doi:10.1111/jog.14343 J. Obstet. Gynaecol. Res.

2020

Uterine fibroids and preterm birth risk: A systematic

review and meta-analysis

Gonzalo R. Pérez-Roncero1, María T. López-Baena1, Lía Ornat1,2, Marcos J. Cuerva3,

Patricia Garcia-Casarrubios3, Peter Chedraui4,5 and Faustino R. Pérez-López1,2
1
Red de Investigación de Ginecología, Obstetricia y Reproducción, Instituto de Investigaciones Sanitarias de Aragón, Zaragoza, Spain
2
Department of Obstetrics and Gynecology, University of Zaragoza Faculty of Medicine, Zaragoza, Spain
3
Department of Obstetrics and Gynecology, Hospital Universitario La Paz, Madrid, Spain
4
Instituto de Investigación e Innovación en Salud Integral, Facultad de Ciencias Médicas, Universidad Católica de Santiago de
Guayaquil, Guayaquil, Ecuador
5
Facultad de Ciencias de la Salud, Universidad Católica Nuestra Señora de la, Asunción, Paraguay

Abstract
Aim: This study explored the association between the presence of uterine fibroids (UF), as determined by
ultrasound, and preterm birth (PB) risk.
Methods: Medline, Embase, Cochrane, Scopus and Web of Science databases. Studies reporting women with
and without UF demonstrated by an ultrasound exam. The primary outcome was the risk of PB < 37 weeks
of gestation in pregnancies with UF diagnosed by an obstetric ultrasound exam. Effects for dichotomous
and continuous outcomes are, respectively, reported as risk ratios (RR) or mean differences and their 95%
confidence intervals (CI).
Results: Eighteen studies were included comprising 276 172 pregnancies to whom obstetric ultrasound
assessment was performed for the presence/absence of UF. Women with UF were older (mean differ-
ence = 2.40 years, 95% CI 0.94–3.85) and were at higher risk of PB before 37 (RR = 1.43, 95% CI 1.27–1.60),
34 (RR = 1.79, 95% CI 1.32–2.42), 32 (RR = 1.94, 95% CI 1.33–2.85) and 28 (RR = 2.17, 95% CI 1.48–3.17)
weeks as compared to those without UF (P < 0.01). In addition, women with UF were at higher risk of
threatened preterm labor, preterm premature rupture of membranes, fetal malpresentation, placental abrup-
tion, lower gestational age and birthweight at delivery and a higher cesarean delivery rate.
Conclusion: Pregnant women with UF are at increased risk of PB and other adverse obstetric outcomes.
Key words: birthweight, preterm birth, preterm delivery, ultrasound diagnosis, uterine fibroids, uterine
myomas.

Introduction proliferation and fewer leucocytes than the normal

Uterine fibroids (UF) are benign tumors that originate
in the uterine musculature compartment, consisting of
smooth muscle cells and fibroblasts embedded in an
extracellular matrix. Large fibroids contain more cell
myometrium, while small fibroids have a similar
amount of leucocytes and are less proliferative as
compared to the normal myometrium.1 The extracel-
lular matrix includes large amounts of collagen and
displays heterogeneity of collagen and tissue stiffness.

Received: January 6 2020.

Accepted: May 16 2020.
Correspondence: Prof. Faustino R. Pérez-López, Department of Obstetrics and Gynecology, University of Zaragoza Faculty of
Medicine, Domingo Miral s/n, Zaragoza, Spain; Email: faustino.perez@unizar.es.
*Gonzalo R. Pérez-Roncero and María T. López-Baena contributed equally to the study.

© 2020 Japan Society of Obstetrics and Gynecology 1

G. R. Pérez-Roncero et al.
These properties are related to the local pressure, bio-
chemical signals and altered growth.2 Many fibroids
are discovered incidentally in asymptomatic women
upon clinical or ultrasonographic examination.3 Age
and ethnicity are risk factors for UF development and
growth, and they may be present in up to 70% of peri-
menopausal women.4 The prevalence is higher in
women of African ancestry.5
During pregnancy, the prevalence of UFs may
range from 3% to 12%,6,7 figure that can reach up to
18% among African American women.8 There is
insufficient evidence regarding the effect (advantages
or risks) of surgical correction of uterine abnormalities
in women with reproductive desire.9 The majority of
pregnant women do not seem to have significant risks
associated with the presence of UF; however, pain
may be the most frequent complaint. Despite this,
there may be a mildly increased risk of complications,
such as miscarriage, premature rupture of mem-
branes, dysfunctional labor, breech presentation,
abruptio placentae and a higher rate of cesarean
delivery and postpartum hemorrhage.10–12
Recent meta-analyses have reported that UF do not
increase the risk of miscarriage.13 Contrary to this, UF
may increase the risk of placental abruption,14 pla-
centa previa15 and the risk of cesarean delivery and
term fetal malpresentation.16 Preterm birth is a major
obstetrical complication that may be associated with
both maternal and fetal adverse events. UF might
interfere with normal labor and delivery by altering
the normal course of uterine contractions, in general
related to limitations of the uterine space. The aim of
this systematic review and meta-analysis was to
explore the association between UF, as determined by
obstetric ultrasound, and the risk of preterm birth.
Methods
Protocol, search strategy, eligibility criteria and
study selection
The systematic review was undertaken following the
principles of the PRISMA guidelines.17 The protocol
study was not registered, and formal institutional
review board approval was not required, due to the
fact that this analysis consisted of the pooling of pub-
lished studies.
A systematic literature search was conducted in
Cochrane Library, PubMed-Medline, Scopus,
EMBASE and Web of Science databases from incep-
tion through July 15 2019, without language
2 © 2020 Japan Society of Obstetrics and Gynecology
restrictions. We searched for free terms ‘UF’ or ‘uter-
ine myoma’ or ‘uterine leiomyoma’ or the Medical
Subject Heading (MeSH) terms ‘myoma’ and
‘leiomyoma’ combined with ‘preterm birth’ (MeSH)
or ‘preterm delivery’. The PubMed search strategy is
available in Table S1. An iterative process was used to
ensure that all relevant articles were obtained. A fur-
ther manual search of bibliographic references was
carried out in selected studies and in existing reviews
to identify potential studies that were not captured by
the electronic database searches.
Relevant cohort and case–control studies were eligi-
ble for inclusion if they: (i) assessed pregnant women
with UF as demonstrated by ultrasound exam;
(ii) presented data on at least one pre-specified out-
come; (iii) controls were pregnant women without UF
and (iv) studies in any language irrespective of age,
race and publication date and (v) studies having the
same population was included if reporting comple-
mentary information to the main paper. Articles were
excluded if they were narrative reviews, abstracts and
conference proceedings or non-human studies. All
disagreements regarding inclusion/exclusion were
discussed and solved by consensus with all authors.
Outcome measures
The pre-specified primary outcome was preterm birth
before 37 weeks. Secondary outcomes included pre-
term birth before 34, 32 and 28 weeks, threatened pre-
term labor, preterm premature rupture of
membranes, placental abruption, fetal mal-
presentation, intrauterine fetal demise, intrauterine
fetal growth restriction, gestational age at delivery,
neonatal birthweight, low birthweight (<2500 g) and
rates of cesarean delivery, postpartum hemorrhage
and infants admitted to the Neonatal Intensive Care
Unit. We used standard international definitions for
outcome measures.7,10,11 Three researchers indepen-
dently evaluated study eligibility by screening titles
and abstracts of retrieved articles. Slight differences in
definitions were not felt to be clinically significant
enough to prevent meta-analysis.
Data extraction and risk of bias assessment
A Microsoft Excel sheet was designed for data input.
Four researchers extracted publication details, eligibil-
ity and exclusion criteria, as well as information about
the study population, period of study, study design,
sample size and primary and secondary outcomes.
Discrepancies and controversies of extracted data
were discussed in order to reach a consensus. Due to

the fact that some results were reported as means and
their standard errors, appropriate calculations were
performed to obtain standard deviations that served
for the meta-analysis.18
The methodological quality of the selected studies
was independently assessed by two authors, using
the Newcastle-Ottawa Scale for the separated assess-
ment of cohort and case–control studies.19 This scale
consists of three broad perspectives, including the
selection of the study group, the comparability of the
groups and the ascertainment of the primary out-
come. The maximum score can be nine stars. Studies
with seven star-items or more are categorized as high
quality, and those with six star-items or less are cate-
gorized as low quality.
Data synthesis and analysis
Forest plots were generated using DerSimonian and
Laird random-effects models and inverse the variance
method20 that allows generalization beyond the stud-
ied results. For dichotomous outcomes, associations
are reported as risk ratios (RRs); and for continuous
outcomes mean differences (MDs) were used, both
with their corresponding 95% confidence interval
(CI). We evaluated statistical heterogeneity using the
Cochrane chi-square (Χ2), the I2 statistic and the
between-study variance using the tau square (τ2).21,22
I2 values of 30–75% indicate a moderate level of het-
erogeneity. A P < 0.1 for the chi-square defined the
presence of heterogeneity and a τ2 > 1 defines the
presence of substantial statistical heterogeneity. To
explore the heterogeneity of effects, we performed
sub-analyses of the primary outcome (preterm birth
<37 weeks) according to (i) the sample size of cases
with UF (<250 vs >250), (ii) region of the world:
Europe, United States and Mexico, Asia and Africa
and (iii) cohort versus case–control studies. We also
explored publication bias with the funnel plot and the
Egger’s test.23
Review Manager (RevMan, version 5.3, Oxford,
UK; The Cochrane Collaboration) and the Compre-
hensive Meta-analysis (Biostat, Englewood, NU, USA)
programs were used for statistical analyses.
Results
General characteristics of studies
A total of 810 records were identified. After excluding
duplicates, 504 studies were carefully reviewed. After
screening by titles and abstracts, 26 relevant articles
© 2020 Japan Society of Obstetrics and Gynecology
Uterine fibroids and preterm birth
were identified in addition to one from another
source. Eight items were excluded: abstracts or pro-
ceedings (n = 3), primary outcomes not reported
(n = 1), had no control group (n = 1) or were narrative
reviews (n = 4). Finally, 19 articles (18 studies) were
included in this meta-analysis.24–42 One of these
papers reported complementary information to the
primary outcome information.35,38 The selection pro-
cess is shown in Figure 1.
There were five cohort studies, including 3449 preg-
nant women with UF and 111 644 control women
without UF reported in five articles.26,33,35,38,41 There
were also 13 case–control studies, including 10 270
pregnant women with UF and 150 795 control women
without UF.24,25,27–32,34–37,40,42 In all included studies,
the presence or absence of UF was determined by
ultrasound examination during the first or second tri-
mesters of gestation. Characteristics of the included
studies and participants are displayed in Table 1. Five
populations were studied in the United
States,26,29,30,35,39 seven in Europe,24,25,28,32–34,41 three
in Asia,27,36,42 two in Africa31,40 and one in Mexico.37
Two articles reported different results of the same
cohort.35,38 Studies were published between 199029
and 2018.31,33 Some clinical information was heteroge-
neously reported (Table 1).
The risk of bias was assessed with the Newcastle-
Ottawa Scale. According to this 5 cohort and
13 case–control studies had a low risk of bias (>7
stars).
Synthesis of the results
Preterm birth and gestational age at delivery
Eighteen studies reported an increased risk of preterm
birth <37 weeks of gestation in women with UF
(RR = 1.43, 95% CI 1.27–1.60, P < 0.001; I2 = 60%;
Figure 2a).24–42 In 10 studies, pregnant women with UF
were older than those without fibroids (MD = 2.40 years,
95% CI 0.94–3.85, P < 0.001).24–26,30–33,37,39,40 Six studies
also showed the association of UF with preterm birth
<34 weeks (RR = 1.79, 95% CI 1.32–2.42, P < 0.001;
I2 = 68%; Figure 2b).24,26,32,33,36,39 These two associations
(<37 and <34 weeks) had moderate degrees of heteroge-
neity. Associations between UF and preterm birth at
<32 weeks (RR = 1.94, 95% CI 1.33–2.85, P < 0.001;
I2 = 0%; Figure 2c) 24,35 and <28 weeks (RR = 2.17, 95%
CI 1.48–3.17, P < 0.001, I2 = 0%) were also demonstrable
(Figure 2d).26,35
There was an association between UF and threat-
ened preterm labor in six studies (RR = 1.67, 95% CI
1.41–1.96, P < 0.001; I2 = 0%; Figure 3a).25,29,32,33,36,40
3
G. R. Pérez-Roncero et al.

Records identified through  Pubmed n = 177
database searching Embase n= 360
Identification

(n = 810) Scopus n = 179
Web of Science n = 91
Cochrane Library n = 3
Records after removing 
duplicates 
(n = 504)

Records after screening 
by title 
Screening

(n = 147)

Records after screening 
by abstract
(n = 26)
Additional record identified 
through other sources
(n = 1)
Eligibility

Full-text articles assessed for 
eligibility
(n = 27)

Full text articles excluded
(n = 8):
Articles included in the  • Abstracts /proceedings (n = 3) 
qualitative synthesis • Not control group (n=1) 
(n = 19) • Narrative reviews (n = 4) 
Included

Articles included in the 
quantitative synthesis
( n = 19) Figure 1 Systematic
review flowchart.

Fifteen studies also found a significant association Obstetric morbidity

between the presence of UF and the risk
of premature preterm rupture of membrane
(RR = 1.35, 95% CI 1.11–1.63, P = 0.003; I2 = 49%;
Figure 3b).24,25,28–30,32–37,39 In nine studies the MD of
gestational age (weeks) at delivery was lower in preg-
nant women with UF (MD = −0.58, 95% CI −0.80,
−0.35, P < 0.001; I2 = 72%; Figure 3c).24,26,28–30,32,39,42 In
six studies, the MD of infant birthweight (grams)
was lower in pregnant women with UF
(MD = −129.83, 95% CI −166.34, −93.33, P < 0.001;
Figure 3d).24,26,29,30,39,40
In 11 studies there was an increased risk of placental
abruption in women with UF as compared to those
without UF (RR = 2.22, 95% CI 1.18–4.17, P = 0.01;
I2 = 83%; Figure 4a).24,25,28–30,32,36,38,39,41,42 An associ-
ation between UF and the risk of intrauterine fetal
demise was not found (RR = 1.74, 95% CI
0.29–10.44, P = 0.55; Figure 4b).24,29,35 The presence
of UF was associated to a higher risk of mal-
presentation in 11 studies (RR = 2.07, 95% CI
1.73–2.49, P < 0.001; Figure 4c)24–26,28,30,33,37–40,42;
cesarean delivery (RR = 2.07, 95% CI 1.73–2.49,

4 © 2020 Japan Society of Obstetrics and Gynecology

Table 1 Characteristics of included studies using ultrasound exam to determine the presence/absence of uterine fibroids
Authors Location and Study design. Gestational Inclusion criteria (IC). Uterine fibroid (UF) Uterine fibroid group: Control group: maternal
period of study age (GA) at US diagnosis Exclusion criteria (EC) characteristics maternal age (MA); sample age (MA); sample (n);
(n); parity parity
Arisoy et al.24 Istanbul, Turkey. Case–control study. IC: singleton pregnancies, Intramural fibroid of at MA: 34.4  4.9 years; MA: 34.3  2.7 years;
2009–2013 GA: 15–24 weeks intramural UF ≥3 cm, no least 3 cm at n = 112; parity: 1.2  1.3 n = 168; Parity: 1.3  1.0
previous surgery. 15–24 weeks US exam.
EC: Women with
subserous or
submucous UF.
Aydeniz et al.25 Heidelberg, Case–control study. IC: singleton pregnancies, All UF sizes: <30 mm, MA: 31.5  3.7 years; MA: 30.2  3.6 years;
Germany. GA: 15–25 weeks intramural UF ≥3 cm, no n = 32; 30–50 mm, n = 94; n = 380.
1990–1995 previous surgery. n = 38; > 50 mm, n = 24 Parity: nulliparous 29.8% Parity: nulliparous 32.1%
EC: Multiple (n = 28); nulliparous (n = 122); nulliparous
pregnancies and 70.2% (n = 66) 67.9% (n = 258).
women with
subserous or
submucous UFs,
fetuses with
chromosomal or
structural
abnormalities and
maternal systemic
diseases were
excluded.
Blitz et al.26 New York, USA. Retrospective cohort study IC: At least one fibroid Myomas of any size. MA: 33.3  3.6 years; MA: 30.9  4.5 years;
January 2010 – GA: 17–23 weeks. and delivery at n = 522; n = 9792;
December 2013 ≥20 weeks. EC: Multiple Parity: Parity:
gestations. A history of nulliparous = 352/522 nulliparous = 5280/9792
cervical conization or (67.4%) (53.9%)
LEEP, uterine
anomalies, and a
previously placed
cerclage, maternal
age > 40 years.
Chen et al.27 Taipei, Taiwan. Case–control study of two IC: US screening early in The presence of myoma MA: 28.7  5.1 years; MA: 28.7  5.1 years;
January population based data. their pregnancy (52.3%). during the ‘index’ US n = 5627; Parity: NS n = 28 135
2001–December GA: US exam at Live singleton births. screening without matching any trait
2003 13.2  9.8 weeks. EC: If a mother had 13.2  9.8 weeks with the cases. Parity:
more than one NS
singleton birth
between 2001 and
2003.

(Continues)
Table 1 Continued
Authors Location and Study design. Gestational Inclusion criteria (IC). Uterine fibroid (UF) Uterine fibroid group: Control group: maternal
period of study age (GA) at US diagnosis Exclusion criteria (EC) characteristics maternal age (MA); sample age (MA); sample (n);
(n); parity parity
Ciavattini et al.28 Ancona, Italy. Case–control study. IC: Singleton pregnancy, Forty-eight women (21.9%) MA: 34.8  4.2 years; MA: 34.8  4.2 years;
January GA: second trimester delivery >24 weeks. showed at least one n = 219; parity: 2  1 n = 219; parity: 2  1
2010–December US exam. EC: Chronic large UF (≥5 cm) with a
2012 hypertension, mean diameter of
gestational diabetes 6.1  1.3, range
or pre-existing 5–10.7 cm and 34
diabetes mellitus, women (15.5%) had two
uterine anomalies or or more UF (range 2–8).
fetal malformations. In 207 women (94.5%)
fibroids were
intramural. Submucosal
and subserosal UF were
detected in 1.8% and
3.7%, respectively.
Davis et al.29 Los Angeles, USA. Case–control study. IC: Single or multiple UF Sixty-nine percent had MA: 33.2  3.9 years; MA: 33.2  3.9 years;
February GA: US exam at by US examination. only one UF, 19% had n = 85; Parity: 59% n = 85; Parity: 59%
1986–February 20–24 weeks of EC: Multiple two, and 12% had three nulliparous nulliparous
1988 pregnancy. pregnancies. Neither or more.
the study nor control
women had a history
of diabetes,
hypertension, preterm
premature rupture of
membranes, or
preterm labor or
delivery.
Do
gan et al.30 Chicago, USA. Matched case–control IC: UF at US exam during Large fibroids (>5 cm), MA: 33.3  4.8 years; MA: 33.2  4.7 years;
January study. GA: US exam the first trimester. A n = 144; small fibroids, n = 267; Parity: 0.81  1.0 n = 267; Parity: 0.92  0.8
2002–December during the first large UF was defined if n = 123
2009 trimester. >5 cm (n = 144 gravids).
EC: Multiple gestations,
prior history of
preterm birth, and 6
with ART were
excluded from the
fibroid group.
Egbe et al.31 Limbe and Buea, Case–control study. IC: Pregnant women aged 63.7% fibroids were MA: 31.4  3.4 years; MA: 27.4  4.2 years;
Cameroon. April– GA: first trimester of ≥21 years. Recruited subserous, 22.7% n = 38; Parity: 2.7  1.6 n = 188; Parity: gravity
December 2013 pregnancy pregnant women submucous, and 13.6% 2.3  1.7
≥28 weeks of gestation. intramural.
EC: No first trimester
US exam.
Exacoustos et al.32 Rome, Italy. January Case–control study. IC; Pregnant women with Single fibroids 434 women, MA: 31.6  4.4 years; MA: 31.3  3.9 years;
1984–December GA: before 20 weeks. uterine fibroids of at and 58 women multiple n = 492; parity: 207 n = 12 216; Parity: 5583
1990 least 3 cm. EC: fibroids (38 included nulliparous and 285 were nulliparous and 6633
Multiple gestations and miscarriage). at least in their second multiparous.
fetal malformations. gestation.
Table 1 Continued
Authors Location and Study design. Gestational Inclusion criteria (IC). Uterine fibroid (UF) Uterine fibroid group: Control group: maternal
period of study age (GA) at US diagnosis Exclusion criteria (EC) characteristics maternal age (MA); sample age (MA); sample (n);
(n); parity parity
Girault et al.32 Paris, France. Retrospective cohort IC: Singleton pregnancies Presence of a myoma of at MA: 36,1  5,0 years; MA: 31.3  3.9 years;
PS: January 1, study. with at least one UF of least 2 cm in US exam n = 301 women, 154 n = 12 216;
2011, to GA: US exams 110 to 20 mm or multiple UF or multiple myomas by without surgery and Parity: 5583 nulliparous
September 31, 136 weeks. of any size, measuring hysteroscopy, 147 treated with and 6633 multiparous.
2015. ≥20 mm with or without laparoscopy, or surgery. Parity:
persistent UF after laparotomy with or nulliparous 108
surgery. Delivering without persistent
>22 weeks. EC: NS. myomas.
Kellal et al.34 Tours, France. Case–control study. IC: Pregnancies with live 75 women had a single UF MA: NS, although MA: NS; n = 234
1999–2009 GA: US exam during births; singleton and 42 several UF. significantly older; Parity: matched NS
the first trimester of pregnancies. Localization: 68% n = 117; Parity: NS.
pregnancy. EC: Intrauterine death. subserous, 9%
submucous, and 23%
intramurals. 50 patients
had at least one UF
≥5 cm. Eight women
(6.8%) had a
myomectomy before
pregnancy.
Lai et al.35 San Francisco, USA. Retrospective cohort IC: Second trimester US At least one UF measuring MA: 33.7 years; n = 401; MA: 28.6 years; n = 14 703;
January study. exam and delivering at ≥1 cm. 315 women had parity: NS parity: NS
1993–December GA: Second trimester. ≥24 weeks. information on size: 39
EC: Multiple gestations, women (13%) had
fetal anomalies, and leiomyoma of ≥10 cm of
absence of second size, and 202 (66%) had
trimester US, or those leiomyoma of ≥5 cm in
delivered at another size.
institution.
Majeed et al.36 Lahore, Pakistan. Case–control IC: Singleton pregnancies. All UF sizes. A 30% were MA: < 25 years, n = 28; MA: < 25 years, n = 35;
January GA: NS. EC: Multiple located in the upper 25–35 years, n = 61; 25–35 years, n = 56;
2009–December pregnancies. Previous segment, 35% were in > 35 years. n = 100; > 35 years; n = 9.
2010 cesarean section or the lower segment and parity: nulliparous 53%. n = 100; parity:
myomectomy scar. 35% UF were in nulliparous 27%.
supracervical region.
Morgan Sinaloa, Mexico. Case–control. IC: 3 planned US exams Mean myoma size MA: 30.8  5.9 years; MA: 25.1  6.3 years;
Ortiz et al.37 March GA: Second trimester (20–24 weeks; 4.3  3.3 cm; n = 65; Parity: 1.6  0.9 n = 165; Parity: 2.4  1.4
2009–October US exam. 30–32 weeks; and 3.6  4.3 cm; and
2010 36–40 weeks. 2.5  3.8 cm.
EC: Diabetes mellitus,
hypertension or
recurrent pregnancy
losses.

(Continues)
Table 1 Continued
Authors Location and Study design. Gestational Inclusion criteria (IC). Uterine fibroid (UF) Uterine fibroid group: Control group: maternal
period of study age (GA) at US diagnosis Exclusion criteria (EC) characteristics maternal age (MA); sample age (MA); sample (n);
(n); parity parity
Qidwai et al.38 San Francisco, USA. Retrospective cohort IC: Routine second At least one leiomyoma MA: 33.7; years; n = 401; MA: 28.6 years; n = 14 703;
January study. trimester US exam and measuring ≥1 cm. 315 Parity: NS Parity: NS
1993–December GA: Second trimester. delivering at ≥24 weeks, women had information
2003 EC: Multiple gestations, on size: 39 women
fetal anomalies, or (13%) had leiomyoma of
those delivered at ≥10 cm of size, and 202
another institution. (66%) had UF of ≥5 cm.
Stout et al.39 St. Louis, Missouri, Retrospective cohort IC: Routine second Women with at least one MA: 35.1  4.6 years; MA: 30.0  6.3 years;
USA. study. trimester fetal anatomic leiomyoma noted at n = 2058 n = 61 989;
1990–2007. GA: Second trimester ultrasound survey; routine second trimester Parity: 0.82  1.1 Parity: 1.06  1.2
US examination singleton pregnancy. ultrasound examination.
EC: No obstetric
outcomes.
Tchente Yaoundé, Case–control study. GA: IC: Age ≥ 18 years; Second trimester US exam. MA: 31.2  8.6 years; MA: years;
Nguefack et al.40 Cameroon. US exam during the first singleton pregnancy. Localization: 89.4% had n = 80; parity: nulliparous 30.8  8.0 years; n = 80;
October or second trimester. EC: Multiple body UF and 10.6% 50 (62.5%); 1–2 23 parity: nulliparous 49
2002–December pregnancies, chronic supracervical. The (28.7%), > 2 7 (8.8%). (61.2%); 1–2 24 (30.0%);
2004 diseases (diabetes, majority were >2 7 (8.8%).
hypertension, hepatic intramural. Mean
failure, kidney failure, diameter 5.4 cm.
drepanocytosis)
Vergani et al.41 Milano, Italy. Retrospective cohort. GA: IC: US exam between 16 Second trimester US exam. MA: 33.1 years; n = 167; MA: 29.5 years; n = 5595;
January US during the second and 20 weeks. Two women underwent parity: 77 nulliparous. parity: 3403 nulliparous
1983–January 1989 trimester. EC: NS. successful myomectomy
at 16 and 25 weeks.
Zhao et al.41 14 provinces of Retrospective case–control. IC: US exam at Women with at least one MA: 32.0  4.9 years; MA: 27.9  5.2 years;
China. GA: US during 18 to 18–22 weeks. Regular fibroid. 2606 women n = 3012; Parity: n = 109 931;
January– 22 weeks of prenatal care once a had one UF ≤5 cm, and 1.15  0.4. Parity: 1.21  0.5.
December 2011. pregnancy. month before 28 weeks, 406 had UF of >5 cm.
every 2 weeks between 2210 patients (73.4%)
28–36 weeks, and once a had a single fibroid
week after 36 weeks. (73.4%) and 802 (26.6%)
EC: Multiple women had UF. UF
pregnancies. were subserosal in 1948
patients (64.7%),
submucosal in 1000
women (33.2%), and
intramural in 64 patients
(2.1%).

ART, assisted reproductive technology; EC, exclusion criteria; GA, gestational age; IC, inclusion criteria; LEEP, loop electrosurgical excision procedure; MA, maternal age; NS, not stated; UF, uter-
ine fibroid; US, Ultrasound; USA, United States of America.
 Uterine fibroids and preterm birth

Figure 2 Risk ratios (RRs) for preterm birth before 37 (a), 34 (b), 32 (c) and 28 (d) weeks in women with uterine fibroids
as compared to women without them.

© 2020 Japan Society of Obstetrics and Gynecology 9

G. R. Pérez-Roncero et al.

Figure 3 Risk ratios (RRs) for threatened preterm labor (a) and premature rupture of membranes (b), and mean differ-
ences (MDs) for gestational age at delivery in weeks (c) and birthweight in grams (d) in women with uterine fibroids as
compared to women without them.

10 © 2020 Japan Society of Obstetrics and Gynecology

 Uterine fibroids and preterm birth

Figure 4 Risk ratios (RRs) for placental abruption (a), intrauterine fetal demise (b), fetal malpresentation (c), cesarean
delivery rate (d) and postpartum hemorrhage (e) in women with uterine fibroids as compared to women without them.

P < 0.001; I2 = 58%, Figure 4d) in Fetal outcomes

24–26,28–34,36,39–42
16 studies and postpartum hemor- In seven studies, women with UF did not have a
rhage (RR = 1.37, 95% CI 0.43–4.33, P = 0.60; higher risk of fetal intrauterine growth restriction
I2 = 99%, Figure 4e) in 8 studies.31,33,34,36–38,41,42 (RR = 1.38, 95% CI 0.97–1.97, P = 0.08, I2 = 47%,

© 2020 Japan Society of Obstetrics and Gynecology 11

G. R. Pérez-Roncero et al.
Figure 4 Continued
Figure 5a).24,29,30,32,35,39,41 Women with UF had a
higher risk of having infants with low birthweight
(RR = 1.51, 95% CI 1.13–2.02, P = 0.005; I2 = 78%;
Figure 5b) in six studies.24,26,31,35,42 The need for Neo-
natal Intensive Care Unit admissions was not signifi-
cantly increased among mothers with UF (RR = 0.99,
95% CI 0.51–1.94, P = 0.99; I2 = 66%; Figure 5c) in
three studies.24,34,36
Subgroup analyses
We performed subgroup analyses of the primary out-
come (preterm birth <37 weeks) according to (i) the
sample size of UF cases (<250 vs >250 cases),
(ii) region of the world (a) Europe (n = 7 studies);
(b) United States and Mexico (n = 6 studies); (c) Asia
(n = 3 studies) and (d) Africa (n = 2 studies) and
(iii) cohort versus case–control studies.
Studies, including less than 250 women with UF
had a higher risk of preterm birth <37 weeks
(RR = 1.81 (95% CI 1.32–2.48;
12
P < 0.001),24,25,28,29,31,34,36,37,40,41 which was similar to
that for the studies, including more than 250 women
(RR = 1.43, 95% CI 1.22–1.53;
P < 0.001)26,27,30,32,33,35,39,42; although the first sub-
group had a lower heterogeneity (I2 = 40%) as com-
pared with the second one (I2 = 72%) (Figure S1).
The second subgroup analysis compared the influ-
ence of the world region where the studies were per-
formed (Figure S2). From top to bottom: (i) RR = 1.38
(95% CI 1.05–1.81, P = 0.02, I2 = 51%) for studies per-
formed in Europe,24,25,28,32–34 (ii) RR = 1.56 (95% CI
1.34–1.82, P < 0.001, I2 = 44%) for studies performed
in the United States and Mexico,26,29,30,35,37
(iii) RR = 1.28 (95% CI 1.03–1.59, P = 0.02, I2 = 82%)
for studies performed in Asia27,36,42 and (iv) RR of
2.13 (95% CI = 1.04–4.35; P = 0.04, I2 = 20%) for stud-
ies performed in Africa.31,40
The third subgroup analysis compared cohort stud-
ies versus case–control studies (Figure S3). The five
included cohort studies showed a RR = 1.49 (95% CI
© 2020 Japan Society of Obstetrics and Gynecology
 Uterine fibroids and preterm birth

Figure 5 Risk ratios (RRs) for intrauterine fetal growth restriction (a), low birthweight (<2500 g) (b), infant Neonatal Inten-
sive Care Unit admission (c) in women with uterine fibroids as compared to women without them.

1.32–1.68, P < 0.001, I2 = 36%).26,33,35,39,40 Case–control Publication bias

studies presented a RR = 1.49 (95% CI 1.24–1.79,
P < 0.001, I2 = 66%).24,25,27–32,34,36,37,40,42
Risk of bias
Table S2 displays the assessment of the risk of bias
using the Newcastle-Ottawa Scale for cohort
(Table S2a) and case–control studies (Table S2b).
Both types of studies had a low risk of bias
(score ≥ 7).
Regarding the main primary outcome (risk of preterm
birth <37 weeks), the visual inspection of the funnel plot
does not suggest the presence of publication bias
(Figure S4).
Discussion
The present meta-analysis found that in studies with
moderate heterogeneity, women with UF were at

© 2020 Japan Society of Obstetrics and Gynecology 13

G. R. Pérez-Roncero et al.
higher risk of preterm birth before 37 weeks gestation;
in addition to preterm birth <34, 32 and 28 weeks.
Women with UF were significantly older and deliv-
ered earlier and had infants with lower birthweights.
Our study also found significant associations between
UF and threatened preterm labor, preterm premature
rupture of membrane, placental abruption, fetal mal-
presentation and cesarean deliveries with no differ-
ences found in rates of intrauterine fetal demise,
intrauterine fetal growth restriction and postpartum
hemorrhage.
This meta-analysis demonstrated that pregnant
women with UF were older with a mean difference of
2.40 years compared to gravid without such pathol-
ogy, which may be related to a certain degree of infer-
tility or implantation complications, lifestyle and
dietary factors.4,6,7
To date, no meta-analysis has analyzed the associa-
tion between UF and the risk of preterm birth before
37, 34, 32 and 28 weeks of gestation. Our inclusion
criteria were based on the demonstration of the pres-
ence of UF by ultrasound exam during the first or sec-
ond trimester of gestation. In general, UF may grow
during the first trimester, while growth during the
second and third trimester is very rare in order to pro-
duce obstetrical /perinatal complications.43,44 UF
growth may be related to the chorionic gonadotropin
secretion,45 although not significantly linked to the
risk of miscarriage.13 Pregnancy and delivery compli-
cations are usually more frequent in women aged
more than 30 years46; as was the case in the studies
we meta-analyzed.
Preterm birth (and related outcomes) can have mul-
tiple causes, such as infectious processes, iatrogenesis,
premature rupture of membranes, cervical incompe-
tence, contractions, polyhydramnios, uterine mal-
formations and probably uterine alterations linked to
the presence of UF, as analyzed in the present meta-
analysis. The mechanisms by which fibroids can
increase the risk of preterm birth are unclear. It is pos-
sible that UF can influence the placement and posi-
tioning of the uterus at the pelvic level causing
patterns of contractions or even partial compressions
of the uterine wall that cause ischemia. This situation
can lead to inflammatory and molecular signals that
enhance contractions and cervical modifications, as
well as an increased likelihood of premature rupture
of membranes.32,39,47
Although there is limited information, cervical
fibroids have the highest risk of growth during preg-
nancy when compared to other locations,44 and in
14
many cases be related in a higher rate to fetal mal-
presentation, obstructed labor, premature rupture of
membranes and higher cesarean delivery rates.16,48
Despite this, we did not find clear information regard-
ing UF localizations in order to perform a specific
sub-analysis. Other studies have also linked UF to
increased blood loss, uterine atony and the need for
emergent cesarean sections.38,49 Higher cesarean
section rates in women with UF can be explained in
several ways, but perhaps the main one is the greater
probability of fetal malpresentation and preterm
deliveries related to myomas. It is known that in cases
of prematurity or suspected lower fetal weight, the
probability of choosing a cesarean section as the safest
way of delivery usually increases.47,50 Gestations
achieved by assisted reproduction techniques may
also increase the cesarean delivery rates.48 However,
there were no pregnancies reported by such technolo-
gies in the meta-analyzed studies.
The present meta-analysis confirms some fetal com-
plications reported in observational studies related to
the presence of UF. Among the fetal outcomes, low
birthweight stands out. Low birthweight is mainly
related to the higher rate of prematurity. In some
studies, low birthweight rates are directly associated
with the higher rate of preterm birth, which in turn
carries a higher risk of being admitted to the Neonatal
Intensive Care Unit10 although we could not find this
association. Reduced fetal growth has been related to
placental implantation and UF location. Indeed,
Knight et al.51 studied the presence or absence of one
or more retroplacental UF during the second trimes-
ter. They found that infant birthweight was 177 grams
less in women with retroplacental UF, and those with
retroplacental UF of more than 4 cm of diameter had
a higher risk of delivering small for gestational age
infants as compared to women without UF. We could
not obtain independent or precise information related
to the UF presence and placental implantation site.
Although some studies have reported a higher inci-
dence of intrauterine fetal growth restriction and pla-
cental defects related to UF,30,31,35,41 our meta-analysis
could not find such association. Our data suggest that
low birthweight is related to preterm birth rather than
to fetal growth restriction as suggested by Lai et al.35
However, it is necessary to conduct studies analyzing
whether UF are in fact related to placentation
alterations.
Our study has some limitations concerning obstetric
complications and related newborn outcomes. Since
these were not our main objective, our conclusions
© 2020 Japan Society of Obstetrics and Gynecology

cannot, therefore, be generalized to these complica-
tions rather only to preterm birth. Hence, specific ana-
lyses are required for future studies. On the other
hand, another factor that can be associated with pre-
term birth is iatrogenesis. One should bear in mind
that UF can cause very intense painful conditions that
involve the admission of patients for observation and
treatment of pain.48,52 These painful conditions are
not related to the size, growth or location of UF;
therefore, any UF can influence the admission of a
pregnant woman with the possible associated iatro-
genesis that can even lead to inducing preterm labor.
The reported information about UF localization
was not sufficient to compare its link with preterm
birth and other related outcomes. Certain UF loca-
tions and sizes may have greater repercussions in pro-
cesses that may exert preterm birth, such as,
obstructive, inflammatory or configurative aspects. As
we have mentioned, although there are several pro-
cesses that can help explain the increased risk of pre-
term birth in women with myomas, birth before term
can occur regardless of tumoral size and location.47,53
Subgroup analyses showed similar trends as those
observed for the main outcome (preterm birth before
37 weeks). However, there were high degrees of het-
erogeneity in studies, including more than 250 women
with UF, in studies performed in Asia, and in case–
control studies. Some of these trends may be related
to the intrinsic populations and clinical scenarios,
their corresponding local health facilities and clinical
routines. Thus, results from registry sources may mix
heterogeneous clinical handlings or may use data that
were not addressed to the specific outcome of interest
of study.54
Our meta-analyses have some strengths, such as
the inclusion of clinical studies with small samples to
prevent publication bias. Studies based on small sam-
ples may be underpowered and produced the so-call
P-hacking effect.55–57 Finally, we cannot omit the
strength of our meta-analysis which is the inclusion of
articles published in indexed journals not only in
English but also in French,34,40 Spanish37 and
German.25
In conclusion, the presence of UF in pregnant
women increases the risk of preterm birth, threatened
preterm labor, premature rupture of membranes, pla-
cental abruption, malpresentation, cesarean deliveries
and low birthweight. We think that the details pres-
ented here will be useful for clinical practice and for
the designing of future studies with a better quality of
evidence.
© 2020 Japan Society of Obstetrics and Gynecology
Uterine fibroids and preterm birth
Acknowledgment
The authors would like to thank Ms. Montserrat Salas
for help with the literature search and Prof. Wieke
Bayer, from the Department of Modern Languages,
for the translation of one article in German language.
Disclosure
The authors have no conflicts of interest. This research
did not receive any specific grant from funding agen-
cies in the public, commercial, or non-for-profit
sectors.
Author contributions
GRPR, PC and FRPL contributed to the study concep-
tion and design. Material preparation, data collection
and analysis were performed by MTLB, LO, MJC and
PGC. Meta-analyses were performed by GRPR and
FRPL. The first draft of the manuscript was written
by FRPL and PC, and all authors contributed to the
final editing of the manuscript. All authors approved
the final version.
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© 2020 Japan Society of Obstetrics and Gynecology 17