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European Journal of Epidemiology

https://doi.org/10.1007/s10654-021-00793-x

ENVIRONMENTAL EPIDEMIOLOGY

Maternal exposure to airborne polychlorinated biphenyls (PCBs)

and risk of adverse birth outcomes

Ane Bungum Kofoed

· Laura Deen

· Karin Sørig Hougaard

2,3

· Kajsa Ugelvig Petersen

· Harald William Meyer

Ellen Bøtker Pedersen

· Niels Erik Ebbehøj

· Berit Lilienthal Heitmann

4,5

· Jens Peter Bonde

Sandra Søgaard Tøttenborg

Received: 26 February 2021 / Accepted: 21 July 2021

Abstract

Human health effects of airborne lower-chlorinated polychlorinated biphenyls (LC-PCBs) are largely unexplored. Since

PCBs may cross the placenta, maternal exposure could potentially have negative consequences for fetal development. We

aimed to determine if exposure to airborne PCB during pregnancy was associated with adverse birth outcomes. In this cohort

study, exposed women had lived in PCB contaminated apartments at least one year during the 3.6 years before conception

or the entire first trimester of pregnancy. The women and their children were followed for birth outcomes in Danish health

registers. Logistic regression was performed to estimate odds ratios (OR) for changes in secondary sex ratio, preterm birth,

major congenital malformations, cryptorchidism, and being born small for gestational age. We performed linear regression to

estimate difference in birth weight among children of exposed and unexposed mothers. All models were adjusted for maternal

age, educational level, ethnicity, and calendar time. We identified 885 exposed pregnancies and 3327 unexposed pregnancies.

Relative to unexposed women, exposed women had OR 0.97 (95% CI 0.82, 1.15) for secondary sex ratio, OR 1.13 (95% CI

0.76, 1.67) for preterm birth, OR 1.28 (95% CI 0.81, 2.01) for having a child with major malformations, OR 1.73 (95% CI

1.01, 2.95) for cryptorchidism and OR 1.23 (95% CI 0.88, 1.72) for giving birth to a child born small for gestational age.

The difference in birth weight for children of exposed compared to unexposed women was − 32 g (95% CI—79, 14). We

observed an increased risk of cryptorchidism among boys after maternal airborne LC-PCB exposure, but due to the proxy

measure of exposure, inability to perform dose–response analyses, and the lack of comparable literature, larger cohort stud-

ies with direct measures of exposure are needed to investigate the safety of airborne LC-PCB exposure during pregnancy

Keywords

PCB · Lower chlorinated PCBs · Airborne PCB · Maternal exposure · Birth outcomes · Cryptorchidism

Ane Bungum Kofoed

[email protected]

Sandra Søgaard Tøttenborg

[email protected]

Background

PCBs are some of the most widespread persistent organic

pollutants in the environment due to their extensive use in

electrical equipment and building materials from late 1920s

to the 1970s and their continuous release from waste and

building materials from that period [1–3]. After decades of

use, PCBs were banned after concern about bioaccumula-

tion and cancer risks. Since their ban, much attention has

been paid to the accumulation of higher chlorinated PCBs

(HC-PCBs) in the food chain, which is thought to constitute

the most important source of human exposure. Studies have

demonstrated conflicting yet concerning results in regards to

health effects of these PCBs [4–9]. It was however recently

discovered that residents of PCB contaminated apartments

have considerably higher blood levels of lower chlorinated

Department of Occupational and Environmental Medicine,

Bispebjerg and Frederiksberg Hospital, Bispebjerg Bakke

23, Building 20F, 2400 Copenhagen, Denmark

National Research Centre for the Working Environment,

Copenhagen, Denmark

Department of Public Health, Faculty of Health, University

of Copenhagen, Copenhagen, Denmark

Research Unit for Dietary Studies, The Parker Institute,

Bispebjerg and Frederiksberg Hospital, Copenhagen,

Denmark

Section for General Practice, Department of Public Health,

Faculty of Health, University of Copenhagen, Copenhagen,

Denmark

Vol.:(0123456789)

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A. B. Kofoed et al.

PCBs (LC-PCBs) compared to residents of uncontaminated

apartments [10,

11],

and as much as 63% of the total PCB

body burden in exposed adults and 36% in exposed toddlers

may be from inhaled LC-PCBs [12].

Yet, human health effects of LC-PCBs remain largely

unexplored [13,

14].

HC-PCBs and LC-PCBs have inher-

ently different toxicological profiles [15]. Studies of HC-

PCBs can therefore not be directly used as basis for e.g.

action levels for LC-PCBs, even if this is presently the case

for private housing and workplaces in Denmark [14]. The

few studies that exist on the toxicity of LC-PCBs are asso-

ciated with cancer, metabolic and reproductive disorders

[15–18] and indicate that they have estrogenic and anti-

androgenic properties [15,

19].

LC-PCBs can furthermore

cross the placenta [20], and at a higher rate than HC-PCBs

[21] and might therefore have potential to negatively affect

fetal development [22,

23].

To date, no previous study has investigated if living in

PCB contaminated buildings is safe for the pregnant woman

and her child. If LC-PCBs can disrupt hormonal balance,

plausible consequences could be changes in secondary sex

ratio, increased risk of preterm birth, major malformations,

and changes in fetal growth [24]. We therefor aimed to

determine, if pre-pregnancy—and first trimester exposure

to LC-PCBs was associated with adverse birth outcomes.

We used nested data from the Health Effects of PCBs in

Indoor Air (HESPAIR) cohort, which included 3307 women

with 4212 pregnancies carried in estates partly contaminated

with PCBs.

Further, the median level of serum PCB-28 (LC-PCB) were

70 times higher among 71 exposed residents compared to 23

unexposed residents.

Inclusion and exposure

In the present study, we included all women from the HES-

PAIR cohort who had lived in the estates up to or during

their pregnancy by linking unique civil registration num-

bers from the HESPAIR cohort to the Danish Medical Birth

Registry (MBR) [26]. We identified 10 226 women who had

had one or more pregnancies resulting in live born single-

tons registered

after

their first relocation to the estates. The

MBR holds data on health of pregnant women and their off-

spring, and all live and still births in Denmark. The register

was established in 1973 and has been updated continuously.

It underwent a major revision in 1997, where the register

became electronic, and a list of new variables was added

[26].

The Danish Central Person register (CPR) was used to

extract information on dates and addresses of relocations.

This enabled calculation of timing and duration of living

in the estates, which served as a proxy for PCB exposure.

Women were defined as exposed if they had lived in a con-

taminated apartment for at least one year during the 3.6-

year period leading up to conception or during the entire

first trimester (Fig. 1). Conception was defined as the child’s

birth date minus gestational age, or child’s birth date minus

38 weeks (266 days) if gestational age was unavailable, e.g.

before 1978. The same criteria were applied for women to

be considered unexposed, but in an uncontaminated apart-

ment, with the additional criterium that they could not have

lived in a contaminated apartment in the two building estates

previously or during the period of interest for this study.

The one year exposure criterium was based on a reanaly-

sis of the data on plasma concentration of PCB-28 among

134 exposed and 139 non-exposed residents, obtained by

Meyer et al. [10] that showed significantly higher plasma

concentrations of LC-PCBs among residents after one year

of living in contaminated apartments. Unfortunately, plasma

samples were not available for this study’s nested popula-

tion. The time window of 3.6 years was constructed from

the half-life of PCB-28. This varies according to different

studies, but one study found the half-life to be 4.6 years

[27], one study reported 5.5 [28], and other studies reported

shorter half-lives (1.4 and 3 years) [29,

30].

The time win-

dow of 3.6 years allowed the mother to live in a contami-

nated apartment and relocate to an uncontaminated apart-

ment up to 2.6 years prior to conception, while the woman

and her future child would still be exposed to over half of the

accumulated LC-PCB. The exposure criterium regarding the

first trimester was included to reflect an ongoing exposure

during establishment of the pregnancy and organogenesis,

Methods

Study population

The current study was nested in the HESPAIR cohort, spe-

cifically designed to study health effects after exposure to

PCB in indoor air. The cohort was established in 2019 by the

Department of Occupational and Environmental Medicine

(Bispebjerg Hospital, Denmark). HESPAIR consists of 52

212 former or current residents of the building estates Farum

Midtpunkt and Brøndby Strand Parkerne during the period

1970–2018. The estates were erected during 1969–1974 and

include both PCB contaminated apartments and uncontami-

nated apartments. This is because PCB containing caulks

and sealants were used during the first stages of construc-

tion, while other building materials were used in later stages

[10]. Measurements of PCB concentrations in indoor air in

contaminated and uncontaminated estates have been con-

ducted and revealed large differences and differences were

dominated by LC-PCBs [3,

25].

Plasma levels of PCBs with

3–4 chlorine atoms were over 50 times higher among 134

exposed compared to 139 unexposed residents [10,

11].

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Maternal exposure to airborne polychlorinated biphenyls (PCBs) and risk of adverse birth…

Conception

Birth

3.6 years

1. trimester

Minimum one year stay in

contaminated/uncontaminated

apartment

Stay in entire 1.trimester in

contaminated/uncontaminated

apartment

mester. Additionally, unexposed could not have lived in a contami-

nated apartment in the two building estates previously or during the

period of interest

Fig. 1

Demonstrating exposure/unexposure criteria of minimum one

year stay in a contaminated/uncontaminated apartment during the

3.6-year period leading up to conception or during the entire first tri-

which is a very sensitive stage of pregnancy, among others

for hormonal disruption and development of the reproduc-

tive organs [23].

Birth outcomes

Birth outcomes were retrieved from birth records in the

MBR available since 1973 and hospital contacts in the Dan-

ish National Patient Register (DNPR) available since 1977.

The DNPR holds information on diagnoses and treatments

for all patients admitted to any public or private hospital and

was used to retrieve data on congenital malformations [31].

The child’s sex was retrieved from birth records of live

births, to examine secondary sex ratio. Secondary sex ratio

was expressed as the chance of having a live born son. This

is of interest since hormonal disruption could decrease

the prevalence of boys [32]. Information on preterm birth,

defined as being born before 37 completed weeks of gesta-

tion [33], was identified using gestational age registered and

available in birth records. Major congenital malformations

were defined after guidelines by European Surveillance of

Congenital Anomalies (EUROCAT) [34]. Major malfor-

mations were included if diagnosed within the first year of

life and registered with a diagnose code in the DNPR (from

1977) and the MBR (from 1997). Only the first diagnose

on any type of major malformation was included. Minor

malformations, also defined as by EUROCAT [35], were

excluded. Cryptorchidism is defined as a minor malforma-

tion, but is of specific interest as an indicator of hormonal

disruption of testicular development [36]. It was therefore

included in a separate analysis. Cryptorchidism was identi-

fied in the MBR and DNPR using the ICD-8 codes: 75210,

75211, 75219, and ICD-10 codes: Q530, Q531, Q531A,

Q532, Q532A or Q539, respectively, or registration with

Surgery and Treatment Classification of the National Board

of Health: 55,640 and Nordic Classification of Surgical

Procedures: KFH00, KFH01 and KFH10, respectively. We

included first diagnosis of cryptorchidism from birth until

2018, since this type of malformation can be diagnosed sev-

eral years after birth [37,

38].

Birth weight for gestational

age and birth weight on a continuous scale was investigated

in two separate analyses. Small for gestational age (SGA)

was determined using birth weight for gestational age, where

SGA is defined as birth weight below the 10th percentile

for each gestational week, stratified by sex [39]. SGA was

calculated by the commonly used Kramer method [40] with

birth weight, gestational age in weeks, and sex retrieved

from birth records.

Covariates

Potential confounders were identified a priori using directed

acyclic graphs [41], see Fig. 2. We distinguished between

two aspects of exposure since we assumed PCB exposure

status (living in a contaminated/uncontaminated resident)

was a proxy of PCB body burden, and confounders were

differently associated with these two aspects. We included

maternal age as a continuous variable was obtained from

the MBR. Maternal education, categorized as low, middle,

and high, and ethnicity + , categorized as coming from the

Nordic countries or not, were obtained from the CPR regis-

ter. We also adjusted for calendar time in decades. Smoking

information was available from the MBR since 1991.

Statistical analysis

In analyses regarding secondary sex ratio, SGA, preterm

birth, major congenital malformations, and cryptorchid-

ism we performed logistic regression with adjustment for

maternal age, educational level, ethnicity, and calendar

time. We restricted the analyses of preterm birth and birth

weight to children born from 1982, since before 1982 we

found many missing values on gestational age and birth

weight was coded in large weight intervals (e.g. 250 g

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A. B. Kofoed et al.

Fig. 2

Show confounders identified a priori in crude (left) and adjusted (right) model. After adjusting for confounders indicated by white circles

(in adjusted model), the purple arrows show remaining biasing paths from maternal BMI to exposure and outcome

intervals), as reported previously [42]. In addition to the

overall analysis on cryptorchidism, we restricted one anal-

ysis to children born full term (week 37–42), since the risk

of cryptorchidism is highly dependent on gestational age.

Risk estimates were expressed as odds ratios (ORs) with

95% confidence intervals (95% CI). Correlation between

siblings were accounted for in all analyses by apply-

ing robust standard errors when calculating confidence

intervals. Birth weight was normally distributed, and we

therefore performed multiple linear regression, express-

ing difference in birth weight as β-coefficient with 95%

CI. In the multiple linear regression, we also checked for

interaction between exposure and sex. In addition to the

overall analysis on birth weight, we restricted one analysis

to children born full term (week 37–42). To take poten-

tial confounding by maternal smoking up to pregnancy

into account, we repeated all analyses with adjustment

for smoking among women who had given birth between

1991 and 2018, because smoking information (no/yes)

was registered only during this period. For all outcomes,

we also checked for interaction between LC-PCB expo-

sure and smoking. We furthermore repeated all analyses

while restricting to nulliparous women, since nulliparous

women represent a more homogenous group where previ-

ous experience with pregnancy and birth does not influ-

ence the desire and motivation for having more children.

Also, nulliparous women have previously been reported

to have higher risks for negative birth outcomes [43]. All

statistical tests were performed using Stata software (ver-

sion 16.0, Stata Corp, College Station, TX).

Results

In the HESPAIR cohort we identified 10 226 women who

had 18 650 pregnancies with live born singletons regis-

tered

after

their first relocation to the estates. Of these,

only 3307 women and their 4212 pregnancies fulfilled the

criteria of being exposed or unexposed during the defined

observation window, of which 885 (21%) pregnancies were

exposed (see Fig. 3).

Maternal characteristics

Mean age of mothers were similar among exposed and

unexposed (Table 1). We found a small difference in eth-

nicity, since more exposed compared to unexposed were

from Nordic countries (68% versus 64%). Fewer exposed

were represented in the lowest and highest educational

group compared to unexposed. However, among the

exposed, a higher percentage had missing data on educa-

tional level compared to unexposed (29% versus 21%). The

first decade, 1970–1979, represented more pregnancies

by exposed women compared to unexposed (16% versus

11%), and the last decade 2010–2018 represented more

pregnancies by unexposed women compared to exposed

(14% versus 10%). In data regarding maternal smoking up

to pregnancy available since 1991, we found no difference

in distribution.

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Maternal exposure to airborne polychlorinated biphenyls (PCBs) and risk of adverse birth…

Fig. 3

Flow chart of identifica-

tion process of exposed and

unexposed residents

52 212

men and women in the

HESPAIR cohort

10 226

women with

18 650

pregnancies with singleton and

live born children after first

relocation to the estates

14 438 singleton pregnancies

did not fulfill exposure

criteria

3307

women with

4212

singleton

pregnancies in the observation

window

710

women with

885

singleton

pregnancies in contaminated

apartments fulfilled exposure

criteria

2597

women with

3327

singleton

pregnancies in uncontaminated

apartments fulfilled non-exposure

criteria

Table 1

Baseline characteristics for 3307 mothers at the time of 4212

pregnancies

Unexposed

(reference)

pregnancies (%)

Maternal age (SD)

Maternal ethncity

Nordic contries %

Non-nordic contries %

Missing %

Maternal level of education

Low %

Middle %

High %

Missing %

Calendar time of conception

1970–1979%

1980–1989%

1990–1999%

2000–2009%

2010–2018%

Maternal smoking up to pregnancy

No %

Yes %

Missing %

standard deviation

Secondary sex ratio

We found no difference in secondary sex ratio in neither

crude nor adjusted analyses (OR 0.97 with 95% CI 0.82,

1.15) (Table 2). Smoking did not interact with LC-PCB

exposure, and adjustment for smoking and restriction to first

born children did not change results.

Exposed

885 (21)

27.5 (5.4)

3327 (79)

27.9 (5.4)

Preterm birth

We found no difference in risk of preterm birth (before 37

completed weeks of gestation) (OR 1.13 with 95% CI 0.76,

1.67) (Table 2). Smoking did not interact with LC-PCB,

but adjustment for smoking elevated the risk estimate to

25% (OR 1.25 with 95% CI 0.73, 2.14) but with a wider CI.

Restriction to first born children was in line with the result

from the main analysis.

Major malformations

In adjusted analyses we observed an indicated 28% higher

risk of major malformations (OR 1.28 with 95% CI 0.81,

2.01) (Table 2). Smoking did not interact with LC-PCB, and

risk attenuated when adjusting for smoking (OR 1.13 with

95% CI 0.66, 1.96). The results were robust to restriction to

first born children.

Available since 1991 (unexposed

2028 and

exposed

= 476)

Cryptorchidism

In adjusted analyses, we found that women exposed to LC-

PCBs had a 73% higher risk of giving birth to sons with

cryptorchidism but with a wide confidence interval (OR

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A. B. Kofoed et al.

1.73 with 95% CI 1.01, 2.95) (Table 3). No interaction

between LC-PCB exposure and smoking was seen, and

the higher risk remained after adjustment for smoking and

restriction to first born children in the sensitivity analyses.

Similarly, when looking at risk of cryptorchidism among

boys born full term, exposed pregnancies had a 75% higher

risk compared to unexposed but still with a wide confi-

dence interval (OR 1.75 with 95% CI 1.01, 3.04).

Table 2

Odds ratios (OR)

with 95% confidence intervals

(CI) of adverse birth outcomes

among 885 pregnancies exposed

to LC-PCB relative to 3327

unexposed

n cases (%)

Crude model

Adjusted model

OR (95% CI)

Secondary sex ratio

Unexposed 1689 (51)

Exposed

442 (50)

Preterm birth

Unexposed 146 (5)

Exposed

37 (5)

Major malformation

Unexposed 114 (3)

Exposed

30 (4)

OR (95% CI)

1 (ref)

0.97 (0.82, 1.15)

1 (ref)

1.13 (0.76, 1.67)

1 (ref)

1.28 (0.81, 2.01)

Restricted to

children born

1991–2018

OR (95% CI)

1 (ref)

0.96 (0.77, 1.19)

1 (ref)

1.20 (0.75, 1.92)

1 (ref)

1.13 (0.66, 1.96)

Restricted

to first born

children

OR (95% CI)

1 (ref)

0.99 (0.80, 1.23)

1 (ref)

1.08 (0.69, 1.71)

1 (ref)

1.37 (0.80, 2.35)

1 (ref)

0.97 (0.84, 1.12)

1 (ref)

1.02 (0.70, 1.49)

1 (ref)

1.01 (0.66, 1.53)

LC-PCB

lower chlorinated polychlorinated biphenyls,

ref

reference,

odds ratio,

confidence interval

Adjusted for maternal age, highest level of education, ethnicity, and calendar time

Adjusted for maternal age, highest level of education, ethnicity, calendar time, and smoking

Table 3

Odds ratios (OR) with 95% confidence intervals (CI) of cryptorchidism among boys of 442 pregnancies exposed to LC-PCB relative to

1689 unexposed

cases (%)

Crude model

Adjusted model

Restricted to children

born 1991–2018

OR (95% CI)

1 (ref)

1.77 (0.96, 3.27)

Restricted to first

born children

OR (95% CI)

1 (ref)

2.18 (1.13, 4.21)

Restricted to

children born full

term

OR (95% CI)

1 (ref)

1.75 (1.01, 3.04)

OR (95% CI)

Cryptorchidism

Unexposed

66 (4)

Exposed

25 (6)

OR (95% CI)

1 (ref)

1.73 (1.01, 2.95)

1 (ref)

1.47 (0.92, 2.36)

LC-PCB

lower chlorinated polychlorinated biphenyls,

ref

reference,

odds ratio,

confidence interval

Adjusted for maternal age, highest level of education, ethnicity, and calendar time

Adjusted for maternal age, highest level of education, ethnicity, calendar time, and smoking

Adjusted for maternal age, highest level of education, ethnicity, and calendar time

Table 4

Odds ratios (OR) with

95% confidence intervals (CI)

of having a child born small

for gestational age among

686 pregnancies exposed

to LC-PCB relative to 2794

unexposed

cases (%)

Crude model

Adjusted model

OR (95% CI)

Small for gestational age

Unexposed 239 (9)

Exposed

68 (10)

OR (95% CI)

1 (ref)

1.23 (0.88, 1.72)

Restricted to

children born

1991–2018

OR (95% CI)

1 (ref)

1.34 (0.88, 2.03)

Restricted

to first born

children

OR (95% CI)

1 (ref)

1.04 (0.72, 1.51)

1 (ref)

1.18 (0.87, 1.60)

LC-PCB

lower chlorinated polychlorinated biphenyls,

ref

reference,

odds ratio,

confidence interval

Adjusted for maternal age, highest level of education, ethnicity, and calendar time

Adjusted for maternal age, highest level of education, ethnicity, calendar time, and smoking

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Maternal exposure to airborne polychlorinated biphenyls (PCBs) and risk of adverse birth…

Birth weight

In adjusted analyses, LC-PCB exposure indicated a 23%

increased risk giving birth to a SGA child (OR 1.23 with

95% CI 0.88, 1.72) (Table

4).

No interaction between

exposure and smoking was found. Adjustment for smok-

ing gave essentially similar results (OR of 1.34 (95% CI

0.88, 2.03)). However, when examining SGA among first

born children, the risk was attenuated.

Adjusted analyses of birth weight on a continuous

scale showed that the difference in birth weight was

− 32 g (β-coefficient − 32 with 95% CI:—79, 14) among

children of exposed compared to children of unexposed

women (Table 5), and no difference in birth weight was

observed across sex. When restricting the analyses to full

term children (i.e. born week 37–42), the same tendency

was observed (Table 5). The tendency was also observed

when adjusting for smoking and when restricting analysis

to first born children. No interaction between exposure

and smoking was observed.

Previous literature and mechanisms

As the historic focus has been on HC-PCB congeners, no

previous evidence related to airborne LC-PCB exposure and

birth outcomes is available. Evidence on HC-PCB and birth

outcomes is conflicting, which may be due to the numerous

differences across the previous studies, e.g. study design,

population characteristics, measure of and differences in

level of exposure [4,

6–9, 39, 44–48].

Currently, the risk

assessment of airborne PCB exposure is based on the knowl-

edge obtained on HC-PCBs. Due to differences in toxico-

logical profiles between HC- and LC-PCBs [15], and the

faster rates of placental transfer for LC-PCBs [21], potential

health effects of LC-PCBs need to be assessed separately.

Very few studies have specifically examined the toxico-

logical mechanisms of LC-PCBs. Based on their mecha-

nisms, the overall group of the 209 PCB congeners can

be divided into dioxin like PCBs (DL-PCBs), and non-

dioxin like PCBs (NDL-PCBs) which includes most HC-

PCBs and LC-PCBs. Like dioxins, the 12 existing DL-

PCBs (PCB 77, 81, 105, 114, 118, 123, 126, 156, 157,

167, 169, and 189) act through the Aryl Hydrocarbon

Receptor (AhR). NDL-PCBs probably act on multiple

other receptors and pathways, for instance the consti-

tutive androstane receptor (CAR) and the pregnane X

receptor (PXR) [49]. The effects of interaction with CAR

and PXR can be modulated gene expression linked to

estrogenic, androgenic and thyroid receptors, and altered

hormonal homeostasis [19]. During metabolism of NDL-

PCBs, hydroxylated metabolites (OH-NDL-PCBs) may be

formed [50], and these can also act on the estrogen and the

androgenic receptors [51]. The existing evidence points to

different toxicological mechanism of LC—and HC-PCBs.

One in vitro study examined the difference between LC

Discussion

Main results

In this first study ever to investigate the relationship

between pre-pregnancy and first trimester exposure to

airborne LC-PCBs and adverse birth outcomes, we found

increased risk of cryptorchidism in sons.

Table 5

Linear regression of birth weight among 686 pregnancies exposed to LC-PCB relative to 2794 unexposed

Mean g (SD) Crude

Adjusted

Restricted to chil-

dren born 1991–

2018

β-coefficient (95%

CI)

(ref)

− 29 (− 86, 28)

(ref)

− 30 (− 89, 28)

Restricted to first born

children

β-coefficient (95% CI)

β-coefficient (95%

CI)

All children

Unexposed 3457 (555)

Exposed

3460 (527)

Full term children

Unexposed 3509 (499)

Exposed

3506 (480)

β-coefficient (95%

CI)

(ref)

− 30 (− 74, 15)

(ref)

− 28 (− 74, 17)

β-coefficient (95%

CI)

(ref)

− 32 (− 79, 14)

(ref)

− 32 (− 80, 16)

(ref)

3 (− 46, 52)

(ref)

− 3 (− 50, 44)

(ref)

1 (− 47, 50)

(ref)

− 25 (− 88, 37)

LC-PCB

lower chlorinated polychlorinated biphenyls,

grams,

standard deviation,

ref

reference,

confidence interval

Unexposed

= 2642 and exposed

= 654

Adjusted for gestational age

Adjusted for gestational age, sex, maternal age, highest level of education, ethnicity, and calendar time

Adjusted for gestational age, sex, maternal age, highest level of education, ethnicity, calendar time and smoking

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A. B. Kofoed et al.

and HC-PCBs, and reported LC-PCBs to have estrogenic

effects, while HC-PCBs mainly had anti-estrogenic effects

[15]. Another in vitro study, found LC-PCBs to have affin-

ity for CAR, PXR, be highly anti-androgenic and estro-

genic, and LC-PCB metabolites were found to have greater

estrogenic effects than their parent congener [19]. These

in vitro studies have been supported by one cross-sectional

study on PCB concentration in umbilical cord sera and

adverse birth outcomes. This study observed different

effects according to the degree of chlorination, and found

LC-PCBs to be associated with lower levels of luteiniz-

ing hormone and testosterone, lower gestational age and

smaller head circumference [52].

We observed an increased risk of cryptorchidism for

exposed pregnancies, but with a wide 95% confidence inter-

val, which implies uncertainty of the risk estimate and could

be due to chance but could also be due few cases in a popula-

tion with a moderate size. However, a plausible mechanism

could be the hypothesized estrogenic and anti-androgenic

activity of LC-PCBs during the ‘male programming win-

dow’ in the first trimester [53]. Previous cross-sectional and

case–control studies on the relationship between HC-PCB

and risk of cryptorchidism have demonstrated conflicting

results [54–56]. No previous studies have examined the

relationship between LC-PCBs and cryptorchidism, but

one study found that maternal blood level of two LC-PCB

congeners (PCB-28 and PCB-74) in the third trimester was

associated with shorter anogenital distance (AGD) in new-

born boys [18]. AGD is considered a marker of endocrine

disruption and reproductive disease [57,

58].

Tang and col-

leagues found LC-PCBs to be associated with lower levels of

luteinizing hormone and testosterone [52], which are crucial

hormones in the process of testicular descent in fetal life

[59].

We observed an indication of impaired organogenesis

after airborne LC-PCB exposure, but again with a wide 95%

confidence interval. However, as we only included major

malformations diagnosed within the child’s first year, we

could have missed some cases as the registration of diagnose

codes in the DNPR started in 1977, and the estates—with

contaminated apartments being built first—were available

for living from the beginning of the 1970’ies. Nevertheless,

when we studied children born 1991–2018, where registra-

tion of malformations and maternal smoking information

were available for the whole period, we found an attenu-

ated risk estimate. Teratogenic effects have been observed

in ‘Yucheng’ children after their mothers accidently ingested

polychlorinated dibenzofurans (PCDFs)—and PCB contami-

nated rice oil in 1978–1979 [60]. ‘Yucheng’ children were

prenatally exposed to very high concentrations of PCB (but

primarily HC-PCBs) and PCDFs. Similarly, other persistent

organic pollutants (POPs) have been associated with certain

congenital malformations [48,

61].

We found no increased risk of preterm birth, and the main

analysis was supported by the analysis among first born chil-

dren where we expected the mothers to represent a more

homogenous group independent of previous experiences

with pregnancy and birth,. This is in contrast to a previ-

ous cross-sectional study reporting an inverse association

between LC-PCBs in umbilical cord blood and gestational

age at birth [52].

We also found indications of affected gestational growth,

but once again with wide 95% confidence intervals. If gesta-

tional growth is affected by LC-PCBs, it may be explained

by a wide range of effects of PCBs on metabolism, e.g. alter-

ation of insulin regulation [62], and thyroid, antiandrogenic

and estrogenic effects [63,

64].

But again, when analysis

was restricted to first born children, birth weight differences

diminished, which weakens our hypothesis of effect on fetal

growth. Studies on prenatal HC-PCB exposure and birth

weight reports conflicting results [6,

8, 44, 46],

and some

studies found the effect to be dependent on maternal smok-

ing and sex of the child [6,

9].

We did not observe interaction

between exposure and smoking, nor exposure and sex of the

child, as reported after HC-PCBs exposure [6].

Problem magnitude and perspectives

Indoor LC-PCB contamination in private homes and public

buildings is a global issue including countries like Germany

and The United States [65–67]. Presently, 0.7–1.5% of all

buildings in Denmark have indoor air levels exceeding the

lower recommended action level, but the problem might

be of larger scale since 37% of the total housing stock was

constructed during the period when PCBs were allowed

and commonly used (1950–1979) [68]. Studies examining

schools and office buildings found concentrations exceeding

the limit in many locations [66,

67, 69].

Since the action

limit for PCB concentration in indoor air is based on knowl-

edge on toxicity of HC-PCBs, this value may be inadequate,

and the public health issue might be of much larger scale.

Our results call for larger cohort studies investigating the

existing limit value and the safety of staying in PCB con-

taminated estates and workplaces.

Strengths and limitations

Our study has several strengths. The relationship was studied

in a residence-based cohort, where people have unknowingly

relocated themselves to contaminated and uncontaminated

apartments, except for the first years of the cohort period

where contaminated apartments were available first. Since

contaminated apartments were built first, the chance of mov-

ing into a contaminated apartment were naturally higher

during this period. Nevertheless, we expect residents from

the estates to be similar in background exposure to PCBs,

BEU, Alm.del - 2020-21 - Bilag 387: Orientering om artikel om sammenhæng mellem udsættelse for PCB i indeluft i bygninger og øget risiko for fosterskader hos drenge, fra beskæftigelsesministeren

Maternal exposure to airborne polychlorinated biphenyls (PCBs) and risk of adverse birth…

socioeconomic status, and health behavior, which previous

studies on subsamples of the total HESPAIR cohort have

demonstrated [10,

11].

We did however adjust for calendar

time, as the quality of registration and sociodemographic

characteristics of residents may have changed over the five

decades of inclusion. Both maternal age at giving birth and

smoking habits have changed over time and is related to

birth outcomes. We therefore considered maternal age a

confounder to be adjusted for (Fig. 2). Smoking could also

be related to the susceptibility to PCB exposure, and due to

the afore mentioned reason be related to PCB body burden

(Fig. 2), and smoking is related to the risk of negative birth

outcomes [50]. Therefore, smoking could interact with the

association between exposure and outcome, but also con-

found the association. In our sensitivity analysis restricted to

children born 1991–2018, where smoking information was

available, no interaction was observed. Preferably, and as

suggested in our directed acyclic graph (Fig. 2), body mass

index (BMI) should also have been adjusted for, because

mobilization of body fat during pregnancy can release

accumulated PCBs to the bloodstream [18], but BMI was

only available since 2004 and were missing for half of the

residents. Nevertheless, we expect residual confounding

regarding maternal body mass index (BMI), and maternal

and paternal smoking to be minimal, as previous studies

on subsamples of estate residents have demonstrated equal

distribution of BMI and smoking among exposed and unex-

posed residents [10,

11].

We were not able to adjust for pos-

sible confounders such as paternal age and fish consumption,

but we do believe these variables to be equally distributed

among exposed and unexposed, in line with other variables,

and residual confounding from these variables is expected to

be minimal. Adjustment for maternal education, which can

be the most appropriate measure of socioeconomic status

for young adults who have yet to establish themselves occu-

pationally [49], also minimized the chance of residual con-

founding as it is closely related to health behavior, including

BMI and smoking. We did however have more missing data

on educational level among exposed women which could

be due to educational data being available since 1981, and

more exposed compared to unexposed pregnancies were rep-

resented before this (1970–1980). In our sensitivity analysis

restricted to children born 1991–2018, data on educational

level was available for the full period, and the difference in

missing data was reduced.

The registers made it possible to avoid self-report of out-

comes, but also presented some issues. First, the DNPR,

the only source of information on congenital malformations

prior to 1997, did not cover the entire cohort period, as the

able since the beginning of the 1970’s. Further, registration

methods, quality, and especially the registration complete-

ness in the MBR changed over time [26]. For instance, the

number of infants registered with congenital malformations

have increased over time, and this is likely due to more sys-

tematic examination and improved registration [70]. We

attempted to reduce the difference over time by adjusting for

calendar time. Also, the imprecise registration of gestational

age (e.g. full term/not full term and many missing values)

and birth weight (e.g. intervals of 250 g) in the beginning

of the MBR [42] caused us to restrict the analyses on birth

weight to children born 1982–2018. Furthermore, data did

not allow for a direct measure of exposure, e.g. of PCB lev-

els in blood (PCB body burden), and we could therefore not

isolate and discriminate effects of individual congeners or

groups of congeners or investigate a dose–response relation-

ship. Instead of a direct measure of PCB body burden, we

used residential status as a proxy for total PCB exposure

in the observational window of 3.6 years up to conception

(based on the half-life of PCB-28), which is associated with

several insecurities. Also, the lack of a direct measure of

PCB body burden allows the risk of residual confounding

from PCB exposure prior to the observational window, and

we cannot reduce exposure to pre-pregnancy and first trimes-

ter only, as mothers may likely have lived in their respec-

tive apartments the whole pregnancy. Also, we do not have

information about how residents of the estates likely have

interacted with each other, and unexposed women may have

spent time in contaminated apartments and vice versa for

exposed. This could have caused non-differential misclas-

sification and have diluted the association between exposure

and birth outcomes.

Lastly, a common source of bias is the ‘live birth bias’

arising when studying prenatal exposure [71]. Only 60–70%

of fertilized eggs will result in live births, and if the exposure

is related to fetal survival and chance of live birth, the con-

sequences of exposure (especially for major malformations)

could be underestimated. But when adjusting for factors that

could be related to fetal survival, e.g. smoking and maternal

age, the risk of this bias type is reduced [71].

In conclusion, we observed increased risk of cryptorchid-

ism among boys after maternal airborne LC-PCB exposure.

Our results indicate LC-PCB might induce developmen-

tal toxicity, but due to the proxy nature of our measure of

exposure, inability to perform dose–response analyses,

and the lack of comparable literature, larger cohort stud-

ies are needed to investigate the safety of staying in PCB

contaminated residences and workplaces up to and during

pregnancy.

Acknowledgements

We are grateful to Lars Gunnarsen, Marie Fred-

eriksen, Helle Vibeke Andersen, and Thomas Hougaard for their exper-

tise regarding the Farum Midtpunkt and Brøndby Strand Estates and

measurements of indoor PCB concentrations. Karin Sørig Hougaard’s

contribution to the present study was supported by FFIKA, Focused

Research Effort on Chemicals in the Working Environment, from the

Danish Government.

BEU, Alm.del - 2020-21 - Bilag 387: Orientering om artikel om sammenhæng mellem udsættelse for PCB i indeluft i bygninger og øget risiko for fosterskader hos drenge, fra beskæftigelsesministeren

A. B. Kofoed et al.

Author’s contributions

Funding was acquired by Jens Peter Bonde.

Material preparation and data collection were performed by Sandra

Søgaard Tøttenborg, Laura Deen, Jens Peter Bonde, and Karin Sørig

Hougaard. All authors contributed to the study conception and design.

Statistical analyses and written manuscript were performed by Ane

Bungum Kofoed. All authors revised several versions of the manu-

scripts critically and approved the final manuscript.

Funding

Bispebjerg hospital, The National Building Foundation,

Realdania (ref. no. PRJ-2017–00176), and The Landowners’ Invest-

ment Foundation (ref. no. 18–58) and Helsefonden (ref. No. 16-B-01-

22 and 21-B-0412). Karin Sørig Hougaard’s contribution to the present

study was supported by FFIKA, Focused Research Effort on Chemicals

in the Working Environment, from the Danish Government.

Availability of data and material

Data was available from the HES-

PAIR cohort established in 2019 by the Department of Occupational

and Environmental Medicine (Bispebjerg Hospital, Denmark) and Dan-

ish health registers provided by Statistics Denmark.

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Declarations

Conflict of interest

The authors declare they have no conflicts or com-

peting interests.

Ethical approvals

The project was approved by the Knowledge Cen-

tre on Data Protection Compliance under the records of processing

regarding health science research projects within the Capital Region

of Denmark (BFH-2016-013, I-Suite nr.: 04461).

Consent to participate

According to Danish legislation, register-based

studies without direct contact to individuals do not require consent or

approval from the scientific ethics committee.

Open Access

This article is licensed under a Creative Commons Attri-

bution 4.0 International License, which permits use, sharing, adapta-

tion, distribution and reproduction in any medium or format, as long

as you give appropriate credit to the original author(s) and the source,

provide a link to the Creative Commons licence, and indicate if changes

were made. The images or other third party material in this article are

included in the article's Creative Commons licence, unless indicated

otherwise in a credit line to the material. If material is not included in

the article's Creative Commons licence and your intended use is not

permitted by statutory regulation or exceeds the permitted use, you will

need to obtain permission directly from the copyright holder. To view a

copy of this licence, visit

http://creativecommons.org/licenses/by/4.0/.

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