5 years, the
toxicants including phthalates and pes-
miologist David J. Barker, claimed that American College of Obstetricians and
ticides were detected in 99%–100% of
the intrauterine environment has a Gynecologists, working with the Amer-
pregnant women in the United States
causal relationship with the origins of ican Society for Reproductive Medi-
(2), underscoring widespread human
chronic adult diseases (5–7). The most cine, published a committee opinion
body burdens. Moreover, air pollution
striking example occurred in the about toxic exposures and reproductive
increasingly affects human health (3).
winter of 1944, when German health (www.acog.org/-/media/Com
Because the preconception and early
occupation of the Netherlands blocked mittee-Opinions/Committee-on-Health-
prenatal periods constitute a critical
fuel and food supplies to an estimated Care-for-Underserved-Women/co575.
window for gamete and embryo devel-
4.5 million people. The children of pdf), as did the International Federation
opment and implantation, which are
pregnant women exposed to famine of Gynecology and Obstetrics in its
highly sensitive to environmental
2016 monograph (9, 10). These
professional organizations reviewed
Received June 28, 2019; revised August 2, 2019; accepted August 5, 2019. effects of specific environmental
T.R.S. has nothing to disclose. L.C.G. has nothing to disclose. exposures and offered some recom
Reprint requests: Thalia R. Segal, M.D., Center for Reproductive Health, University of California, 499
Illinois St., 6th Floor, San Francisco, CA 94158 (E-mail: thalia.segal@ucsf.edu).
mendations for counseling patients on
approaches to minimize or prevent
Fertility and Sterility® Vol. 112, No. 4, October 2019 0015-0282/$36.00 such exposures (9). Evidence of effects
Copyright ©2019 American Society for Reproductive Medicine, Published by Elsevier Inc.
https://doi.org/10.1016/j.fertnstert.2019.08.001 of some of the most common

VOL. 112 NO. 4 / OCTOBER 2019 613

VIEWS AND REVIEWS
chemicals found in Americans, according to the National
Health and Nutrition Examination Survey (NHANES), with
a particular focus on the preconception and gestational
periods, are the focus of the present review. These include
endocrine-disrupting chemicals (EDCs), several plasticizers,
pesticides, and heavy metals, such as mercury, lead, and cad-
mium, which are found in over 90% of the population (10).
We do not discuss smoking or alcohol, because these are
well known toxicants that most health care providers already
emphasize to patients. Reproductive endocrinology and infer-
tility specialists see patients before they are pregnant and
have a unique opportunity to counsel them on ways to opti-
mize their health and mitigate environmental exposures
which could have detrimental downstream effects on preg-
nancy and perinatal and life-long health outcomes. Thus,
we present an overview of chemicals known to induce adverse
health effects due to preconception and prenatal exposures.
MERCURY
Mercury is released as a byproduct of coal burning, waste incin-
eration, and other industrial processes. It leaches into water and
accumulates as methylmercury in fish, especially large preda-
tory fish such as tuna, swordfish, and shark. Eating fish with
high levels of mercury is the primary route of exposure for hu-
mans. Mercury is also found in topical skin creams sold outside
the United States, broken thermometers, dental supplies, and
fluorescent lamp manufacturing factories. Mercury is a neuro-
toxin, increasing the incidence of cerebral palsy, mental retar-
dation, blindness, and other neurologic conditions (2, 11). This
was first discovered in 1956 in Minamata, Japan, where the
Chisso Corporation, an industrial chemical factory, released
waste products including methylmercury into the Minamata
bay. The toxins accumulated in the fish eaten by the local
community and caused mercury poisoning. More than 2,200
people were diagnosed with Minamata disease. Symptoms in
adults included sensory disturbances, ataxia, visual field
defects, auditory abnormalities, and tremor (12). Congenital
Minamata disease manifests with brain lesions, cerebral
palsy, coma, and death (13).
Even low levels of mercury in pregnant women have led
to lower IQ scores in children (14). In the Faroe Islands, where
fish is a substantial part of the main diet, in one in eight births
maternal hair mercury levels exceeded the 10 mg/g limit. In
more than 900 mother-child pairs studied, cognitive deficits
in 7-year-old children with prenatal exposure to methylmer-
cury were observed (15). Methyl mercury crosses the placenta
and accumulates in the fetus, leading to higher levels of fetal
exposure to mercury compared with maternal levels (15, 16).
Recommendations. Screen all patients on their exposure to
mercury by asking about occupation and fish consumption,
types, and amount (Table 1). The U.S. Environmental Protec-
tion Agency (EPA) recommends that pregnant women,
reproductive-age women, and young children eat fish lower
in mercury once or twice a week (8–12 oz.). Pregnant and
breastfeeding women should avoid king mackerel, shark,
swordfish, marlin, orange roughy, tile fish, and tuna (17).
The EPA recommends seafood and fish low in mercury,
such as shrimp, salmon, pollock, and catfish. Couples at-
614
tempting pregnancy should check local advisories on water
quality in oceans, lakes, and rivers where local fish are caught.
LEAD
Before 1978, lead was used in gas, paint, and water pipes. Cou-
ples living in older homes are at high risk for lead poisoning,
especially in the setting of remodeling and renovation (18).
Other high-risk populations include battery factory workers,
jewelry making, recent immigrants from areas without lead
regulations, and women using pica- or lead-glazed pottery
for cooking. Other nonoccupational exposures include lead
toys, jewelry, and use of traditional remedies or imported cos-
metics (19). Elevated levels of lead in maternal serum are asso-
ciated with gestational hypertension, preterm delivery, low
birth weight, miscarriage, birth defects, and abnormal placen-
tation (20). Lead has been shown to induce alterations in
genomic methylation of DNA in the umbilical cord (21). Pre-
natal exposure of lead has been associated with permanently
impaired intellectual development in children (22).
Recommendations. For women of reproductive age and
children, inquire if they have exposure to lead in parental
occupation, use pica, or live in a house built before 1978
that is undergoing renovation. Ask patients if they have a his-
tory of elevated lead levels. Also discuss whether they have
lived abroad, use imported skin creams, or cook with lead-
glazed pottery. If lead levels are >20 mg/dL, patients need
to be sent to toxicologists for evaluation and possible chela-
tion therapy (23).
CADMIUM
Cadmium is a heavy metal used in rechargeable batteries, as a
pigment in paint, and in plastic production. It enters the food
chain through soil absorption of leaking sewage and is found
in shellfish, organ meats, rice, wheat, leafy vegetables, po-
tatoes, and celery root (24). Smokers are exposed to cadmium
through tobacco smoke and nonsmokers through second hand
smoke. It is also released into the environment as a waste prod-
uct of mining, smelting, waste burning, and electroplating of
consumer products (25). Cadmium has a half-life of 10–
30 years and there is no efficient way of recycling it (26).
The largest catastrophe of cadmium poisoning occurred in
Toyama prefecture in Japan. Cadmium was released in the
Jinzu river by mining companies, which contaminated the wa-
ter, fish, produce, and rice fields from 1910 through the 1960s
(27). Cadmium exposure causes itai-itai disease, which is char-
acterized by osteomalacia and renal tubular dysfunction (28,
29). In a cohort study of Japanese women in 1999 who
delivered at the Toyama Medical University Hospital,
cadmium exposure during pregnancy was associated with
preterm delivery and was detected in breast milk (30).
Annually, the United States produces 600 tons and im-
ports 150 tons of cadmium (31). Notably, pregnant women
have the highest levels of cadmium, which may be due to
lower iron stores and increased cadmium absorption in the
gastrointestinal tract during pregnancy (32, 33). Cadmium
accumulates in the liver, kidneys, testes, ovaries, and the
placenta (34). In the placenta, cadmium toxicity causes
lysosomal vesiculation, nuclear chromatin clumping, and a
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 Fertility and Sterility®

TABLE 1

Summary of reproductive health effects of preconception and prenatal exposure to environmental toxins.
Chemical Health risk Assess exposure Recommendations
Mercury Neurotoxin How often do you eat fish, which Eat fish 1–2 times per week, 6 oz.
Lower IQ type and how much? per serving
Poor language and motor Is it locally caught fish? Avoid shark, swordfish, marlin,
development Do you use personal care products orange roughy, king mackerel,
with known mercury content? tilefish, and big eye tuna
Do you work with mercury? Recommend seafood and fish low in
Do you have mercury thermometers mercury such as shrimp, salon,
at home? pollock, and catfish.
Check local advisories on water
quality
Lead Neurotoxin Do you work with lead? Do not eat clay, soil, pottery, or
Pregnancy-induced Do you live in a home built before paint chips
hypertension 1978 and are you Avoid jobs which may have lead
renovating an older home? exposure (construction, jewelry
Do you use imported pottery for making, lead battery industry)
cooking? Avoid renovation of homes built
Have you eaten clay, soil, dirt, before 1978
pottery, or paint chips? Avoid imported cosmetics and
traditional remedies
Take shoes off before entering the
home
Cadmium Placental epigenetic Do you eat organ meats? Avoid working in battery or plastic
modifications Are you a exposed to tobacco manufacturing
LBW, smaller head smoke? Avoid tobacco smoke
circumference Do you work in mining Buy organic grains and root
Emotional issues in boys or battery or plastic vegetables (e.g., rice, potato,
manufacturing? carrot, celeriac)
Do you buy organic produce? Stop eating organ meats while
pregnant or breastfeeding
Pesticides IUGR, birth defects Do you use pesticides Avoid use of pesticides and
Childhood cancers or insecticides in the home insecticides
Lower IQ or on pets? Wash produce before consuming,
Do you work in agriculture? and buy organic
Do you buy organic produce? Remove shoes before entering the
home
Use gloves if working in agriculture,
and wash hands often
Endocrine-disrupting Bisphenol A: Bisphenol A and phthalates: Reduce eating processed and
chemicals (EDCs) Obesity Do you eat or drink from cans, canned foods
Poor oocyte quality plastic bottles, or plastic food Avoid use of plastics with recycling
Phthalates: containers? codes #3 and #7, because they
Pregnancy loss and Do you microwave plastic food contain EDCs
earlier delivery containers? Replace plastic bottles and
Shorter anogenital distance Do you use fragrant personal containers with glass or steel
in baby boys care products Do not microwave plastic dishes or
Abnormal semen parameters PBDEs: containers
Earlier puberty in girls Do you purchase new curtains, Avoid touching cash register
Endometriosis rugs, and furniture with flame receipts
PBDEs: retardants? Buy ‘‘fragrance-free’’ laundry,
PTD, LBW, and still birth Do you clean the dust in your cleaning, and personal care
Impaired neurodevelopment house frequently? products
Thyroid dysfunction Do you take off your shoes Use ‘‘phthalate-free’’ products; buy
before entering the home? nail polish that says ‘‘no di-butyl
phthalate’’
Avoid buying new furniture, rugs, or
curtains during pregnancy to
reduce PBDE exposure
When purchasing new furniture or
rugs, ask whether flame
retardants were used
Air pollution Miscarriage Do you live in a high traffic area? Avoid outdoor activities when air
LBW Are there wildfires where you live? quality is poor
PTD and stillbirth Use a HEPA air purifier to reduce
chemical exposures
Note: IUGR ¼ Intrauterine growth restriction; LBW ¼ low birth weight; PBDE ¼ polybrominated diethyl ethers; PTD ¼ preterm delivery.
Segal. Environmental exposures and outcomes. Fertil Steril 2019.

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decline in progesterone and hCG production (35, 36). It can
enhance production of reactive oxidative species, resulting
in free radicals and oxidative stress (37).
The Study of Metals in Assisted Reproductive Technolo-
gies (SMART), a prospective cohort study of infertile couples,
assessed whether preconception exposure to lead, mercury,
and cadmium affects in vitro fertilization (IVF) outcomes.
The researchers found that increased cadmium levels were
associated with decreased oocyte fertilization (38) and
decreased implantation rates (39).
Cadmium competes with essential metals such as zinc and
copper in fetal liver, brain, kidney, and intestines (40). This
leads to abnormal growth and development because of insuf-
ficient zinc or copper, which may persist into adulthood. Dur-
ing pregnancy, exposure to cadmium has been associated
with decreased birth weight, smaller head circumference,
and premature birth, with a stronger association in baby girls
compared with boys (37, 40–44). Although the cause of this
imbalance is not well understood it has been shown that
cadmium exposure alters female fetal DNA methylation to a
greater extent than in male fetuses (45).
Studies have shown cadmium to be associated with
epigenetic changes in placental DNA (46). In a study of pre-
conception cadmium intake, measured through food fre-
quency questionnaires, cadmium exposure was associated
with hypomethylation of DNA in the umbilical cord (47).
Other studies also observed altered methylation of genes
related to apoptosis (48).
After puberty, cadmium exposure can cause significant
damage in the reproductive system. In men, cadmium expo-
sure is associated with lower semen quality, decreased
motility, and decreased testosterone levels. (49–51). As an
endocrine disruptor, cadmium may mimic or inhibit
endogenous estrogens, leading to abnormal hormone levels
and irregular menstrual cycles (49). Elevated levels of
cadmium in cord blood was associated with emotional and
cognitive problems in 7–8-year-old boys. Interestingly, there
was no such correlation for girls (52).
Recommendations. Asking patients about their work envi-
ronment and smoking habits (including second-hand smoke)
can give insights into whether they are at risk for cadmium
exposure. If patients live near an active mining, smelting or
industrial areas, they may have increased risk of exposure.
Encouraging buying organic rice and produce, especially
root crops such as potatoes, celery root, and carrots, and
avoiding organ meats while trying to conceive or pregnant
are recommended.
Pesticides
More than 1 billion pounds of pesticides are used in the
United States annually (53). Many of these chemicals can
persist in the environment for years, slowly degrading and
contaminating our food, water, air, dust, and soil. More than
90% of the population in the United States have detectable
levels of pesticides and their metabolites in the urine or serum
(54). Pesticide exposure during the preconception period can
lead to adverse outcomes including intrauterine growth
restriction and low birth weight (55). A study of pregnant
616
women who lived and worked in an agricultural community
in Salinas, California, had elevated pesticide levels in their
urine, which was associated with lower IQ and performance
testing in their children (56). Notably, high pesticide levels
during the preconception and pregnancy were associated
with childhood leukemia, increasing the risk by 50%–90%
(57). Parental pesticide use was also associated with pediatric
brain tumors (58). In a small case-control study, prenatal
exposure to DDT was associated with development of testic-
ular cancer 30 years later (59). Women who ate more fruits
and vegetables with a higher pesticide residue had a greater
risk of pregnancy loss than women who ate fewer high-
pesticide-residue fruits and vegetables (60). Men with an occu-
pational exposure to pesticides had children with an increased
risk of cancer and birth defects, including cryptorchidism (61).
Recommendations. Ask patients about the use of pesticides
and insecticides in the home or on pets. To reduce pesticide
exposure, encourage patients to choose organic fruits and
vegetables, especially for a category known as the ‘‘dirty
dozen’’: grapes, plums, peaches, string beans, potatoes, kale,
strawberries, apples, pears, spinach, celery, and peppers
(www.ewg.org/foodnews/dirty-dozen.php). If they work in
agriculture, instruct patients to wash their hands after work,
wear appropriate protective gear, and remove their shoes
before entering the home.
ENDOCRINE-DISRUPTING CHEMICALS
EDCs are chemicals that can mimic or block endogenous hor-
mones leading to adverse health outcomes. In addition to the
heavy metals, this review highlights three of the most studied
and highest-impact EDCs: bisphenol A (BPA), phthalates, and
polybrominated diethyl ethers (PBDEs). Industrial food pro-
cessing, personal care products, and cosmetics, constitute a
large source of phthalates and BPA. Dust in the home is a
source of exposure of all three. Phthalates and BPA have short
half-lives of hours to days, whereas PBDE can persist in adi-
pose tissue for months. The NHANES data have demonstrated
detectable levels of all three EDCs in urine in most Americans,
especially reproductive-age women (62, 63). In animals, in
utero exposure to these EDCs has led to abnormal urogenital
development, neurodevelopmental abnormalities, and
thyroid disruption. These widespread chemicals are hard to
avoid. Buying organic produce, cooking at home, and
decreasing processed food can reduce exposures (11, 64, 65).
In addition, checking websites for content of these chemicals
in commercial products, when such information is available,
is a reasonable approach (e.g., ewg.org).
Bisphenol A
BPA is ubiquitously produced and used for plastics, canned
food liners, cash register receipts, and epoxy resins (66). It is
found in plastic baby bottles, pacifiers, and baby toys, com-
puters, cell phones, and reusable food and drink containers.
Exposure is through inhalation, ingestion and dermal absorp-
tion. According to NHANES, 93% of the U.S. population has
detectable levels of BPA in the urine (67). BPA has been
shown to affect oocyte quality, implantation, embryo
VOL. 112 NO. 4 / OCTOBER 2019

development, and placentation (11). A revealing accidental
finding of BPA toxicity on oocytes occurred in the laboratory
of Patricia Hunt, who observed a spontaneous increase in
aneuploid oocytes in mice that coincided with damaged plas-
tic cages and water bottles. The Hunt team then treated mice
with daily oral BPA and induced dose-dependent increases in
oocyte aneuploidy, confirming BPA as the culprit (68–70).
In vitro studies also confirmed that BPA could disrupt
meiotic spindle formation (71). Higher levels of BPA were
associated also with miscarriage (72). Among women
undergoing IVF, elevated levels of urinary BPA were
associated with fewer oocytes retrieved and peak serum E2
levels (73). In addition, high levels of urinary BPA in
mothers before conception was associated with lower birth
weight and head circumference in infants (74). Indeed, BPA
can cross the human placenta and remains in active
unconjugated form (75). Some studies have shown BPA to
alter gene expression of factors controlling fetal growth and
metabolism (76). Concerns over BPA have led to BPA
substitutes being used and marketed as ‘‘BPA-free.’’
However, some of these substitutes are also harmful, such
as bisphenol S (68). BPA interferes with epigenetic
mechanisms in the placenta which may account for some of
the observed adverse obstetrical outcomes (77). In men, BPA
is associated with decreased semen quality, and it has been
demonstrated to alter prostate development in rodents (78).
Recommendations. Ask patients about their diet and use of
plastic drinking items and food containers. Educate patients
to limit the use of plastic containers, especially reheating in
microwaves and advise switching from plastic containers to
glass and stainless steel. Avoid taking cash registers receipts
printed on thermal paper (79). During the preconception,
pregnancy, and lactation periods, avoid canned foods and
bottled water with the number 7 stamped on the bottom.
Phthalates
Phthalates are synthetically derived and used as plasticizers in
personal, medical, and consumer care products such as intrave-
nous tubing, body lotions, toys, cosmetics, flooring products,
and food processing (80, 81). Another major source for
phthalates is the diet; one study showed significantly higher
urinary phthalate levels in people who dine out compared
with cooking at home (82). Several phthalate metabolites are
detectable in the serum of more than 95% of the population
(83). Women with endometriosis had elevated levels of
phthalate metabolites, suggesting a possible role in the
pathogenesis or pathophysiology (84). In utero exposure to
phthalates has been associated with delivery at an earlier
gestational age (85). Several studies found that higher levels,
compared with lower levels of phthalate metabolites in
pregnant mothers were associated with shorter anogenital
distance in baby boys (86). The Environment and
Reproductive Health (EARTH) study found that women
undergoing IVF with a higher concentration of phthalates had
lower numbers of oocytes retrieved, lower pregnancy rates,
and higher risk of early pregnancy loss before 20 weeks'
gestation (87, 88). Interestingly, paternal preconception
urinary concentrations of phthalates metabolites were
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Fertility and Sterility®
associated with lower birth weight in singletons conceived
with the use of IVF (89).
In men, phthalates have been shown to cause sperm DNA
damage (90). Elevated phthalate exposure has also been asso-
ciated with abnormal semen parameters, specifically
decreased motility (91) and increased time to pregnancy
(92). Moreover, postnatal exposure to phthalates has been
associated with early puberty in girls (93). In rats, in utero
exposure to phthalates reduced fetal testosterone levels and
induced male reproductive malformations, likely owing to
their antiandrogenic actions (94).
Recommendations. To reduce exposure to phthalates, cou-
ples should replace plastic bottles with glass or stainless steel
and avoid reheating food in plastic containers. Try to choose
‘‘fragrance free’’ when shopping for personal care products,
laundry detergents, or cleaning supplies. Couples should be
encouraged to cook at home and reduce the amount of fast
food and processed foods.
Polybrominated Diethyl Ethers
PBDEs are used in flame retardants on upholstered furniture,
textiles, carpeting, and some electronics. Most PBDEs in the
United States have been replaced by replacement flame retar-
dant (RFR) alternatives. However, because these chemicals are
lipophilic, they persist in adipose tissue with a half-life of a
few months to 12 years (95). PBDEs can also be detected in
fatty fish, lipid-rich oils, and breast milk. Another major
exposure is through dust brought into the home from shoes
and outerwear (96). PBDEs have been detected in urine of
pregnant women and in cord blood (97). In an electronics re-
cycling area in China, neonates with the highest PBDE expo-
sure had a higher incidence of still birth, low birth weight, and
premature birth (98). Owing to California's strict furniture
flammability standards, some of the highest levels in the
nation have been found in pregnant women in California
and were found to be associated with thyroid abnormalities,
a critical hormone for fetal brain development (99). A recent
prospective study looking at preconception levels of PBDEs
found a 28% pregnancy loss in women with high serum levels
of PBDEs (100, 101). In children, PBDE exposure impairs
neurodevelopment, leading to lower IQ and poorer attention
span (102).
Recommendations. Ask patients about their occupation and
whether they are exposed to new furniture or textiles. Women
and men of reproductive age should avoid purchasing new
furniture, carpets, or curtains containing PBDEs when at-
tempting conception or during pregnancy. Also, children
should be kept away from newly upholstered furniture con-
taining PBDEs. It is important to emphasize that basic habits
such as leaving shoes outside and washing hands to avoid
bringing in PBDE-contaminated dust are quite effective.
AIR POLLUTANTS
Epidemiologic studies increasingly demonstrate an associa-
tion between air pollution and adverse obstetrical outcomes
including spontaneous pregnancy loss (103), preterm delivery
(104, 105), low birth weight (106, 107), and stillbirth (108).
617
VIEWS AND REVIEWS
The Longitudinal Investigation of Fertility and the
Environment (LIFE) prospective study found that elevated
ambient air pollution during the preconception period was
associated with higher risk of pregnancy loss (109). Ozone
and particulate matter (especially sulfate compounds) were
associated with 12% and 13% increased risks of
miscarriage, respectively. Similarly, a case study of more
than 1,000 women with spontaneous pregnancy loss in
Utah found acute exposure to air pollutants, especially
nitrogen dioxide, was associated with a 16% increase in
miscarriage (104). Some have suggested that air pollution
may induce oxidative stress and inflammation leading to
abnormal placentation and adverse fetal development (105).
Indeed, a large cohort study found that first-trimester expo-
sure to ambient air pollution, mainly particulate matter
<2.5 mm and ozone, increased the risk of developing pre-
eclampsia, gestational hypertension, preterm delivery, and
small for gestational age newborns (110). In addition to
adverse obstetrical outcomes, prenatal exposure to air pollu-
tion has been associated with lower IQ at age 5 years (111) and
lower cognitive function scores in 8–11-year-old children
(112). The origins of this may involve the placenta's influence
on fetal brain development (113). Levels of in utero fine par-
ticulate matter during early pregnancy have been correlated
with decreased placental gene expression of essential proteins
for healthy neurodevelopment (114). A recent systematic re-
view of animal and epidemiologic studies on preconception
exposure to air pollutants found decreased fertility among
couples living in close proximity to major highways (115),
and those exposed to nitrogen dioxide had a decreased live
birth rate (114).
Recommendations. Although it is hard to control living con-
ditions, it may be beneficial to avoid outdoor activities when
the air quality is poor. Try to avoid areas with heavy traffic or
traveling during rush hour. Use a HEPA filter inside the home
to reduce chemicals from air pollution.
CONCLUSION
The magnitude of chemical exposures and their effects on
parental, fetal, and postnatal health make it imperative that
clinicians assess an individual's and a couple's risk of expo-
sure to environmental hazards as a routine part of the fertility
consultation. The preconception visit provides an ideal time
to assess a patient's environmental exposures at work, in
the home, and in the community. In this review we have pro-
vided a ‘‘quick guide’’ to relevant questions and recommenda-
tions to educate patients on how to reduce their exposures
(Table 1). A practical and easy-to-read handout for patients
on how to reduce toxic exposures is available from the Uni-
versity of California, San Francisco, in English and Spanish
(https://prhe.ucsf.edu/toxic-matters). In addition, the Centers
for Disease Control and Prevention published an informative
overview of reproductive health and the workplace (https://
www.cdc.gov/niosh/topics/repro/pregnancy.html). Incorpo-
rating an environmental history into the electronic medical
record (116) could be transformative for preconception, pre-
natal, and postnatal care.
618
It is also important to recognize the inequity of environ-
mental exposures due to social and economic disparities.
Many individuals such as those living near industrial farms,
construction zones, highways, or any space where damaging
chemicals are concentrated may have limited options to move
or otherwise improve their exposure profile. Moreover, eco-
nomics can limit access to low-pesticide fruits and vegetables.
Therefore it is critical for health professionals to support pub-
lic policies aimed at reducing the presence of harmful chem-
icals in our everyday environment.
Beyond public policy there are some straightforward stra-
tegies that health providers can share with patients to limit
exposures. These include taking off shoes before entering
the home, vacuuming frequently, avoiding the use of
common pesticides, and, when possible, eating organic and
nonprocessed foods. Health care providers have a unique
opportunity to reinforce these healthy habits and others
during the preconception window when patients are highly
motivated to make lifestyle changes (117).
Chemicals are ubiquitous in our environment and
increasingly present in our bodies. Starting the conversation
with patients regarding their exposure risk, educating them
on potential health effects, and implementing interventions
is anticipated to promote healthy pregnancies with improved
obstetrical and reproductive outcomes.
REFERENCES
1. Unites States Environmental Protection Agency. The Toxic Substance
Chemical Act chemical substance inventory. Available at: www.epa.gov/
tsca-inventory. Accessed May 20, 2019.
2. Woodruff TJ, Zota AR, Schwartz JM. Environmental chemicals in pregnant
women in the United States: NHANES 2003–2004. Environ Health Perspect
2011;119:878–85.
3. World Health Organisation Regional Office for Europe. Noncommunicable
diseases and air pollution. Available at: www.euro.who.int/_data/assets/
pdf_file/0005/397787/Air-Pollution-and-NCDs.pdf?ua¼1. Accessed May
30, 2019.
4. Guidice L, Woodruff T, Conry J. Reproductive and developmental environ-
mental health. Obstet Gynecol Reprod Med 2017;27:99–101.
5. Barker DJ. The fetal and infant origins of adult disease. BMJ 1990;301:
1111.
6. Barker DJ. The effect of nutrition of the fetus and neonate on cardiovascu-
lar disease in adult life. Proc Nutr Soc 1992;51:135–44.
7. Barker DJ, Osmond C, Golding J, Kuh D, Wadsworth ME. Growth in utero,
blood pressure in childhood and adult life, and mortality from cardiovascu-
lar disease. BMJ 1989;298:564–7.
8. Ravelli GP, Stein ZA, Susser MW. Obesity in young men after famine expo-
sure in utero and early infancy. N Engl J Med 1976;295:349–53.
9. di Renzo GC, Conry JA, Blake J, DeFrancesco MS, DeNicola N, Martin JN,
et al. International Federation of Gynecology and Obstetrics opinion on
reproductive health impacts of exposure to toxic environmental chemicals.
Int J Gynaecol Obstet 2015;131:219–25.
10. American College of Obstetricians and Gynecologists. Committee opinion
no. 575: exposure to toxic environmental agents. Obstet Gynecol 2013;
122:931–5.
11. Calafat AM, Ye X, Wong LY, Reidy JA, Needham LL. Exposure of the U.S.
population to bisphenol A and 4-tertiary-octylphenol: 2003–2004. Environ
Health Perspect 2008;116:39–44.
12. Rice KM, Walker EM, Wu M, Gillette C, Blough ER. Environmental mercury
and its toxic effects. J Prev Med Public Health 2014;47:74–83.
13. Harada M. Minamata disease: methylmercury poisoning in Japan caused
by environmental pollution. Crit Rev Toxicol 1995;25:1–24.
VOL. 112 NO. 4 / OCTOBER 2019

14. Kondo K. Congenital Minamata disease: warnings from Japan’s experi-
ence. J Child Neurol 2000;15:458–64.
15. Debes F, Budtz-Jørgensen E, Weihe P, White RF, Grandjean P. Impact of
prenatal methylmercury exposure on neurobehavioral function at age 14
years. Neurotoxicol Teratol 2006;28:363–75.
16. Grandjean P, Weihe P, White RF, Debes F, Araki S, Yokoyama K, et al.
Cognitive deficit in 7-year-old children with prenatal exposure to methyl-
mercury. Neurotoxicol Teratol 1997;19:417–28.
17. Stern AH, Smith AE. An assessment of the cord blood:maternal blood
methylmercury ratio: implications for risk assessment. Environ Health Per-
spect 2003;111:1465–70.
18. Spanier AJ, Wilson S, Ho M, Hornung R, Lanphear BP. The contribution of
housing renovation to children's blood lead levels: a cohort study. Environ
Health 2013;12:72.
19. Council on Environmental Health. Prevention of childhood lead toxicity. Pe-
diatrics 2016;138:e20161493.
20. United States Food and Drug Administration; Environmental Protection
Agency. Advice about eating fish, what pregnant women & parents should
know. Available at: https://www.fda.gov/food/consumers/advice-about-
eating-fish. Accessed May 20, 2019.
21. Bellinger DC. Teratogen update: lead and pregnancy. Birth Defects Res A
Clin Mol Teratol 2005;73:409–20.
22. Pilsner JR, Hu H, Ettinger A, S
anchez BN, Wright RO, Cantonwine D, et al.
Influence of prenatal lead exposure on genomic methylation of cord blood
DNA. Environ Health Perspect 2009;117:1466–71.
23. Schnaas L, Rothenberg SJ, Flores MF, Martinez S, Hernandez C, Osorio E,
et al. Reduced intellectual development in children with prenatal lead
exposure. Environ Health Perspect 2006;114:791–7.
24. Olsson IM, Bensryd I, Lundh T, Ottosson H, Skerfving S, Oskarsson A. Cad-
mium in blood and urine—impact of sex, age, dietary intake, iron status,
and former smoking—association of renal effects. Environ Health Perspect
2002;110:1185–90.
25. J€
arup L, Berglund M, Elinder CG, Nordberg G, Vahter M. Health effects of
cadmium exposure—a review of the literature and a risk estimate. Scand J
Work Environ Health 1998;24(Suppl 1):1–51.
26. Nordberg GF. Cadmium and health in the 21st century—historical remarks
and trends for the future. Biometals 2004;17:485–9.
27. Aoshima K. Itai-itai disease: lessons from the investigations of environ-
mental epidemiology conducted in the 1970's, with special reference to
the studies of the Toyama Institute of Health. Nihon Eiseigaku Zasshi
2017;72:149–58.
28. Ikeda M, Zhang ZW, Shimbo S, Watanabe T, Nakatsuka H, Moon CS, et al.
Urban population exposure to lead and cadmium in east and south-east
Asia. Sci Total Environ 2000;249:373–84.
29. Watanabe K, Kobayashi E, Suwazono Y, Okubo Y, Kido T, Nogawa K. Toler-
able lifetime cadmium intake calculated from the inhabitants living in the
Jinzu River basin, Japan. Bull Environ Contam Toxicol 2004;72:1091–7.
30. Nishijo M, Nakagawa H, Honda R, Tanebe K, Saito S, Teranishi H, et al. Ef-
fects of maternal exposure to cadmium on pregnancy outcome and breast
milk. Occup Environ Med 2002;59:394–6, discussion 397.
31. Bernhoft RA. Cadmium toxicity and treatment. ScientificWorldJournal
2013;2013:394652.
32. J€
arup L, Akesson A. Current status of cadmium as an environmental health
problem. Toxicol Appl Pharmacol 2009;238:201–8.
33. Nishijo M, Satarug S, Honda R, Tsuritani I, Aoshima K. The gender differ-
ences in health effects of environmental cadmium exposure and potential
mechanisms. Mol Cell Biochem 2004;255:87–92.
34. Satarug S, Moore MR. Adverse health effects of chronic exposure to low-
level cadmium in foodstuffs and cigarette smoke. Environ Health Perspect
2004;112:1099–103.
35. Wier PJ, Miller RK, Maulik D, DiSant’Agnese PA. Toxicity of cadmium in the
perfused human placenta. Toxicol Appl Pharmacol 1990;105:156–71.
36. Piasek M, Blanusa M, Kostial K, Laskey JW. Placental cadmium and progester-
one concentrations in cigarette smokers. Reprod Toxicol 2001;15:673–81.
37. Staessen JA, Roels HA, Emelianov D, Kuznetsova T, Thijs L, Vangronsveld J,
et al. Public Health and Environmental Exposure to Cadmium (PheeCad)
Study Group. Environmental exposure to cadmium, forearm bone density,
VOL. 112 NO. 4 / OCTOBER 2019
Fertility and Sterility®
and risk of fractures: prospective population study. Lancet 1999;353:
1140–4.
38. Bloom MS, Parsons PJ, Steuerwald AJ, Schisterman EF, Browne RW, Kim K,
et al. Toxic trace metals and human oocytes during in vitro fertilization
(IVF). Reprod Toxicol 2010;29:298–305.
39. Bloom MS, Fujimoto VY, Steuerwald AJ, Cheng G, Browne RW,
Parsons PJ. Background exposure to toxic metals in women adversely
influences pregnancy during in vitro fertilization (IVF). Reprod Toxicol
2012;34:471–81.
40. Gardner RM, Kippler M, Tofail F, Bottai M, Hamadani J, Grand
er M, et al.
Environmental exposure to metals and children's growth to age 5 years: a
prospective cohort study. Am J Epidemiol 2013;177:1356–67.
41. Kippler M, Tofail F, Gardner R, Rahman A, Hamadani JD, Bottai M, et al.
Maternal cadmium exposure during pregnancy and size at birth: a prospec-
tive cohort study. Environ Health Perspect 2012;120:284–9.
42. Kippler M, Wagatsuma Y, Rahman A, Nermell B, Persson L, Raqib R, et al.
Environmental exposure to arsenic and cadmium during pregnancy and
fetal size: a longitudinal study in rural Bangladesh. Reprod Toxicol 2012;
34:504–11.
43. Lin CM, Doyle P, Wang D, Hwang YH, Chen PC. Does prenatal cadmium
exposure affect fetal and child growth? Occup Environ Med 2011;68:
641–6.
44. Salpietro CD, Gangemi S, Minciullo PL, Briuglia S, Merlino MV, Stelitano A, et al.
Cadmium concentration in maternal and cord blood and infant birth weight: a
study on healthy nonsmoking women. J Perinat Med 2002;30:395–9.
45. Kippler M, Engstro €m K, Mlakar SJ, Bottai M, Ahmed S, Hossain MB, et al.
Sex-specific effects of early life cadmium exposure on DNA methylation
and implications for birth weight. Epigenetics 2013;8:494–503.
46. Vilahur N, Vahter M, Broberg K. The epigenetic effects of prenatal cad-
mium exposure. Curr Environ Health Rep 2015;2:195–203.
47. Boeke CE, Baccarelli A, Kleinman KP, Burris HH, Litonjua AA, Rifas-
Shiman SL, et al. Gestational intake of methyl donors and global LINE-1
DNA methylation in maternal and cord blood: prospective results from a
folate-replete population. Epigenetics 2012;7:253–60.
48. Sanders AP, Smeester L, Rojas D, DeBussycher T, Wu MC, Wright FA, et al.
Cadmium exposure and the epigenome: exposure-associated patterns of
DNA methylation in leukocytes from mother-baby pairs. Epigenetics
2014;9:212–21.
49. Kumar S, Sharma A. Cadmium toxicity: effects on human reproduction and
fertility. Rev Environ Health 2019; https://doi.org/10.1515/reveh-2019-0016.
50. Pizent A, Tariba B, Zivkovi
c T. Reproductive toxicity of metals in men. Arh
Hig Rada Toksikol 2012;63(Suppl 1):35–46.
51. Thompson J, Bannigan J. Cadmium: toxic effects on the reproductive sys-
tem and the embryo. Reprod Toxicol 2008;25:304–15.
52. Sioen I, Den Hond E, Nelen V, Van de Mieroop E, Croes K, van Larebeke N,
et al. Prenatal exposure to environmental contaminants and behavioural
problems at age 7–8 years. Environ Int 2013;59:225–31.
53. Centers for Disease Control and Prevention. Guidelines for the identifica-
tion and management of lead expsoure in pregnant and lactating women.
Available at: www.cdc.gov/nceh/lead/publications/leadandpregnancy
2010.pdf. Accessed May 23, 2019.
54. Centers for Disease Control and Prevention. Fourth national report in hu-
man exposure to environmental chemicals, updated tables. Available at:
http://www.cdc.gov/expsurereport/index.html. Accessed May 24, 2019.
55. United States Environmental Protection Agency. Pesticides industry sales
and usage 2006 and 2007 market estimates. Available at: http://www.
epa.gov/sites/production/files/2015-10/documents/market_estimates2007.
pdf. Accessed May 24, 2019.
56. Whyatt RM, Rauh V, Barr DB, Camann DE, Andrews HF, Garfinkel R, et al.
Prenatal insecticide exposures and birth weight and length among an ur-
ban minority cohort. Environ Health Perspect 2004;112:1125–32.
57. Rauh V, Arunajadai S, Horton M, Perera F, Hoepner L, Barr DB, et al. Seven-year
neurodevelopmental scores and prenatal exposure to chlorpyrifos, a common
agricultural pesticide. Environ Health Perspect 2011;119:1196–201.
58. Turner MC, Wigle DT, Krewski D. Residential pesticides and childhood leu-
kemia: a systematic review and meta-analysis. Environ Health Perspect
2010;118:33–41.
619
VIEWS AND REVIEWS
59. van Maele–Fabry G, Hoet P, Lison D. Parental occupational exposure to
pesticides as risk factor for brain tumors in children and young adults: a sys-
tematic review and meta-analysis. Environ Int 2013;56:19–31.
60. Cohn BA, Cirillo PM, Christianson RE. Prenatal DDT exposure and testicular
cancer: a nested case-control study. Arch Environ Occup Health 2010;65:
127–34.
61. Chiu YH, Williams PL, Gillman MW, Gaskins AJ, Mínguez-Alarco
n L,
Souter I, et al. Association between pesticide residue intake from consump-
tion of fruits and vegetables and pregnancy outcomes among women un-
dergoing infertility treatment with assisted reproductive technology. JAMA
Intern Med 2018;178:17–26.
62. van Wijngaarden E, Stewart PA, Olshan AF, Savitz DA, Bunin GR. Parental
occupational exposure to pesticides and childhood brain cancer. Am J Epi-
demiol 2003;157:989–97.
63. Braun JM, Messerlian C, Hauser R. Fathers Matter: Why it's time to consider
the impact of paternal environmental exposures on children’s health. Curr
Epidemiol Rep 2017;4:46–55.
64. Silva MJ, Barr DB, Reidy JA, Malek NA, Hodge CC, Caudill SP, et al. Urinary
levels of seven phthalate metabolites in the U.S. population from the Na-
tional Health and Nutrition Examination Survey (NHANES) 1999–2000. En-
viron Health Perspect 2004;112:331–8.
65. Lakind JS, Naiman DQ. Daily intake of bisphenol A and potential sources of
exposure: 2005–2006 National Health and Nutrition Examination Survey. J
Expo Sci Environ Epidemiol 2011;21:272–9.
66. Rudel RA, Gray JM, Engel CL, Rawsthorne TW, Dodson RE, Ackerman JM,
et al. Food packaging and bisphenol A and bis(2-ethyhexyl) phthalate
exposure: findings from a dietary intervention. Environ Health Perspect
2011;119:914–20.
67. Vandenberg LN, Hauser R, Marcus M, Olea N, Welshons WV. Human expo-
sure to bisphenol A (BPA). Reprod Toxicol 2007;24:139–77.
68. Susiarjo M, Sasson I, Mesaros C, Bartolomei MS. Bisphenol A exposure dis-
rupts genomic imprinting in the mouse. PLoS Genet 2013;9:e1003401.
69. Ehrlich S, Williams PL, Missmer SA, Flaws JA, Berry KF, Calafat AM, et al.
Urinary bisphenol A concentrations and implantation failure among
women undergoing in vitro fertilization. Environ Health Perspect 2012;
120:978–83.
70. Ziv-Gal A, Flaws JA. Evidence for bisphenol A–induced female infertility: a
review (2007–2016). Fertil Steril 2016;106:827–56.
71. Hunt PA, Koehler KE, Susiarjo M, Hodges CA, Ilagan A, Voigt RC, et al. Bi-
sphenol a exposure causes meiotic aneuploidy in the female mouse. Curr
Biol 2003;13:546–53.
72. Lenie S, Cortvrindt R, Eichenlaub-Ritter U, Smitz J. Continuous exposure to
bisphenol A during in vitro follicular development induces meiotic abnor-
malities. Mutat Res 2008;651:71–81.
73. Sugiura-Ogasawara M, Ozaki Y, Sonta S, Makino T, Suzumori K. Exposure
to bisphenol A is associated with recurrent miscarriage. Hum Reprod 2005;
20:2325–9.
74. Mok-Lin E, Ehrlich S, Williams PL, Petrozza J, Wright DL, Calafat AM, et al.
Urinary bisphenol A concentrations and ovarian response among women
undergoing IVF. Int J Androl 2010;33:385–93.
75. Mustieles V, Williams PL, Fernandez MF, Mínguez-Alarco
n L, Ford JB,
Calafat AM, et al. Maternal and paternal preconception exposure to bi-
sphenols and size at birth. Hum Reprod 2018; https://doi.org/10.1093/
humrep/dey234.
76. Balakrishnan B, Henare K, Thorstensen EB, Ponnampalam AP, Mitchell MD.
Transfer of bisphenol A across the human placenta. Am J Obstet Gynecol
2010;202:393.e1–7.
77. Rochester JR, Bolden AL. Bisphenol S and F: a systematic review and com-
parison of the hormonal activity of bisphenol A substitutes. Environ Health
Perspect 2015;123:643–50.
78. Strakovsky RS, Schantz SL. Impacts of bisphenol A (BPA) and phthalate ex-
posures on epigenetic outcomes in the human placenta. Environ Epigenet
2018;4:dvy022.
79. Bernier MR, Vandenberg LN. Handling of thermal paper: Implications for
dermal exposure to bisphenol A and its alternatives. PLoS One 2017;12:
e0178449.
620
80. Timms BG, Howdeshell KL, Barton L, Bradley S, Richter CA, vom Saal FS.
Estrogenic chemicals in plastic and oral contraceptives disrupt develop-
ment of the fetal mouse prostate and urethra. Proc Natl Acad Sci U S A
2005;102:7014–9.
81. Cariati F, d’Uonno N, Borrillo F, Iervolino S, Galdiero G, Tomaiuolo R. Bi-
sphenol A: an emerging threat to male fertility. Reprod Biol Endocrinol
2019;17:6.
82. Sathyanarayana S. Phthalates and children’s health. Curr Probl Pediatr
Adolesc Health Care 2008;38:34–49.
83. Varshavsky JR, Morello-Frosch R, Woodruff TJ, Zota AR. Dietary sources of
cumulative phthalates exposure among the U.S. general population in
NHANES 2005–2014. Environ Int 2018;115:417–29.
84. Parlett LE, Calafat AM, Swan SH. Women’s exposure to phthalates in rela-
tion to use of personal care products. J Expo Sci Environ Epidemiol 2013;
23:197–206.
85. 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 endometri-
osis. Hum Reprod 2003;18:1512–5.
86. 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 preg-
nancy. Environ Health Perspect 2003;111:1783–5.
87. Swan SH, Sathyanarayana S, Barrett ES, Janssen S, Liu F, Nguyen RH, et al.
First trimester phthalate exposure and anogenital distance in newborns.
Hum Reprod 2015;30:963–72.
88. Zarean M, Keikha M, Feizi A, Kazemitabaee M, Kelishadi R. The role of
exposure to phthalates in variations of anogenital distance: a systematic re-
view and meta-analysis. Environ Pollut 2019;247:172–9.
89. Messerlian C, Wylie BJ, Mínguez-Alarco
n L, Williams PL, Ford JB, Souter IC,
et al. Urinary concentrations of phthalate metabolites and pregnancy loss
among women conceiving with medically assisted reproduction. Epidemi-
ology 2016;27:879–88.
90. Duty SM, Singh NP, Silva MJ, Barr DB, Brock JW, Ryan L, et al. The relation-
ship between environmental exposures to phthalates and DNA damage in
human sperm using the neutral comet assay. Environ Health Perspect
2003;111:1164–9.
91. Messerlian C, Braun JM, Mínguez-Alarco
n L, Williams PL, Ford JB,
Mustieles V, et al. Paternal and maternal urinary phthalate metabolite con-
centrations and birth weight of singletons conceived by subfertile couples.
Environ Int 2017;107:55–64.
92. 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.
93. Buck Louis GM, Sundaram R, Sweeney AM, Schisterman EF, Maisog J,
Kannan K. Urinary bisphenol A, phthalates, and couple fecundity: the Lon-
gitudinal Investigation of Fertility and the Environment (LIFE) study. Fertil
Steril 2014;101:1359–66.
94. Lomenick JP, Calafat AM, Melguizo Castro MS, Mier R, Stenger P,
Foster MB, et al. Phthalate exposure and precocious puberty in females. J
Pediatr 2010;156:221–5.
95. Gray LE, Ostby J, Furr J, Price M, Veeramachaneni DN, Parks L. Perinatal
exposure to the phthalates DEHP, BBP, and DINP, but not DEP, DMP, or
DOTP, alters sexual differentiation of the male rat. Toxicol Sci 2000;58:
350–65.
96. Geyer HJ, Schramm K-W, Darnerud PO, Aune M, Feicht EA, Fried KW, et al.
Terminal elimination half-lives of the brominated flame retardants TBBPA,
HBCD, and lower brominated PBDEs in humans. Organohalogen Com-
pounds 2004;66:3867–72.
97. Frederiksen M, Vorkamp K, Thomsen M, Knudsen LE. Human internal and
external exposure to PBDEs—a review of levels and sources. Int J Hyg En-
viron Health 2009;212:109–34.
98. Chen A, Park JS, Linderholm L, Rhee A, Petreas M, DeFranco EA, et al. Hy-
droxylated polybrominated diphenyl ethers in paired maternal and cord
sera. Environ Sci Technol 2013;47:3902–8.
99. Wu K, Xu X, Liu J, Guo Y, Li Y, Huo X. Polybrominated diphenyl ethers in
umbilical cord blood and relevant factors in neonates from Guiyu, China.
Environ Sci Technol 2010;44:813–9.
VOL. 112 NO. 4 / OCTOBER 2019

100. Zota AR, Park JS, Wang Y, Petreas M, Zoeller RT, Woodruff TJ. Polybromi-
nated diphenyl ethers, hydroxylated polybrominated diphenyl ethers, and
measures of thyroid function in second trimester pregnant women in Cal-
ifornia. Environ Sci Technol 2011;45:7896–905.
101. Stapleton HM, Eagle S, Anthopolos R, Wolkin A, Miranda ML. Associations
between polybrominated diphenyl ether (PBDE) flame retardants, phenolic
metabolites, and thyroid hormones during pregnancy. Environ Health Per-
spect 2011;119:1454–9.
102. Choi G, Wang YB, Sundaram R, Chen Z, Barr DB, Buck Louis GM, et al. Pol-
ybrominated diphenyl ethers and incident pregnancy loss: The LIFE study.
Environ Res 2019;168:375–81.
103. Lam J, Lanphear BP, Bellinger D, Axelrad DA, McPartland J, Sutton P, et al.
Developmental PBDE exposure and IQ/ADHD in childhood: a systematic re-
view and meta-analysis. Environ Health Perspect 2017;125:086001.
104. Ha S, Sundaram R, Buck Louis GM, Nobles C, Seeni I, Sherman S, et al.
Ambient air pollution and the risk of pregnancy loss: a prospective cohort
study. Fertil Steril 2018;109:148–53.
105. Leiser CL, Hanson HA, Sawyer K, Steenblik J, Al-Dulaimi R, Madsen T, et al.
Acute effects of air pollutants on spontaneous pregnancy loss: a case-
crossover study. Fertil Steril 2019;111:341–7.
106. Jacobs M, Zhang G, Chen S, Mullins B, Bell M, Jin L, et al. The association
between ambient air pollution and selected adverse pregnancy outcomes
in China: a systematic review. Sci Total Environ 2017;579:1179–92.
107. Padula AM, Mortimer KM, Tager IB, Hammond SK, Lurmann FW, Yang W,
et al. Traffic-related air pollution and risk of preterm birth in the San Joa-
quin Valley of California. Ann Epidemiol 2014;24:888–95.e4.
108. Lamichhane DK, Leem JH, Lee JY, Kim HC. A meta-analysis of exposure to
particulate matter and adverse birth outcomes. Environ Health Toxicol
2015;30:e2015011.
VOL. 112 NO. 4 / OCTOBER 2019
Fertility and Sterility®
109. Yang S, Tan Y, Mei H, Wang F, Li N, Zhao J, et al. Ambient air pollution the
risk of stillbirth: a prospective birth cohort study in Wuhan, China. Int J Hyg
Environ Health 2018;221:502–9.
110. Lee PC, Roberts JM, Catov JM, Talbott EO, Ritz B. First trimester expo-
sure to ambient air pollution, pregnancy complications and adverse
birth outcomes in Allegheny County, PA. Matern Child Health J
2013;17:545–55.
111. Edwards SC, Jedrychowski W, Butscher M, Camann D, Kieltyka A, Mroz E,
et al. Prenatal exposure to airborne polycyclic aromatic hydrocarbons and
children’s intelligence at 5 years of age in a prospective cohort study in
Poland. Environ Health Perspect 2010;118:1326–31.
112. Suglia SF, Gryparis A, Wright RO, Schwartz J, Wright RJ. Association of
black carbon with cognition among children in a prospective birth cohort
study. Am J Epidemiol 2008;167:280–6.
113. Minichiello L. TrkB signalling pathways in LTP and learning. Nat Rev Neuro-
sci 2009;10:850–60.
114. Saenen ND, Plusquin M, Bijnens E, Janssen BG, Gyselaers W, Cox B,
et al. In utero fine particle air pollution and placental expression of
genes in the brain-derived neurotrophic factor signaling pathway: an
ENVIRONAGE birth cohort study. Environ Health Perspect 2015;123:
834–40.
115. Carr
e J, Gatimel N, Moreau J, Parinaud J, L
eandri R. Does air pollution play a
role in infertility? A systematic review. Environ Health 2017;16:82.
116. Friedman DJ, Parrish RG, Ross DA. Electronic health records and US public
health: current realities and future promise. Am J Public Health 2013;103:
1560–7.
117. Lindqvist M, Lindkvist M, Eurenius E, Persson M, Mogren I. Change of life-
style habits—motivation and ability reported by pregnant women in north-
ern Sweden. Sex Reprod Healthc 2017;13:83–90.
621