Taiwanese Journal of Obstetrics & Gynecology 58 (2019) 454e459

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Taiwanese Journal of Obstetrics & Gynecology

journal homepage: www.tjog-online.com

Review Article

Effects of maternal smoking on human placental vascularization: A

systematic review
Daniela Pintican a, Alexandra Andreea Poienar b, *, Stefan Strilciuc c, Dan Mihu a
a
Emergency Hospital of Cluj-Napoca e Dominic Stanca Clinic, University of Medicine and Pharmacy “Iuliu Hatieganu”, Cluj-Napoca, Romania
b
Emergency Hospital of Cluj-Napoca e Dominic Stanca Clinic, Cluj-Napoca, Romania
c
Babes-Bolyai University, Public Health, Romania

a r t i c l e i n f o a b s t r a c t

Article history: The abnormal development of placental vascularization leads to placental insufficiency, which further
Accepted 15 March 2019 reduces the nutrient and trace exchange between maternal circulation and fetal circulation. These
changes cause maternal and fetal complications. The objective of our systematic review was to explore
Keywords: the effects of maternal smoking on placental vascularization. The eligibility criteria were: articles with
Doppler experimental, quasi-experimental or observational design, performed on human subjects, that study the
Fetal
association, correlation or causation between maternal smoking and changes in placental vascular
Pregnancy
network. A total of 33 full-text papers were assessed for eligibility, resulting in 12 original articles that
Smoking
were included in the systematic review. Doppler studies confirm reductions in blood flow velocity
waveforms and increase in RI in the uterine, umbilical and fetal middle cerebral arteries. These findings
are confirmed by morphometric measurements of fetal capillaries in villi that were shown to be smaller
in smoke exposure groups.
© 2019 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction reduction in the vascularization. These anatomical changes are

Cigarette smoke contains about 4000 toxic chemical com-
pounds that exert direct effect on cell proliferation and differenti-
ation in the placenta and the fetus. Maternal smoking may lead to
spontaneous abortion, premature descent of placenta, premature
rupture of membranes, premature birth, intrauterine growth re-
striction, sudden death syndrome in the newborn and a 150% in-
crease in overall perinatal mortality [1]. Although maternal
smoking has been a well-known risk factor for pregnancy for a long
period of time [2], estimates of maternal smoking vary between 1
and 30% among countries, with a 19% prevalence in the Unites
States [3].
Nicotine is the most important pharmacologically active com-
pound in cigarette smoke. Nicotine quickly passes the fetal-
placental barrier, reaching the fetus at concentrations 15% higher
than in the mother [4]. At the beginning of pregnancy, the placenta
presents with thickening of the trophoblastic basal membrane, an
increase in collagen content in villous mesenchyme, and a
* Corresponding author. 408E Avram Iancu street, app 43, Floresti, Cluj, Romania.
E-mail address: Alexandra.poienar@gmail.com (A.A. Poienar).
associated with changes in placental enzymatic and synthetic
functions. In vivo and in vitro studies have shown that nicotine acts
directly on the placenta, being involved in the alteration of
maternalefetal circulation by influencing the mechanisms of
trophoblastic invasion [1]. Administration of nicotine in vivo and
in vitro inhibits trophoblastic invasion and differentiation. The ef-
fects of nicotine on placental development are most likely mediated
by placental nACHR (nicotinic acetylcholine receptors). Nicotine
exposure both in vivo and in vitro resulted in increased levels of
alpha-4 subunit of nACHR. In pregnant women who smoke, an
increase in proliferation of the capillary villosis occurs [1]. The poor
development of placental vascularity has been identified by an
increased umbilical artery Doppler resistivity index (indicating
abnormal vascularization). The exposure of placenta to cigarette
smoke has been shown to influence the balance between proan-
giogenic factors (placental growth factor (PLGF) and anti-
angiogenic factors (fms-like tyrosine kinase-1, sFlt-1) [5].
The abnormal development of placental vascularization leads to
placental insufficiency, which further reduces the nutrient and
trace exchange between maternal circulation and fetal circulation.
All these changes eventually cause maternal and fetal complica-
tions (gestational hypertension, intrauterine growth restriction,

https://doi.org/10.1016/j.tjog.2019.05.004
1028-4559/© 2019 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
 D. Pintican et al. / Taiwanese Journal of Obstetrics & Gynecology 58 (2019) 454e459
premature birth). Understanding the factors that can influence
placental vascularization is of vital importance to ensure a safe
pregnancy [5e7].
The extent to which effects of smoking on the placenta, as
indicated by morphological studies [8,9], are validated by addi-
tional methods, such as Doppler ultrasonography, is still unknown.
The objective of our systematic review was to explore the effects of
maternal smoking on placental vasculature. Although previous re-
view and best practice guideline papers have explored this topic
indirectly over 12 years in the past [10,11], these are relevant for
broader topics, such as the feto-placental unit. A systematic review
approach is needed to extensively cover specialty articles on this
topic and to highlight more recent evidence. This provides a win-
dow of opportunity for a novel review article on this topic.
Materials and methods
The systematic review was conducted according to the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses:
PRISMA statement [12] requirements and the protocol was sub-
mitted for registration at PROSPERO international database of
prospectively registered systematic reviews. The eligibility criteria
for items to be included in the review were: articles with experi-
mental, quasi-experimental or observational design, performed on
human subjects, that study the association, correlation or causation
between maternal smoking and changes in the placental vascular
network. Only scientific articles published in English, were
considered for inclusion in the review.
Two independent operators (DP, AAP e first two authors of this
article) systematically searched two scientific databases (PubMed,
Google Scholar) between JanuaryeFebruary 2018 for the following
keyword MeSh combinations: maternal smoke, smoking, nicotine,
tobacco AND placenta vascularization, placental vasculature. Titles
and abstracts of studies retrieved using the search strategy and
Fig. 1. PRISMA 2009 flow diagram highlighting study identification, screening, eligibility and inclusion.
455
those from additional sources were screened independently by two
review authors to identify studies that potentially meet the inclu-
sion criteria outlined above using Python 3.0 [13] and Excel
(Microsoft). Duplicate entries were removed using Open Refine [14]
clustering software. The full text of these potentially eligible studies
was retrieved and independently assessed for eligibility by two
review team members. Relevant references of full-text screened
articles were included in the eligibility assessment process. Dis-
agreements were resolved through discussion with a third and a
forth reviewer (SS and DM - last two authors of this article).
A standardized form was used to extract data from the included
studies for assessment of study quality and evidence synthesis.
Extracted information included: year of publication; author(s) in-
formation; study population demographics; methodology; out-
comes; times of measurement; information for assessment of the
risk of bias, performed using the ROBIS tool [15]. Full-text articles
included in the systematic review were appraised using the Quality
Assessment Tool for Observational Cohort and Cross-Sectional
Studies developed by the National Institutes of Health (NIH).
Results
A total of 1497 queries were retrieved using the search meth-
odology. After screening for duplicates and relevance based on title
and abstract, 33 full-text papers were assessed for eligibility,
resulting in 12 original articles that were included in the systematic
review (Fig. 1).
A majority of papers focused on active (n ¼ 11) as opposed to
passive (n ¼ 1) exposure. For first-hand maternal smoking, three or
more levels of exposure were analyzed in 54.5% of cases. The
sample size varied significantly among studies included in the
summary (range ¼ 5102): two important outliers [16,17] had large,
population based samples. For placental evaluation, most studies
used histomorphometric methods (n ¼ 6), while more recent
 456
Table 1
Descriptive and methodological variables for studies included in review.

Author(s), Year of publication Title N (study Exposure Exposure groups Gestational period Maternal age (years old) lacental evaluation
sample) type (cigarettes/day) at evaluation (weeks) (method)

(Asmussen, 1980) [18] Ultrastructure of the villi and fetal capillaries in 26 active 0; 10 N/A N/A Histomorphometry

D. Pintican et al. / Taiwanese Journal of Obstetrics & Gynecology 58 (2019) 454e459

placentas from smoking and nonsmoking
mothers
(Andersen and Hermann, 1984) [19] Placenta flow prediction in pregnant smokers 46 active 0; 2-20 33e37 N/A Radio-isotope
(Burton et al., 1989) [20] Morphometric differences between the 75 active 0; 1e15; >15 38e42 <35 Histomorphometry
placental vasculature of non-smokers, smokers
and ex-smokers
(Castro et al., 1993) [21] Cigarette smoking during pregnancy: acute 19 active smokers - non-smokers 27e29 N/A Doppler US
effects on uterine flow velocity waveforms.
(Mayhew, 1996) [22] Patterns of villous and intervillous space growth 37 active 0; <12; >12 N/A N/A Histomorphometry
in human placentas from normal and abnormal
pregnancies
(Bush et al., 2000) [23] A Quantitative Study on the Effects of Maternal 39 active smokers - non-smokers 13 Mean: 22.2 (smokers), Histomorphometry
Smoking on Placental Morphology and 26.6 (non-smokers)
Cadmium Concentration
(Rath, G. et al., 2001) [24] The Effects of Passive Smoking on the Terminal 100 passive 0; >30 (husband/relative) 38e42 N/A Histomorphometry
Villi of Human Placenta
(Lees et al., 2001) [17] Individualized Risk Assessment for Adverse 5121 active smokers - non-smokers Mean: 22.9 Mean: 29.7 Doppler US
Pregnancy Outcome by Uterine Artery Doppler
at 23 Weeks
(Larsen et al., 2002) [25] Stereologic examination of placentas from 72 active 0; 5e10; 11e20; >20 37e41 Median: 28 (non-smokers), Histomorphometry
mothers who smoke during pregnancy 29 (5e10/day group),
27 (11e20/day group),
28 (>20/day group)
(Albuquerque et al., 2004) [26] Influence of maternal tobacco smoking during 74 active 0; <10; >10 34e35 Median: 22 (smokers), Doppler US
pregnancy on uterine, umbilical and fetal 26 (non-smokers)
cerebral artery blood flows
(Kho et al., 2009) [16] Changes in Doppler flow velocity waveforms 2459 active 0; 1e5; 6e10; >10 19e21 Mean: 23.2 (smokers), Doppler US
and fetal size at 20 weeks gestation among 29.1 (non-smokers)
cigarette smokers
(Rizzo et al., 2009) [27] Effects of maternal cigarette smoking on 80 active 0; 0e10; 10e20; >20 Mean: 12.4 (non-smokers), Mean: 30.8 (non-smokers), Doppler US
placental volume and vascularization measured 12.6 (0e10/day group), 31.3 (0e10/day group),
by 3-dimensional power Doppler 12.7 (10e20/day group), 30.7 (10e20/day group),
ultrasonography at 11 þ 0 to 13 þ 6 weeks of 12.6 (>20/day group) 29.8 (>20/day group)
gestation
 D. Pintican et al. / Taiwanese Journal of Obstetrics & Gynecology 58 (2019) 454e459 457

studies preferred Doppler ultrasonography (n ¼ 5). A single study

NA

NA
26
from 1984 used radio-isotopes to assess placental vasculature

þ
N

N
Y
Y

Y
Y

Y
[Table 1].
5 out of 12 (41.66%) articles included in the analysis were

NA

NA
CD
15
deemed Good in terms of methodology, based on the NIH Quality

þ
N

N
Y
Y

Y
Assessment Tool. The most common limitations were lack of mul-
tiple measurements over time, clear and valid definition of expo-

NA

NA
CD
25
sure variables, adjustment for confounding variables, blinding of

þ
N

N
Y
Y

Y
assessors to exposure status of participants and definition of study
population [Table 2]. The results that highlight the effects of

NA

NA
24
maternal exposure to cigarette smoke on placental vasculature

þ
N
N

N
Y
Y

Y
Y
from studies that passed quality assessment are summarized in
Table 3. Three Doppler studies confirm reductions in blood flow

NIH Quality assessment tool; Assessment scores: Y - Yes; N - No; NA - Not applicable; NR - Not reported; CD - Could not determine. Assessment results: þ - Good; j - Fair; e - Poor.

NA

NA
16
velocity waveforms and RI in the uterine, umbilical and fetal middle

N
N

N
Y
Y

j
cerebral arteries. These findings are confirmed by morphometric
measurements of fetal capillaries in villi that were shown to be

NA

NA
23
smaller in smoke exposure groups.

e
N

N
N

N
N
Y

Y
Discussion

NA

NA
22

þ
N
N

N
Y
Y

Y
The objective of this systematic was to present the effects of
maternal smoking on placental vasculature. The results of our study

NA

NA
21
confirm that one of the main mechanisms that determines the in-

e
N

N
N

N
N
Y

Y
trauterine growth restriction is the increased resistance of umbil-
ical cord blood flow. Smoking pregnant women show increased

NA

NA
NR
20
vascular resistance on the fetal part of the placenta, as stem villi

e
N

N
N

N
Y

Y
arteries (abdominal villi) present abnormal mechanical properties
as well as a more vasoconstrictive response to endothelin-1 [28].
NA

NA
CD
19

The most important effect of these abnormalities that has been

N
Y
Y

j
linked to the subsequent development of both neonatal and adult
disease is intrauterine or fetal growth restriction [29]. Furthermore,
NA

NA
NR
18

the confirmation of changes in the case of maternal smoking is

N

N
N

N
Y

j
important because placental health is a proxy indicator for feto-
placental metabolism, which in turn influences birth weight [30].
NA

NA
17

Recent studies highlight the potential value of placental vascu-

e
N

N
N

N
N

N
Y

Y
larization 3D power Doppler indices in predicting preeclampsia
[31]. We therefore infer that the effect of smoking on placental
same time period)? Were inclusion and exclusion criteria for being in the study pre-specified
4. Were all the subjects selected or recruited from the same or similar populations (including the

8. For exposures that can vary in amount or level, did the study examine different levels of the
5. Was a sample size justification, power description, or variance and effect estimates provided?

vasculature may contribute to this risk, based on studies that

exposure as related to the outcome (e.g., categories of exposure, or exposure measured as

9. Were the exposure measures (independent variables) clearly defined, valid, reliable, and

14. Were key potential confounding variables measured and adjusted statistically for their
11. Were the outcome measures (dependent variables) clearly defined, valid, reliable, and
confirm the pathway between maternal smoking exposure during
7. Was the timeframe sufficient so that one could reasonably expect to see an association
6. For the analyses in this paper, were the exposure(s) of interest measured prior to the

pregnancy and daughter's preeclampsia risk [32]. However, the

effects of smoking on the risk of pre-eclampsia are still uncertain.

12. Were the outcome assessors blinded to the exposure status of participants?
Some studies have shown that smoking during pregnancy reduces
the risk of pre-eclampsia [33,34] by reducing circulating levels of
sFLT-1 and increasing the VGF/sFLT-1 ratio. Other studies, however,
1. Was the research question or objective in this paper clearly stated?

did not show changes in FLT-1 or VEGF/FLT-1, suggesting that

nicotine is a protective factor against pre-eclampsia, but rather impact on the relationship between exposure(s) and outcome(s)?

tobacco products [35].

10. Was the exposure(s) assessed more than once over time?
3. Was the participation rate of eligible persons at least 50%?
2. Was the study population clearly specified and defined?

One of the main contributions of this review to existing litera-

implemented consistently across all study participants?

implemented consistently across all study participants?

ture is the assessment of the entire placental circulation described

13. Was loss to follow-up after baseline 20% or less?

by Rizzo et al. (2009). Through recent advances in ultrasonography

(combination of 3-D ultrasound with power Doppler) the authors
between exposure and outcome if it existed?

have proven the effects of smoking on placental volume by Doppler

and applied uniformly to all participants?

measurement of the placental vascular network. Furthermore, their

study showed that changes in the indexes evaluated by 3-D
Doppler occur only in pregnant women who report that they
outcome(s) being measured?

smoke more than 10 cigarettes/day [27].

Pregnant women who smoked had an increase in the resistance
Quality assessment criteria

continuous variable)?

index (RI) of the uterine and umbilical arteries as compared with

non-smoking pregnant women. The RI of the middle cerebral artery
Assessment result

was significantly higher in smokers above ten cigarettes/day as

compared to smokers below ten cigarettes/day. There is no differ-
ence in RI of the fetal MCA between smokers and non-smokers [26].
Maternal smoking, like maternal obesity and pre-eclampsia,
Table 2

causes oxidative stress, by disrupting the production of reactive

oxygen species (ROS). These maternal factors have been associated
458 D. Pintican et al. / Taiwanese Journal of Obstetrics & Gynecology 58 (2019) 454e459

Table 3
Results of studies included in the review, as extracted from results Only references that were graded þ using the methodological assessment were summarized.

Study results

The placentas showed increases in [...] the relative volumes of maternal intervillous space, the relative surface areas of fetal capillaries and decreases in the relative and
absolute volumes of fetal capillaries. Findings indicate that changes in capillary volume are the result of a decrease in mean capillary diameter rather than total length.
The mean thickness of the trophoblast component of the villous membrane was also increased in the smoking group [23].
Cigarette smoking during pregnancy influences the placental vasculature. The reduced dimensions of fetal capillaries in villi may affect the placental blood flow, and the
diminished area for exchange of gasses and nutrients between the mother and the fetus will increase the risk of fetal undernourishment [25].
Smoking-related differences in the blood flow velocity waveforms and RI in the uterine, umbilical and fetal middle cerebral arteries [26].
At 20 weeks' gestation, women who smoke have higher umbilical artery RI, a surrogate measure for an abnormal placental villous vascular tree [16].
In exposure groups >10 cigarettes/day, lower values were found for vascularization index (VI). Maternal smoking is associated with altered 3-dimensional placental
Doppler indices and these changes are related to birth weight [27].

with aberrant angiogenesis and placental dysfunction, leading to
unwanted pregnancy outcomes [36]. Oxidative stress can influence
the expression of important transcription factors in mediating
angiogenesis [1]. Smoking is a factor of oxidative insult, causing an
abnormal development of placental vasculature through pathways
mediated by oxidative stress. Smoking leads to important changes
in the genes involved in the management of oxidative stress [37].
The novelty of our review consists in its analysis of the blood
flow through the fetal and maternal vessels and the impact of
cigarette smoking on them, finding a causation relationship be-
tween cigarette smoking and fetal and maternal hemodynamics.
Older reviews are partially consistent with ours, but they do not
find a causation relationship between smoking and umbilical and
uterine flood flow [38]. Also, older reviews analyze the impact of
smoking over the fetal growth and overall fetal outcome [39]. The
newer studies and reviews, including ours, tend to investigate the
underlying physiopathology of these changes, allowing for a
better, more active pregnancy surveillance and optimum fetal
extraction [40].
Our results are based on data from prospective and retrospec-
tive studies, and not all studies have comparison groups matched
for variables such as age, parity, ethnicity and co-morbidities. The
biggest limitation of descriptive data gathered from published case
series is that these data are subject to publication bias. The data
may be misleading, with the potential of either augmenting or
under-reporting the effects of smoking on placental vasculature.
Large-scale studies are required using prospective and repeated-
measures designs to further evaluate the effects of smoking on
the placenta.
In conclusion, this review indicates that maternal exposure to
passive and active smoking is associated with altered placental
vasculature.
Conflict of interest
We do not have any conflict of interest to declare.
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