Journal of

Clinical Medicine

Systematic Review
Effects of Prenatal Paracetamol Exposure on the Development
of Asthma and Wheezing in Childhood: A Systematic Review
and Meta-Analysis
Agnieszka Barańska 1, * , Wiesław Kanadys 2 , Artur Wdowiak 3 , Maria Malm 1 , Agata Błaszczuk 4 ,
Urszula Religioni 5 , Anita Wdowiak-Filip 6 and Małgorzata Polz-Dacewicz 4

1 Department of Medical Informatics and Statistics with e-Health Laboratory, Medical University of Lublin,
20-954 Lublin, Poland
2 Specialistic Medical Center Czechow, 20-848 Lublin, Poland
3 Chair of Obstetrics and Gynecology, Medical University of Lublin, 20-081 Lublin, Poland
4 Department of Virology with SARS Laboratory, Medical University of Lublin, 20-093 Lublin, Poland
5 School of Public Health, Centre of Postgraduate Medical Education of Warsaw, 01-826 Warsaw, Poland
6 Department of Cosmetology and Aesthetic Medicine, Medical University of Lublin, 20-093 Lublin, Poland
* Correspondence: agnieszkabaranska@umlub.pl

Abstract: The aim of the report was to evaluate whether in utero exposure to paracetamol is associated
with risk towards developing respiratory disorders such as asthma and wheeze after birth. MEDLINE
(PubMed), EMBASE and Cochrane Library databases were searched for articles published in English
to December 2021. The study involved 330,550 women. We then calculated the summary risk
estimates and 95% CIs and plotted forest plots using random effect models (DerSimonian–Laird
method) and fixed effect models. We also performed a systematic review of the chosen articles and a
meta-analysis of studies based on the guidelines outlined in the PRISMA statement. Accordingly,
maternal exposure to paracetamol during pregnancy was associated with a significant increased
Citation: Barańska, A.; Kanadys, W.;
risk of asthma: crude OR = 1.34, 95% CI: 1.22 to 1.48, p < 0.001; and significant increased risk of
Wdowiak, A.; Malm, M.; Błaszczuk, wheeze: crude OR = 1.31, 95% CI: 1.12 to 1.54, p < 0.002. Results of our study confirmed that maternal
A.; Religioni, U.; Wdowiak-Filip, A.; paracetamol use in pregnancy is associated with an enhanced risk of asthma and wheezing in their
Polz-Dacewicz, M. Effects of Prenatal children. We believe paracetamol should be used with caution by pregnant women, and at the lowest
Paracetamol Exposure on the effective dose, and for the shortest duration. Long-term use or the use of high doses should be
Development of Asthma and limited to the indications recommended by a physician and with the mother-to-be under constant
Wheezing in Childhood: A supervision.
Systematic Review and
Meta-Analysis. J. Clin. Med. 2023, 12,
Keywords: paracetamol; asthma; wheeze; prenatal exposure; pregnancy; acetaminophen
1832. https://doi.org/10.3390/
jcm12051832

Academic Editor: Laura Pini

1. Introduction
Received: 12 January 2023
Revised: 15 February 2023 Paracetamol, also called “acetaminophen” or “N-acetyl-p-aminophenol” (APAP), is
Accepted: 22 February 2023 a mild-to-moderate antipyretic/analgesic drug widely used across the world, among a
Published: 24 February 2023 wide range of populations (from pregnant, pediatric and adult, to elderly people). At
therapeutic doses, paracetamol is metabolized mainly by the formation of conjugates
by glucuronidation and sulphation and is then excreted in the urine. Around 10% of
all paracetamol is metabolized by cytochrome P450 (CYP) enzymes to form n-acetyl-p-
Copyright: © 2023 by the authors. benzoquinoneimine (NAPQI), which is subsequently conjugated with intracellular glu-
Licensee MDPI, Basel, Switzerland. tathione, and ultimately excreted as cysteine and mercapturic acid conjugates. Less than
This article is an open access article 5% is excreted unchanged [1–3].
distributed under the terms and Pregnancy is a special period in a woman’s life, characterized not only by metabolic
conditions of the Creative Commons
and physiological changes in her organism, but also by the possibility of susceptibility
Attribution (CC BY) license (https://
to pathological conditions. This may have consequences for the fetus, as well as affect
creativecommons.org/licenses/by/
the further health of the woman [4]. Use of over-the-counter medications or drugs for
4.0/).

J. Clin. Med. 2023, 12, 1832. https://doi.org/10.3390/jcm12051832 https://www.mdpi.com/journal/jcm

J. Clin. Med. 2023, 12, 1832 2 of 11

acute/short-term illnesses and chronic/long-term disorders, as well as for temporary pain

control, is common in pregnancy [5]. One of the more frequently employed drugs as an
analgesic and antipyrotic during this period is paracetamol [6].
Cytochrome P450s metabolizes endogenous and exogenous substrates and is involved
in metabolizing toxins and procarcinogens [7]. Therefore, paracetamol must be metabolized
either to sulfate via sulfation or to N-acetyl-p-benzoquinone imine (NAPQI) via cytochrome
P450s in early pregnancy [8,9]. Paracetamol freely crosses the placenta [10]; however, the fe-
tus has a limited ability to metabolize paracetamol through glucoronidation. Detoxification
of paracetamol may deplete stores of glutathione, leading to increased oxidative damage to
the lung epithelium and, thus, contributing to wheezing or asthma [11–13].
The aim of this review and meta-analysis is to assess the relationship between prenatal
paracetamol exposure and wheezing or asthma in children.

2. Methods
We performed a systematic review of articles and a meta-analysis studies based on the
guidelines outlined in the PRISMA statement [14].

2.1. Search Strategy

We considered all epidemiological studies that compared the risk of asthma or wheeze
in childhood with prenatal paracetamol use. There were no limitations in searching for
articles of interest in assessing the dependencies between prenatal paracetamol exposure
and asthma or wheeze risk in childhood [15].
A thorough search was conducted in the electronic databases MEDLINE (PubMed),
EMBASE and Cochrane to identify relevant research. Studies published up to December
2021 were included. The following search terms were used for all databases in various com-
binations: “asthma” or “wheeze” AND “paracetamol” or “acetaminophen” AND “prenatal”
or “pregnancy”. Taking into account the possibility of not finding all the articles of interest
to us during the database search, references lists of relevant articles were additionally
analyzed. The search results were compared with previously published meta-analyses on
this topic. All data were extracted by two investigators (A.B. and W.K.), and disagreements
were resolved in discussion with a third investigator (A.W.).

2.2. Eligibility Criteria

Definitions that were adopted in our analysis include: “wheeze”—definition char-
acterized by paroxysmal transient or persistent, symptoms affecting breathing, such as
noisy breathing (“wheezing” or “whistling”), shortness of breath, or a troublesome cough
affecting sleep or everyday activity; “asthma”—definition established by doctor’s diagnosis,
clinical symptoms (shortness of breath, chest tightness or pain, cough, wheezing episodes)
and/or use of asthma medication (note: certain differences in the definitions contained in
some works made it difficult to qualify them to the finale definitions we have adopted).
The following inclusion criteria were established in the selection of studies: (i) trials
that involve the comparison of women who used paracetamol during pregnancy with
an observational group; (ii) studies evaluating the effect of prenatal paracetamol use on
offspring, using wheeze or asthma as a primary outcomes; (iii) structure interview and
clinical research; (iv) articles written in English; (v) data included in the articles were
sufficient to calculate the odds ratio (OR) and 95% confidence interval (CI) and (vi) if there
was an overlap in the cases included, only the latest and most comprehensive data were
selected.
The exclusion criteria were as follows: (i) insufficient quantitative data (not possi-
ble to extract sufficient data for statistical calculations); (ii) duplicate reports; (iii) articles
published in languages other than English and (iv) publications that were reviews, com-
mentaries/letters, editorials, conference abstracts, cross-sectional studies.
Full texts of potential articles were selected for evaluation on the basis of a review
of the titles and/or abstracts of all identified studies. After analyzing the selected works,
J. Clin. Med. 2023, 12, 1832 3 of 11

a decision was made to include or exclude them. Papers meeting these conditions were
qualified for meta-analysis, data collection on clinical characteristics and for test statistics.

2.3. Data Abstraction

Extracted data included: age of children’s diagnosis and number of children with
asthma or wheeze; number of women using paracetamol during pregnancy; trimester of
pregnancy in which paracetamol use took place, and number of pregnant women in a
particular trimester (if recorded).

2.4. Quality Assessment

The Newcastle-Ottawa Scale (NOS) was applied to assess the methodological quality
of all the included studies [16]. The NOS included three categorical criteria with a maximum
score of 9 points: (1) selection of the study group; (2) comparability of the groups; and
(3) identification of the exposure for studies. The quality of each study was rated using
the following scoring algorithms: ≥7 points were considered as “high”, 4 to 6 points were
considered as “moderate”, and ≤3 point was considered as “low”.

2.5. Statistical Analysis

The distribution of cases, ORs and 95% CIs were separately identified based on the
risk of childhood wheezing/asthma and prenatal exposure to paracetamol (ever or never)
and use of paracetamol in each trimester (if available).
We calculated the summary risk estimates and 95% CIs and plotted forest plots using
random-effects models (DerSimonian–Laird method) and fixed effect models for the as-
sociation between prenatal paracetamol exposure and wheeze/asthma in childhood. The
value of I2 statistics was adopted as a criterion—in the case of I2 < 50, we used a fixed effect
model, and when I2 ≥ 50, a random effect model. The results indicated that the taking of
paracetamol may have a high probability of increase in risk if OR was above 1, compared
with non-use of paracetamol [17].
Heterogeneity among articles was estimated by engaging the I2 statistic and p values
associated with Q statistics. Herein, I2 statistic indicates the percentage of total variability
explained by heterogeneity, and values of ≤25%, 25%–75%, and ≥75% are arbitrarily
considered as indicative of low, moderate, and high heterogeneity, respectively [18].
To explain the possible presence of publication bias, Begg’s test (a rank correlation
method based on Kendall’s tau) and Egger’s test (a linear regression method) were ap-
plied [19,20]. We also checked for funnel plot symmetry. Here, in the absence of bias, the
plots will resemble a symmetrical funnel, as the results of minor studies will scatter at
the left side of the plot and the spread will narrow among the major studies on the right
side of the plot [21]. Meta-analysis of summary statistics from individual studies was
performed through Statistica 13.3 software (StatSoft Poland, Kraków, Poland), using the
Medical Package program.

3. Results
As result of the search of electronic databases, 532 citations were identified. Titles and
abstracts were checked in the initial selection phase, in which 424 items were excluded
due to irrelevance. In the second phase, 108 articles with potentially significant studies
were identified and submitted for full-text assessment. There were 96 papers which did not
meet all the inclusion criteria, contained duplicate publications, and the required data were
missing, amongst others. We identified twelve articles fulfilling the criteria for inclusion, in
which the effect of paracetamol exposure during pregnancy on disorders of the respiratory
system in children was analyzed [22–33]. The outcome of the search strategy is shown in
Figure 1.
 which did not meet all the inclusion criteria, contained duplicate publications, and t
required data were missing, amongst others. We identified twelve articles fulfilling t
criteria for inclusion, in which the effect of paracetamol exposure during pregnancy
J. Clin. Med. 2023, 12, 1832 disorders of the respiratory system in children was analyzed [22–33]. The outcome
4 of 11 of t
search strategy is shown in Figure 1.

532 records identified through the electronic

databases Embase PubMED/MEDLINE
and the Cochrane Library by using keywords
and relevant bibliographies

424 articles excluded on basis of title and abstract

108 potentially relevant publications retrieved

for full-text detailed review

96 articles were excluded due to data inconsistent

with the work assumptions: the data presented was
for total population; no separate data was available
for pregnancy; lack of an appropriate concurrent
control group; included insufficient data

12 studies paracetamol exposure during

pregnancy on disorders of the respiratory
system in children qualified for systematic
review and meta-analysis

Studies with usable information, by outcome

of individual subgroups:
asthma = 10, wheeze = 7

Figure 1. Flow
Figure diagram
1. Flow ofofliterature
diagram search
literature search and
and research
research selection
selection procedure.
procedure.

The studies involved 330,550 women and 44,502 women intake of paracetamol during
The studies involved 330,550 women and 44,502 women intake of paracetam
pregnancy. Table 1 presents a tabular summary of the individual clinical–control studies
during pregnancy.
discussed Table 1All
in this review. presents a tabular
studies included summary
were of the
in accordance individual
with clinical–cont
NOS scale and all
studies discussed
studies in this
were defined as review. AllThe
high-quality. studies included
average were
value was 8.03.in accordance with NOS sc
and all studies were defined as high-quality. The average value was 8.03.
J. Clin. Med. 2023, 12, 1832 5 of 11

Table 1. Characteristics of included studies evaluating the association between prenatal paracetamol intake and asthma or wheezing risk in childhood.

Child With Outcome

Exposure Classification The Children’s Respiratory Age of Children’s Population:
Author, Year Country Study Asthma or Period Nos Scale
Research Period (Years) Disorders Diagnosis Paracetamol Use
Wheezing (Months)
Studies Included in Meta-Analysis
Environment and Paracetamol use during
Asthma: diagnosed by
Pregnancy Outcomes pregnancy: 1st trimester, 2nd Asthma: 118
1. Liew [22], 2021 USA medical professional early childhood 958 48 9
Study trimester, 3rd trimester, ever. Wheeze: 304
Wheezing
Cohort study 2003–2007
Czech European
Piler [23], 2018 Czech
Longitudinal Study of Paracetamol use during Paediatrician-diagnosed
2. Republic/Brno and 3, 5, 7 and 11 years 1105 Asthma: 41 132 9
Pregnancy and pregnancy. 1991–1992 asthma
Znojmo regions
Childhood
Magnus [24], 2016 Norwegian Mother and Paracetamol use during 3 years;
3. Childhood asthma 34,703 Asthma: 1751 36 9
Norway Child Cohort Study pregnancy. 1999–2014 7 years
Paracetamol use during Asthma: at least two
Danish National Birth pregnancy: 1st trimester, 2nd prescriptions for inhalants or
4. Liu [25], 2016 Denmark 3 years or later 63,652 Asthma: 7644 36 8
Cohort trimester, 3rd trimester, ever. cases diagnosed by a hospital
1996–2010 doctor.
Paracetamol use during Asthma: diagnosed by doctor
Nascita e INFanzia: Effeti Asthma: 185
5. Migliore [26], 2015 Italy
dell Ambiente study pregnancy: 1st trimester, 3rd Wheezing or whistling: at 18 months 3358
Wheeze 535
18 7
trimester. 2005–2013 least one episode
Paracetamol use during
pregnancy: 1st trimester, both Asthma: hospital diagnosed,
Andersen [27], 2012 Danish Medical Birth
6. anti-asthmatic drug median—6.8 years 197,060 Asthma: 24,506 ~82 8
Denmark Registry 2nd and 3rd trimesters, ever. prescription
1996–2008
Asthma: Inhaled
Swedish Medical Birth Paracetamol use during corticosteroid-treated 6, 12 months and 4, 5 Asthma: 258
7. Goksör [28], 2011 Sweden 4496 54 7
Register pregnancy. 2003 Wheezing: three or more years Wheeze: 235
episodes
Columbia Center for Paracetamol used during
Perzanowski [29], 2010 Asthma: self-reported Asthma: 99
8. Children’s pregnancy by low-income 5 years 297 60 7
USA Wheezing: self-reported Wheeze: 99
Environmental Health women. 1998–2006
Paracetamol used in 1st and 3rd Asthma: diagnosed by a 6 years +/− 3
9. Kang [30], 2009 USA The Yale Study 1505 Asthma: 172 72 7
trimesters pregnancy. 1997–2000 doctor or health professional months
Garcia-Marcos [31], 2009 Paracetamol use during 4.08 +/− 0.8 (3–4
10. Murcia (Spain) Study Wheezing: self-reported 1741 Wheeze: 341 36–60 8
Spain pregnancy. years)
Paracetamol use during Asthma: symptoms reported,
Rebordosa [32], 2008 Danish National Birth pregnancy: physician- 18 months—wheeze; Asthma: 12,530
11. 12,733 84 9
Denmark Cohort study 1st trimester, 2nd trimester, 3rd diagnosedWheezing: 7 years—asthma Wheeze: 11,980
trimester, ever. 1996–2003 self-reported
Avon Longitudinal Study Paracetamol use during
12. Saheen [33], 2002 UK Wheezing: self-reported 30–42 months 8942 Wheeze: 1195 30–42 9
of Parents and Children pregnancy. 1992–1999
J. Clin. Med. 2023, 12, 1832 6 of 11

3.1. Sensitivity Analysis

In the study on the relationship between childhood asthma and paracetamol use
(ever vs. never) during pregnancy and each trimester of pregnancy, sensitivity analysis
showed that in the case of a total study and 3rd trimester, removing any of the studies
would not significantly affect the result of the meta-analysis. However, in the case of
the 1st trimester, deleting one of the studies: Andersen [27], Liu [25], Migliore [26] or
Rebordosa [32] would change the result of the meta-analysis to be statistically insignificant.
On the other hand, in the case of the 2nd trimester, the result of the meta-analysis would be
statistically insignificant after excluding the study of Liu [25] or Rebordosa [32].
In the study on the relationship between childhood wheeze and paracetamol use
(ever vs. never) during pregnancy and each trimester of pregnancy, sensitivity analysis for
total study, 2nd trimester and 3rd trimester indicated that the results would not change
significantly after excluding any of the studies. In turn, in the 1st trimester, the exclusion of
the Liew study [22] would change the result of the meta-analysis to a statistically significant
one.

3.2. Association between Paracetamol Exposure during Pregnancy and Asthma in Children
The present meta-analysis was conducted on the basis of data from ten studies [22–
30,32] assessing the effect of paracetamol exposure in pregnancy on the risk of occurrence of
asthma in children. Paracetamol was taken at any time during the trimesters of pregnancy.
The crude OR amounted to 1.34, 95% CI: 1.22 to 1.48, p <0.001, with moderate heterogeneity
of I2 = 64.75% (Figure 2). The Begg and Mazumdar’s test for rank correlation did not
indicate evidence of publication bias (Kendall’s tau = 0.142, z = 0.495, p < 0.622; similarly,
Egger’s test: b0 = 0.966, 95% CI − 0.748 to 2.681, t = 1.299, p < 0.231).
Results of five studies [22,25–27,32] analyzing the relationship between of intake of
paracetamol during first trimester and childhood asthma pointed to increased risk (crude
OR = 1.21, 95% CI: 1.01 to 1.45, p < 0.035, I2 = 79.48%), (Figure 2). The Begg Mazumdar’s
test and Egger’s test did not indicated evidence of publication bias (Kendall’s tau b =
−1.000, z = −1.567, p < 0.118 and b0 = −1.288, 95% CI: −7.752 to 5.177, t = −0.634, p < 0.572,
respectively). The major problem indicated by this analysis is the large heterogeneity of
effect of paracetamol.
Further analysis involving three studies [22,25,32] also suggested that use of paraceta-
mol during the second trimester of pregnancy was associated with increased childhood
asthma risk (crude OR = 1.10, 95% CI: 1.01 to 1.19, p < 0.030, I2 = 0.00%), (Figure 2). Evidence
of publication bias was not shown in the Begg and Mazumdar’s test (Kendall’s tau = 0.333,
z = 0.522, p < 0.603); or in the Egger’s test (b0 = −0.237, 95% CI: −6.686 to 6.212, t = −0.468,
p < 0.723).
In turn, meta-analysis based on the results of four studies [22,25,26,32] showed that
paracetamol intake by women in the third trimester of pregnancy was associated with
an enhanced risk of asthma in the child (crude OR = 1.18, 95% CI: 1.11 to 1.26, p < 0.001,
I2 = 0.00%), (Figure 2). The Begg and Mazumdar’s test and Egger’s test did not indicate
evidence of publication bias (Kendall’s tau = −0.667, z = −1.359, p = 0.174 and b0 = 0.966,
95% CI: −0.748 to 2.681, t = 1.299, p < 0.231, respectively).
J. J.Clin.
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First author, year Ever Never Odds ratio p- Weight

References Cases / Control Cases / Control (95% CI) value Odds ratio (95% confidence interv %

A. Total study
Andersen 2012 176 / 24 330 800 / 171 754 1.55 (1.32, 1.83) 0.000 14.23
Goksör 2011 32 / 226 302 / 3791 1.78 (1.20, 2.62) 0.004 5.05
Kang 2009 113 / 922 59 / 411 0.85 (0.61, 1.19) 0.356 6.30
Liew 2021 47 / 71 132 / 404 2.03 (1.33, 3.08) 0.001 4.50
Liu 2016 4 657 / 2 987 31 159 / 24 849 1.24 (1.18, 1.31) 0.000 22.16
Magnus 2016 875 / 876 13 962 / 19 036 1.36 (1.24, 1.50) 0.000 19.16
Migliore 2015 69 / 120 957 / 2 212 1.33 (0.98, 1.80) 0.068 7.20
Perzanowski 2010 30 / 69 34 / 164 2.10 (1.19, 3.69) 0.010 2.69
Piller 2018 2 / 39 46 / 1 018 1.13 (0.27, 4.84) 0.864 0.45
Rebordosa 2008 866 / 644 5 866 / 5 134 1.20 (1.08, 1.34) 0.001 18.27

Summary 6 867 / 30 284 53 317 / 228 773 1.34 (1.22, 1.48) 0.000 100.00
2 2
Test for heterogeneity: Q = 25.5289, p < 0.002; T = 0.0108; I = 64.75%
B. 1st trimester
Andersen 2012 104 / 24 330 462 / 172 164 1.59 (1.29, 1.97) 0.000 21.20
Liew 2021 15 / 103 132 / 404 0.45 (0.25, 0.79) 0.006 7.24
Liu 2016 806 / 2 987 5 242 / 24 849 1.28 (1.18, 1.39) 0.000 28.60
Migliore 2015 67 / 118 959 / 2 214 1.31 (0.96, 1.79) 0.086 15.85
Rebordosa 2008 504 / 1 026 3 282 / 7 718 1.15 (1.03, 1.29) 0.013 27.10
S
Summary 1 419 / 28 564 10 077 / 207 349 1.21 (1.01, 1.45) 0.034 100.00
2 2
Test for heterogeneity: Q = 19.4915, p < 0.002; T = 0.0269; I = 79.48%
C. 2nd trimester
Liew 2021 30 / 88 132 / 404 1.04 (0.66, 1.65) 0.856 3.35
Liu 2016 382 / 2 987 2 927 / 24 849 1.09 (0.97, 1.22) 0.154 55.03
Rebordosa 2008 333 / 1 197 2 190 / 8 810 1.12 (0.98, 1.27) 0.090 41.62

Summary 745 / 4 272 5 249 / 34 063 1.10 (1.01, 1.19) 0.029 100.00
2 2
Test for heterogeneity: Q = 0.1680, p < 0.920; T = 0.0000; I = 0.00%
D. 3rd trimester
Liew 2021 27 / 91 132 / 404 0.91 (0.57, 1.46) 0.689 1.82
Liu 2016 909 / 2 987 6 411 / 24 849 1.18 (1.09, 1.28) 0.000 64.88
Migliore 2015 68 / 110 1 126 / 1 947 1.07 (0.78, 1.46) 0.675 4.20
Rebordosa 2008 448 / 1 082 2 789 / 8 211 1.22 (1.08, 1.37) 0.001 29.10

Summary 1452 / 4 270 10 458 / 35 411 1.18 (1.11, 1.26) 0.000 100.00
2 2
Test for heterogeneity: Q = 0.8597, p <0.001; T = 0.0000; I = 0.00%

0.2 0.5 1.0 1.5 2.0 2.5

Never Paracetamol use

Figure2.2.The
Figure Thecrude
crude relationship
relationship between childhood asthma and
childhood asthma and paracetamol
paracetamoluse
use(ever
(evervs.
vs.never)
never)
duringpregnancy
during pregnancyand
and each
each trimester
trimester of pregnancy [22–30,32].

3.3.
3.3. Association
Association between
between Paracetamol Exposure during
Paracetamol Exposure during Pregnancy
Pregnancy and and Wheezing
Wheezingin inChildren
Children
In
In the
the eight
eight studies
studies [22,26,28–33]
[22,26,28–33] analyzed
analyzed in in order
order to to assess
assess prenatal
prenatalparacetamol
paracetamol
exposure
exposure during any time of pregnancy, we noted a significant increased risk childhood
during any time of pregnancy, we noted a significant increased risk of of child-
wheeze (crude (crude
hood wheeze OR = 1.31,
OR =95% CI:95%
1.31, 1.12CI: 1.54,top 1.54,
to 1.12 < 0.002;
p < with
0.002;relatively high heterogeneity,
with relatively high heter-
2 = 75.29%), (Figure 3). The Begg and Mazumdar’s test for rank correlation indicated no
Iogeneity, I2 = 75.29%), (Figure 3). The Begg and Mazumdar’s test for rank correlation in-
evidence
dicated no of evidence
publication bias (Kendall’s
of publication biastau b = 0.333,
(Kendall’s 0.333,p z<=0.349).
tauz b= =0.939, 0.939, Egger’s testEg-
p < 0.349). for
regression
ger’s test for regression intercept also demonstrated no evidence of publication bias (b0 CI:
intercept also demonstrated no evidence of publication bias (b0 = 2.161 (95% =
− 1.775(95%
2.161 to 6.097), t = 1.344,
CI: −1.775 p < 0.229).
to 6.097), t = 1.344, p < 0.229).
J. J.Clin.
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8 of

The
The use
use of
of paracetamol
paracetamol in in the first trimester
the first trimester of of pregnancy
pregnancyin inthree
threestudies
studies[22,26,32]
[22,26,32]
indicated a marginal, insignificant increase in the risk of wheezing
indicated a marginal, insignificant increase in the risk of wheezing in childhood (crude in childhood (crude OR
=OR1.04, 95% CI: 0.78 to 1.37, p > 0.801, I 2 = 80.73%), (Figure 3). The results of Begg’s test
= 1.04, 95% CI: 0.78 to 1.37, p > 0.801, I2 = 80.73%), (Figure 3). The results of Begg’s test
were
wereinaccessible.
inaccessible. Egger’s
Egger’s testtest did
did not
not indicate
indicate evidence
evidence of of publication
publication bias bias (b0 −3.819,
(b0 == −3.819,
95%
95%CI:CI:− 56.874 to
−56.874 to 49.237, −0.915,p >p 0.529).
49.237,tt==−0.915, > 0.529).
Two
Twostudies
studies[22,32]
[22,32] have
have been
been identified
identified thatthat meet
meet thethe inclusion
inclusioncriteria,
criteria,ininassessing
assessing
the association between paracetamol exposure during the second
the association between paracetamol exposure during the second trimester of pregnancy trimester of pregnancy
and
andchildhood
childhood wheezing
wheezing revealed convergent results
revealed convergent results (OR
(OR ==0.95,
0.95,95%
95%CI: CI:0.68 1.32,pp>>
0.68toto1.32,
0.760 OR = 0.95, 95% CI: 0.80 to 1.12, p
0.760 and OR = 0.95, 95% CI: 0.80 to 1.12, p > 0.517; respectively), (Figure 3). However, ititisis
and > 0.517; respectively), (Figure 3). However,
difficult
difficulttotodraw
draw reliable
reliable result
result onon their
their basis.
basis.
The
The crude odds ratio
crude odds ratio(OR)
(OR)forforthe
the risk
risk of of wheezing
wheezing in children
in children of mothers
of mothers usingusing
pa-
paracetamol
racetamol ininthe thethird
thirdtrimester
trimesterofofpregnancy
pregnancywas was1.11,
1.11,95%
95%CI:CI:0.92
0.92toto1.34, 0.266,II22==
1.34,pp<<0.266,
57.80%,
57.80%,based
basedon onthree
threestudies
studies [22,26,32],
[22,26,32], (Figure 2). 2).
(Figure Egger’s
Egger’stesttest
diddid
not not
indicate evidence
indicate evi-
of publication bias (b0 = − 0.277, 95% CI: − 55.078 to 54.525, t = − 0.0641,
dence of publication bias (b0 = −0.277, 95% CI: −55.078 to 54.525, t = −0.0641, p < 0.959). p < 0.959). Results
of Begg’softest
Results weretest
Begg’s inaccessible.
were inaccessible.

First author, year Ever Never Odds ratio p- Weight

References Cases / Control Cases / Control (95% CI) value Odds ratio (95% confidence interv %

A. Total study
Garcia-Marcos 2009 194 / 147 719 / 659 1.21 (0.95, 1.55) 0.119 13.16
Goksör 2011 23 / 212 311 / 3 805 1.33 (0.85, 2.07) 0.213 7.49
Kang 2009 450 / 585 200 / 270 1.04 (0.83, 1.29) 0.737 13.79
Liew 2021 118 / 186 132 / 404 1.94 (1.43, 2.63 0.000 11.10
Migliore 2015 203 / 364 823 / 1 968 1.33 (1.10, 1.61) 0.003 14.28
Perzanowski 2010 38 / 61 41 / 157 2.38 (1.40, 4.06) 0.001 5.97
Rebardosa 2008 543 / 417 6 209 / 4 829 1.01 (0.89, 1.16) 0.852 16.67
Shaheen 2002 587 / 3 226 608 / 4 526 1.35 (1.20, 1.53) 0.000 16.99

Summary 2 156 / 5 198 9 043 / 16 618 1.31 (1.12, 1.54) 0.001 100.00
2 2
Test for heterogeneity: Q = 28.3306, p < 0.001; T = 0.0338; I = 75.29%
B. 1st trimester
Liew 2021 55 / 249 132 / 404 0.68 (0.47, 0.96) 0.029 25.47
Migliore 2015 196 / 357 830 / 1 975 1.31 (1.08, 1.58) 0.006 35.71
Rebordosa 2008 323 / 637 3 463 / 7 575 1.11 (0.96, 1.28) 0.146 38.83
S
Summary 574 / 1 243 4 425 / 9 954 1.04 (0.78, 1.37) 0.800 100.00
2 2
Test for heterogeneity: Q = 10.3793, p < 0.001; T = 0.0467; I = 80.73%
C. 2nd trimester
Liew 2021 72 / 232 132 / 404 0.95 (0.68, 1.32) 0.759 19.87
Rebordosa 2008 194 / 766 2 329 / 8 709 0.95 (0.80, 1.12) 0.516 80.13

Summary 266 / 998 2 461 / 9 113 0.95 (0.82, 1.10) 0.473 100.00
2 2
Test for heterogeneity: Q = 0.0002, p < 0.988; T = 0.0000; I = 0.00%
D. 3rd trimester
Liew 2021 73 / 231 132 / 404 0.97 (0.70, 1.34) 0.842 20.61
Migliore 2015 225 / 309 969 / 1 748 1.31 (1.09, 1.59) 0.005 36.53
Rebordosa 2008 264 / 696 2 973 / 8 065 1.03 (0.89, 1.19) 0.705 42.87

Summary 562 / 1 236 4 074 / 10 217 1.11 (0.92, 1.34) 0.265 100.00
2 2
Test for heterogeneity: Q = 4.7389, p < 0.095; T = 0.0151; I = 57.80%

0.2 0.5 1.0 1.5 2.0 2.5

Never Paracetamol use

Figure3.3.The
Figure Thecrude
crude relationship
relationship between
between childhood
childhood wheeze
wheeze and
andparacetamol
paracetamoluse
use(ever
(evervs.
vs.never)
never)
during pregnancy and each trimester of pregnancy [22,26,28–33].
during pregnancy and each trimester of pregnancy [22,26,28–33].
J. Clin. Med. 2023, 12, 1832 9 of 11

4. Discussion
The aim of our systematic review with meta-analysis was to summarize the current
evidence on the exposures associated with paracetamol use in utero, focusing on postnatal
breathing disorders in children. The study is important for the development of clinical
recommendations regarding the consumption of paracetamol during pregnancy. The results
of our systematic review and performed meta-analysis indicate a significant increase of the
risk of asthma (crude OR = 1.34, 95% CI: 1.22 to 1.48, p > 0.001); or wheezing (crude OR =
1.31, 95% CI: 1.12 to 1.54, p > 0.002) among children with a history of prenatal exposure to
paracetamol.
Singh et al. [34] noted that the odds ratio for the asthma outcome in the offspring of
mothers who used paracetamol in the prenatal period in any trimester of pregnancy was
1.28, 95% CI: 1.13 to 1.39. Fan et al. [35] also held the opinion that prenatal paracetamol
exposure was significantly associated with the increased risk of child asthma. In their work,
OR = 1.19, 95% CI: 1.12 to 1.27. In turn, Eyers et al. [36] showed increased risk of recurrent
wheeze in the children of women who were exposed to paracetamol during pregnancy.
In their study, OR was 1.21, 95% CI: 1.24 to 1.44. Paracetamol use during pregnancy can
affect both the mother and the fetus. Researches of fetal exposure to paracetamol have
concerns on: premature birth [37], neurological development [38] low birth weight [39],
hyperactivity disorder/hyperkinetic disorder or adverse development issues [40,41], and
other birth defects [42,43]
Several limitations should be identified with regard to our study. Firstly, various
prenatal ailments and illnesses may themselves have an impact on the risk of postnatal
respiratory disorders. In addition, from the studies included into our meta-analysis, it
was not possible to obtain confounding factor data that could have an impact on the final
results of our analysis. It is difficult to conclude at what age prenatal paracetamol exposure
affects children. Secondly, these are observational studies extended over time. During their
duration, we cannot avoid the influence of various factors that may affect the final result.
Furthermore, the study drug may have been administered to the children post-partum, as
mothers who take paracetamol in pregnancy may be more likely to give paracetamol to their
children. There are a number of other methodological problems that are also relevant for the
interpretation of the results. Firstly, as a meta-analysis of observational studies, it was prone
to the bias (e.g., recall and selection bias) inherent in the original studies. Secondly, most of
the studies were observational in nature, did not establish a dose–response relationship,
and were conceived to be subject to numerous errors and misleading outcomes regarding
period of administration. Indeed, in some studies, a progressive increase in risk associated
with increasing number of days of prenatal paracetamol exposure, or increased frequency
of use, was observed [29,31–33]. Moreover, a limitation may posed by publication high
statistical heterogeneity.

5. Conclusions
In summary, the results of our study confirmed that maternal paracetamol use in
pregnancy is associated with an increased risk of asthma or wheezing in their children. The
current findings are consistent with results of previous meta-analyses showing increase in
asthma/wheeze symptoms from paracetamol exposure. We believe paracetamol should be
used with caution by pregnant women, and at the lowest effective dose, for the shortest
duration. Long-term use or the use of high doses should be limited to the indications
recommended by a physician, while the mother-to-be should be under constant supervision.

Author Contributions: Conceptualization, W.K., A.B. (Agnieszka Barańska), A.B. (Agata Błaszczuk);
data curation, W.K.; formal analysis, M.P.-D.; funding acquisition, A.W.; investigation, A.B. (Ag-
nieszka Barańska); methodology, W.K., M.M., A.B. (Agnieszka Barańska); project administration,
W.K., A.B. (Agnieszka Barańska); resources, W.K., A.B. (Agata Błaszczuk); software, U.R.; supervision,
A.W.-F., validation, A.W-F.; visualization, W.K., A.B. (Agnieszka Barańska), A.B. (Agata Błaszczuk),
M.M.; writing—original draft, W.K., A.B. (Agnieszka Barańska); writing—review and editing, A.B.
J. Clin. Med. 2023, 12, 1832 10 of 11

(Agnieszka Barańska), A.W-F. All authors have read and agreed to the published version of the
manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: The data are available upon request from the corresponding author.
Conflicts of Interest: The authors declare no conflict of interest.

References
1. Mazaleuskaya, L.L.; Sangkuhl, K.; Thorn, C.F.; FitzGerald, G.A.; Altman, R.B.; Klein, T.E. PharmGKB summary: Pathways of
acetaminophen metabolism at the therapeutic versus toxic doses. Pharm. Genom. 2015, 25, 416–426. [CrossRef] [PubMed]
2. McCrae, J.C.; Morrison, E.E.; MacIntyre, I.M.; Dear, J.W.; Webb, D.J.B. Long-term adverse effects of paracetamol-a review. Br. J.
Clin. Pharmacol. 2018, 84, 2218–2230. [CrossRef] [PubMed]
3. Nuttall, S.L.; Khan, J.N.; Thorpe, G.H.; Langford, N.; Kendall, M.J. The impact of therapeutic doses of paracetamol on serum total
antioxidant capacity. J. Clin. Pharm. Ther. 2003, 28, 289–294. [CrossRef]
4. Williams, M.A. Pregnancy complications. In Reproductive and Perinatal Epidemiology; Louis, G.M.B., Platt, R.W., Eds.; Oxford
University Press: London, UK, 2011; pp. 101–128.
5. Lupattelli, A.; Spigset, O.; Twigg, M.J.; Zagorodnikova, K.; Mårdby, A.C.; Moretti, M.E.; Drozd, M.; Panchaud, A.; Hämeen-Anttila,
K.; Rieutord, A.; et al. Medication use in pregnancy: A cross-sectional, multinational web-based study. BMJ Open 2014, 4, e004365.
[CrossRef] [PubMed]
6. Ishitsuka, Y.; Kondo, Y.; Kadowaki, D. Toxicological Property of Acetaminophen: The Dark Side of a Safe Antipyretic/Analgesic
Drug? Biol. Pharm. Bull. 2020, 43, 195–206. [CrossRef] [PubMed]
7. Ryu, R.; Hebert, M.F. Impact of pregnancy on maternal pharmacokinetics of medications. In Clinical Pharmacology during Pregnancy;
Academic Press: Cambridge, MA, USA, 2022; pp. 19–46. [CrossRef]
8. Pacifici, G.M.; Allegaert, K. Clinical Pharmacology of Paracetamol in Neonates: A Review. Curr. Ther. Res. 2015, 77, 24–30.
[CrossRef] [PubMed]
9. Mian, P.; Allegaert, K.; Conings, S.; Annaert, P.; Tibboel, D.; Pfister, M.; van Calsteren, K.; Anker, J.N.V.D.; Dallmann, A. Integration
of Placental Transfer in a Fetal–Maternal Physiologically Based Pharmacokinetic Model to Characterize Acetaminophen Exposure
and Metabolic Clearance in the Fetus. Clin. Pharmacokinet. 2020, 59, 911–925. [CrossRef]
10. Nitsche, J.F.; Patil, A.S.; Langman, L.J.; Penn, H.J.; Derleth, D.; Watson, W.J.; Brost, B.C. Transplacental Passage of Acetaminophen
in Term Pregnancy. Am. J. Perinatol. 2017, 34, 541–543. [CrossRef]
11. Chiew, A.L.; Gluud, C.; Brok, J.; Buckley, N.A. Interventions for paracetamol (acetaminophen) overdose. Cochrane Database Syst.
Rev. 2018, 23, CD003328. [CrossRef]
12. Rahman, I.; MacNee, W. Oxidative stress and regulation of glutathione in lung inflammation. Eur. Respir. J. 2000, 16, 534–554.
[CrossRef]
13. Hehua, Z.; Qing, C.; Shanyan, G.; Qijun, W.; Yuhong, Z. The impact of prenatal exposure to air pollution on childhood wheezing
and asthma: A systematic review. Environ. Res. 2017, 159, 519–530. [CrossRef] [PubMed]
14. Moher, D.; Liberati, A.; Tetzlaff, J.; Altman, D.G.; PRISMA Group. Preferred reporting items for systematic reviews and
meta-analyses: The PRISMA statement. PLoS Med. 2009, 6, e1000097. [CrossRef] [PubMed]
15. Higgins, J.P.T.; Thomas, J.; Chandler, J.; Cumpston, M.; Li, T.; Page, M.J.; Welch, V.A. (Eds.) Cochrane Handbook for Systematic
Reviews of Interventions; John Wiley & Sons: Hoboken, NJ, USA, 2019.
16. Stang, A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in
meta-analyses. Eur. J. Epidemiol. 2010, 25, 603–605. [CrossRef] [PubMed]
17. DerSimonian, R.; Laird, N. Meta-analysis in clinical trials revisited. Contemp. Clin. Trials 2015, 45, 139–145. [CrossRef] [PubMed]
18. Higgins, J.P.T.; Thompson, S.G. Quantifying heterogeneity in a meta-analysis. Stat. Med. 2002, 21, 1539–1558. [CrossRef]
19. Begg, C.B.; Mazumdar, M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994, 50, 1088–1101.
[CrossRef]
20. Egger, M.; Smith, G.D.; Schneider, M.; Minder, C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997, 315,
629–634. [CrossRef]
21. Duval, S.; Tweedie, R. Trim and Fill: A Simple Funnel-Plot-Based Method of Testing and Adjusting for Publication Bias in
Meta-Analysis. Biometrics 2000, 56, 455–463. [CrossRef]
22. Liew, Z.; Yuan, Y.; Meng, Q.; von Ehrenstein, O.S.; Cui, X.; Flores, M.E.S.; Ritz, B. Prenatal Exposure to Acetaminophen and
Childhood Asthmatic Symptoms in a Population-Based Cohort in Los Angeles, California. Int. J. Environ. Res. Public Health 2021,
18, 10107. [CrossRef]
23. Piler, P.; Švancara, J.; Kukla, L.; Pikhart, H. Role of combined prenatal and postnatal paracetamol exposure on asthma development:
The Czech ELSPAC study. J. Epidemiol. Community Health 2018, 72, 349–355. [CrossRef]
J. Clin. Med. 2023, 12, 1832 11 of 11

24. Magnus, M.C.; Karlstad, Ø.; Håberg, S.E.; Nafstad, P.; Smith, G.D.; Nystad, W. Prenatal and infant parace-tamol exposure and
development of asthma: The Norwegian Mother and Child Cohort Study. Int. J. Epidemiol. 2016, 45, 512–522. [CrossRef] [PubMed]
25. Liu, X.; Liew, Z.; Olsen, J.; Pedersen, L.H.; Bech, B.H.; Agerbo, E.; Yuan, W.; Li, J. Association of prenatal exposure to ac-
etaminophen and coffee with childhood asthma. Pharmacoepidemiol. Drug Saf. 2016, 25, 188–195. [CrossRef] [PubMed]
26. Migliore, E.; Zugna, D.; Galassi, C.; Merletti, F.; Gagliardi, L.; Rasero, L.; Trevisan, M.; Rusconi, F.; Richiardi, L. Prenatal
Paracetamol Exposure and Wheezing in Childhood: Causation or Confounding? PLoS ONE 2015, 10, e0135775. [CrossRef]
[PubMed]
27. Andersen, A.B.; Farkas, D.K.; Mehnert, F.; Ehrenstein, V.; Erichsen, R. Use of prescription paracetamol during pregnancy and risk
of asthma in children: A population-based Danish cohort study. Clin. Epidemiol. 2012, 4, 33–40. [CrossRef] [PubMed]
28. Goksör, E.; Thengilsdottir, H.; Alm, B.; Norvenius, G.; Wennergren, G. Prenatal paracetamol exposure and risk of wheeze at
preschool age. Acta Paediatr. 2011, 100, 1567–1571. [CrossRef] [PubMed]
29. Perzanowski, M.S.; Miller, R.L.; Tang, D.; Ali, D.; Garfinkel, R.S.; Chew, G.L.; Goldstein, I.F.; Perera, F.P.; Barr, R.G. Prenatal
acetaminophen exposure and risk of wheeze at age 5 years in an urban low-income cohort. Thorax 2010, 65, 118–123. [CrossRef]
30. Kang, E.M.; Lundsberg, L.S.; Illuzzi, J.L.; Bracken, M.B. Prenatal Exposure to Acetaminophen and Asthma in Children. Obstet.
Gynecol. 2009, 114, 1295–1306. [CrossRef]
31. Garcia-Marcos, L.; Sanchez-Solis, M.; Perez-Fernandez, V.; Pastor-Vivero, M.D.; Mondejar-Lopez, P.; Valverde-Molina, J. Is the
effect of prenatal paracetamol exposure on wheezing in preschool children modified by asthma in the mother? Int. Arch. Allergy
Immunol. 2009, 149, 33–37. [CrossRef]
32. Rebordosa, C.; Kogevinas, M.; Sørensen, H.T.; Olsen, J. Pre-natal exposure to paracetamol and risk of wheezing and asthma in
children: A birth cohort study. Int. J. Epidemiol. 2008, 37, 583–590. [CrossRef]
33. Shaheen, S.O.; Newson, R.B.; Sherriff, A.; Henderson, A.J.; Heron, J.E.; Burney, P.G.J.; Golding, J.; ALSPAC Study Team.
Paracetamol use in pregnancy and wheezing in early childhood. Thorax 2002, 57, 958–963. [CrossRef]
34. Singh, M.; Varukolu, S.; Chauhan, A.; Jaiswal, N.; Pradhan, P.; Mathew, J.L.; Singh, M. Paracetamol exposure and asthma: What
does the evidence say? An overview of systematic reviews. Pediatr. Pulmonol. 2021, 56, 3189–3199. [CrossRef] [PubMed]
35. Fan, G.; Wang, B.; Liu, C.; Li, D. Prenatal paracetamol use and asthma in childhood: A systematic review and meta-analysis.
Allergol. Immunopathol. 2017, 45, 528–533. [CrossRef] [PubMed]
36. Eyers, S.; Weatherall, M.; Jefferies, S.; Beasley, R. Paracetamol in pregnancy and the risk of wheezing in offspring: A systematic
review and meta-analysis. Clin. Exp. Allergy 2011, 41, 482–489. [CrossRef] [PubMed]
37. Sujan, A.C.; Quinn, P.D.; Rickert, M.E.; Wiggs, K.K.; Lichtenstein, P.; Larsson, H.; Almqvist, C.; Öberg, A.S.; D’Onofrio, B.M.
Maternal prescribed opioid analgesic use during pregnancy and associations with adverse birth outcomes: A population-based
study. PLoS Med. 2019, 16, e1002980. [CrossRef] [PubMed]
38. de Fays, L.; Van Malderen, K.; De Smet, K.; Sawchik, J.; Verlinden, V.; Hamdani, J.; Dogné, J.-M.; Dan, B. Use of paracetamol
during pregnancy and child neurological development. Dev. Med. Child Neurol. 2015, 57, 718–724. [CrossRef] [PubMed]
39. Arneja, J.; Hung, R.J.; Seeto, R.A.; Knight, J.A.; Hewko, S.L.; Bocking, A.; Lye, S.J.; Brooks, J.D. Association between maternal
acetaminophen use and adverse birth outcomes in a pregnancy and birth cohort. Pediatr. Res. 2020, 87, 1263–1269. [CrossRef]
[PubMed]
40. Thompson, J.M.D.; Waldie, K.E.; Wall, C.R.; Murphy, R.; Mitchell, E.A.; ABC Study Group. Associations between Acetaminophen
Use during Pregnancy and ADHD Symptoms Measured at Ages 7 and 11 Years. PLoS ONE 2014, 9, e108210. [CrossRef] [PubMed]
41. Liew, Z.; Ritz, B.; Rebordosa, C.; Lee, P.-C.; Olsen, J. Acetaminophen Use during Pregnancy, Behavioral Problems, and Hyperkinetic
Disorders. JAMA Pediatr. 2014, 168, 313–320. [CrossRef]
42. Cooper, M.; Langley, K.; Thapar, A. Antenatal acetaminophen use and attention-deficit/hyperactivity disorder: An interesting
observed association but too early to infer causality. JAMA Pediatr. 2014, 168, 306–307. [CrossRef]
43. Bauer, A.Z.; Swan, S.H.; Kriebel, D.; Liew, Z.; Taylor, H.S.; Bornehag, C.-G.; Andrade, A.M.; Olsen, J.; Jensen, R.H.; Mitchell, R.T.;
et al. Paracetamol use during pregnancy—A call for precautionary action. Nat. Rev. Endocrinol. 2021, 17, 757–766. [CrossRef]

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