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\begin{document}

\title{Uterine hemangioma in pregnancy: a case report and systematic review}



\author[1]{Emma Bauters}%
\author[2]{Michael Aertsen}%
\author[1]{Wouter Froyman}%
\author[3]{Johannes Van der Merwe}%
\affil[1]{Katholieke Universiteit Leuven UZ Leuven}%
\affil[2]{Universitaire Ziekenhuizen Leuven}%
\affil[3]{KU Leuven}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\selectlanguage{english}
\begin{abstract}
Objectives: This systematic review summarizes all published uterine
hemangioma cases in pregnant women. Search strategy: The databases
PubMed and Scopus were searched systematically. The reference lists of
all retrieved articles were also screened. Selection criteria: The
online tool Rayyan QCRI was used for registration of the selection
process. Articles reporting on cases of uterine hemangioma in pregnancy
were included, non-English articles were excluded. Data collection and
analysis: Data extraction was done by one reviewer and thereafter
verified by the second reviewer. All data were described in a narrative
format. Results: Fifteen case reports were included. In most cases, the
diagnosis was established by antenatal ultrasound and pregnancy course
was uneventful. More than half of the patients developed a postpartum
hemorrhage, necessitating a hysterectomy for bleeding control in four
cases, although the risk for both seemed lower in those patients in whom
the hemangioma was diagnosed before delivery. One case of maternal
mortality and two cases of fetal death were reported. There was one case
of neonatal respiratory morbidity, although the neonatal data were not
routinely reported upon. Conclusion: Current knowledge on uterine
hemangioma in pregnancy is limited, but it seems to hold substantial
risks for both mother and child. We recommend routine screening for this
condition at the standard mid-trimester anomaly scan. Pregnant women
with uterine hemangioma should ideally be cared for in centers of
expertise. An international registry will help to build a better
understanding of this rare pathology. Funding: None.%
\end{abstract}%



\sloppy


\textbf{Uterine hemangioma in pregnancy: a case report and systematic
review}

Bauters E\textsuperscript{1}, Aertsen M\textsuperscript{2}, Froyman
W\textsuperscript{1}, van der Merwe JL\textsuperscript{1,3}

\textsuperscript{1} Department of Obstetrics and Gynaecology, Division
Woman and Child, University Hospitals Leuven, Herestraat 49, 3000
Leuven, Belgium

\textsuperscript{2} Department of Radiology, University Hospitals
Leuven, Herestraat 49, 3000 Leuven Leuven, Belgium

\textsuperscript{3} Department of Development and Regeneration, Cluster
Woman and Child, Faculty of Medicine, KU Leuven University, Herestraat
49, 3000 Leuven, Belgium

Correspondence: Dr Johannes van der Merwe

UZ Leuven, Herestraat 49, 3000 Leuven, Belgium

E-mail: hannes.vandermerwe@uzleuven.be

Tel: +32 016 341732

\textbf{Running Title:} Uterine hemangioma in pregnancy

\emph{Abstract word count} : 250

\emph{Manuscript word count} : 1900

\textbf{Abstract}

\textbf{Objectives:} This systematic review summarizes all published
uterine hemangioma cases in pregnant women.

\textbf{Search strategy:} The databases PubMed and Scopus were searched
systematically. The reference lists of all retrieved articles were also
screened.

\textbf{Selection criteria:} The online tool Rayyan QCRI was used for
registration of the selection process. Articles reporting on cases of
uterine hemangioma in pregnancy were included, non-English articles were
excluded.

\textbf{Data collection and analysis:} Data extraction was done by one
reviewer and thereafter verified by the second reviewer. All data were
described in a narrative format.

\textbf{Results:} Fifteen case reports were included. In most cases, the
diagnosis was established by antenatal ultrasound and pregnancy course
was uneventful. More than half of the patients developed a postpartum
hemorrhage, necessitating a hysterectomy for bleeding control in four
cases, although the risk for both seemed lower in those patients in whom
the hemangioma was diagnosed before delivery. One case of maternal
mortality and two cases of fetal death were reported. There was one case
of neonatal respiratory morbidity, although the neonatal data were not
routinely reported upon.

\textbf{Conclusion:} Current knowledge on uterine hemangioma in
pregnancy is limited, but it seems to hold substantial risks for both
mother and child. We recommend routine screening for this condition at
the standard mid-trimester anomaly scan. Pregnant women with uterine
hemangioma should ideally be cared for in centers of expertise. An
international registry will help to build a better understanding of this
rare pathology.

\textbf{Funding:} None.

\textbf{Key words:} hemangioma; uterine; pregnancy; case report; review

\textbf{Tweetable abstract}

Uterine hemangioma holds substantial risks for both mother and child
during pregnancy.

\textbf{Introduction}

Hemangiomas are benign vascular tumors that originate from either
endothelial cells lining the vessels or pericytes that are found outside
the vascular wall.\textsuperscript{1} They consist of multiple
anastomosing vessels lined by a single layer of endothelium. Hemangiomas
are named `capillary' when they are composed of small size capillary
vessels, and `cavernous' if they consist of large anastomosing vascular
spaces (`caverns').\textsuperscript{1--5} They rarely occur in the
uterus and the exact incidence of uterine hemangioma is unknown.
Hemangioma can be found at all levels of the uterine wall, although most
cases involve the myometrium.\textsuperscript{6} The lesion has been
described in various age groups and is known to have many heterogenous
clinical presentations, commonly reported in the context of obstetric
complications.\textsuperscript{1--3}

Current literature on uterine hemangioma in pregnancy mainly consists of
case reports. The hormonal and physical changes of pregnancy have been
proposed to affect these pre-existing lesions. The most reported
complication is peripartum hemorrhage which can be
life-threatening.\textsuperscript{2,7} Diagnosis is often made on
hysterectomy specimens or more recently through antepartum imaging, by
ultrasound (US) and/or magnetic resonance imaging
(MRI).\textsuperscript{8}

Herein we present a recent case in our tertiary care center followed by
a systematic review of all published uterine hemangioma cases in
pregnant women.

\textbf{Case report}

A 30-year-old nulliparous patient was referred to our center, University
Hospitals Leuven, for a suspicion of a molar pregnancy. The patient had
an unremarkable medical and familial history. On initial ultrasound
examination, an intrauterine pregnancy with crown-rump length (CRL)
corresponding to a gestational age of 8 weeks 4 days was seen. The
trophoblast appeared normal, but the myometrium was overall diffusely
thickened due to venous plexuses that contained low flow
rates\textbf{(figure 1)} . The presumptive diagnosis of a uterine
hemangioma was confirmed on MRI at 10 weeks of gestation that
demonstrated marked T2-hyperintens, T1-hypointens and non-diffusion
restrictive enlargement of the entire myometrium enclosing multiple
vessels \textbf{(figure 2)} .

The course of the pregnancy was rather uneventful, except for a minor
bleeding episode at 13 weeks of pregnancy and a short admission at 28
weeks due to a single episode of nonspecific lower abdominal pain. The
sonographic appearance of the myometrium remained unchanged during
pregnancy \textbf{(figure 3)} . The patient was hospitalised from the
36\textsuperscript{th} week of pregnancy onwards for observation to
address the increased intra- and postpartum bleeding risk.

At 38 weeks and 5 days, labour was induced by means of prostaglandin E2
administration and subsequent artificial rupture of the membranes. This
was followed by oxytocin labour augmentation and a spontaneous vaginal
delivery of a healthy son weighing 2835 grams. Apgar scores were 9/10/10
and umbilical artery pH was 7.29. Intravenous carbetocin 100 \selectlanguage{greek}µ\selectlanguage{english}g and
tranexamic acid 1 g were administered immediately, but within minutes a
primary postpartum hemorrhage occurred with the placenta still in-utero.
Sulprostone 500 \selectlanguage{greek}µ\selectlanguage{english}g perfusion was initiated, and a manual removal of the
placenta was done. Additionally, a gentle curettage was performed to
remove some retained membranes after which the uterus atony resolved,
and the bleeding ceased. The total blood loss was estimated to be 1200
mL. Both the mother and newborn had an unremarkable postpartum course.
Prophylactic postpartum low-molecular-weight heparin was continued for 6
weeks. After 3 months the myometrial hemangioma was markedly regressed
on ultrasound. A whole-body MRI performed 8 months after delivery
additionally noted a small 11 mm hemangioma in the liver segment 7.

Written consent was obtained from the patient whose case is presented
above.

\textbf{Methods}

The protocol for this systematic review was prospectively registered on
The International Prospective Register of Systematic Reviews (PROSPERO,
registration number CRD42021237519). We reported it according to the
Preferred Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA) statement.\textsuperscript{9}

\emph{Types of studies}

We included case reports, case series, randomized studies, and case
control studies. All articles of other types (systematic reviews,
narrative review articles and studies published only as abstracts) were
excluded. Non-English articles were also excluded, except for those with
an English abstract that already provided the primary outcomes.

\emph{Types of participants}

Study participants were pregnant women with a hemangioma of the uterine
corpus, diagnosed either before, during or directly after pregnancy.
Articles reporting on non-pregnant women with uterine hemangioma that
provided information on their obstetrical antecedents were also
included.

\emph{Outcomes}

The primary outcomes were maternal and neonatal (until discharge)
mortality and morbidity. Secondary outcomes were the occurrence of
pregnancy complications, preterm delivery rate, perinatal blood loss,
perinatal hysterectomy incidence and neonatal ICU-admission.

\emph{Search strategy}

We searched the electronic databases PubMed and Scopus from their
inception until 21 February 2021 using the following search terms:
``((hemangioma) OR (cavernous) OR (vascular malformation)) AND
(pregnancy) AND (uterus)''. We also screened the reference list of all
retrieved articles to identify additional eligible articles not captured
by our electronic search, thereby identifying 2 additional case reports.

\emph{Process of study selection, data extraction and risk of bias
assessment}

The online tool Rayyan QCRI was used for registration of the selection
process.\textsuperscript{10} Duplicate articles were automatically
excluded. Two assessors independently screened all titles and abstracts.
Eligible articles were retained for full-text reading. Uncertainties at
each stage were discussed and resolved by consensus with a low threshold
for inclusion.

One reviewer extracted all data on pregnancy course and complications
occurring during delivery and the postpartum period, which was
thereafter verified by the second reviewer. Uncertainties at each stage
were again discussed and resolved by consensus. All data were described
in a narrative format.

\textbf{Results}

Of the initial 476 identified articles, 23 full text articles were
assessed for eligibility. Eventually, 15 case reports were included in
this review \textbf{(figure S1)} . Baseline patient characteristics,
clinical presentation, mode of diagnosis, pregnancy course and the
maternal and neonatal outcomes in the 15 pregnancies described in these
articles are given in \textbf{table S1 and S2.}

Of the 15 pregnancies, two (2/15, 13.3\%) resulted in a stillbirth
possibly due to the uterine hemangioma. The first one occurred at 28
weeks after massive thrombosis of the uterine and placental vessels, the
latter following acute rupture of the uterine hemangioma at 36 weeks.
Another two pregnancies were delivered preterm (2/15, 13.3\%). One
patient delivered at 35 weeks after preterm prelabour rupture of the
membranes (PPROM) at 26 weeks, and a second patient had a cesarean
section at 30 weeks due to progressive abdominal discomfort and the
assumed bleeding risk of the hemangioma. Forty percent of women (6/15,
40.0\%) went into labour spontaneously, which resulted into a vaginal
delivery in four cases. Most patients were delivered by cesarean section
(10/15, 66.7\%), of which seven (7/10, 70\%) were unplanned/in an
emergency setting. The postpartum period was complicated by a hemorrhage
in eight women (8/15, 53.3\%), which necessitated a hysterectomy in four
cases (4/8, 50\%). Two women developed progressive hypovolemic shock
(2/8, 25\%). Of those for whom data was provided (5/8, 62.5\%), all had
an estimated blood loss of [?] 1000 mL. Furthermore, another two patients
developed a pulmonary embolism in the postpartum period, ultimately
fatal in one of them. Perinatal outcomes were mentioned in only six
reports (6/15, 40\%). Only half of these cases (3/6, 50\%) had an
uneventful outcome. One case of respiratory problems due to preterm
birth at 30 weeks was described beyond the two stillbirths mentioned
above.

The hemangioma was diagnosed before delivery in the majority of cases
(10/15, 66.7\%), generally during the second trimester of pregnancy.
Most often, symptoms such as abdominal discomfort, dyspnea, or vaginal
bleeding and/or the finding of an enlarged uterus led to a work-up. Four
patients were referred for abnormal ultrasound findings, which in all
but one case were suspicious for a partial mole. The antenatal diagnosis
was generally based on ultrasound findings, MRI was used to confirm the
hemangioma in only one patient.

Half of the patients (5/10, 50\%) with an established diagnosis of
hemangioma before delivery had a non-planned cesarean section. In two of
these patients (2/5, 40\%), this was for reasons related to the
hemangioma: one patient had a cesarean section for fetal death at 28
weeks and another patient was delivered at 30 weeks due to progressive
abdominal discomfort as mentioned earlier. Five of the 10 antenatal
diagnosed patients (5/10, 50\%) developed a postpartum hemorrhage, which
necessitated a hysterectomy in only one of them. Among the patients with
an antenatal diagnosis of a uterine hemangioma, one more patient
underwent a hysterectomy at 17 weeks because of recurrent syncopes and
the presumed risk of uterine rupture.

These numbers contrast with the undiagnosed group in which three out of
the five patients (3/5, 60\%) had a postpartum hemorrhage and a
hysterectomy was necessary in all of them (3/3, 100\%). There were no
cases of maternal mortality in the group of antenatal diagnosed
patients.

\textbf{Discussion}

\emph{Main findings}

Our literature search identified 15 cases of uterine hemangioma during
pregnancy. High rates of complications were encountered in these women,
particularly peripartum hemorrhage that in some cases even necessitated
a hysterectomy. Above and beyond the clear maternal risks, there is also
significant fetal-neonatal morbidity.

\emph{Strengths and limitations}

As far as we know, this is the first systematic review reporting on
uterine hemangioma and pregnancy outcomes. We have adopted the
international PRISMA guidelines in our study methodology. Since it is
clear from this review that uterine hemangioma can go unnoticed during
pregnancy, it begs the questions whether there is an underreporting of
uncomplicated outcomes.

\emph{Interpretation (in light of other evidence)}

As this is the first systematic review on uterine hemangioma in
pregnancy, a comparison of our findings with literature is difficult.
Establishing the diagnosis of a uterine hemangioma before delivery seems
beneficial for maternal outcome, as we found a lower number of
postpartum hemorrhages and peripartum hysterectomies in this patient
group. This highlights the importance of delivery planning to anticipate
the peripartum bleeding risk. On the one hand, antenatal diagnosis is
relatively straightforward and can be made by standard 2D ultrasound.
Once identified the patient can be referred to a tertiairy care center
for more comprehensive care. On the other hand however, this could lead
to overtreatment, as in the case where a hysterectomy was performed at
17 weeks of gestation because of the assumed risk of uterine rupture.
Furthermore, subsequent pregnancies may lead to more morbidity since
four of the included patients were multiparous and half of them
developed a severe postpartum hemorrhage with the need for hysterectomy.
Data on obstetrical antecedents were provided for only one patient, who
had an uneventful pregnancy followed by a spontaneous post-term delivery
complicated by placental retention and a postpartum
hemorrhage.\textsuperscript{17}

\emph{Future perspective}

Data are currently too limited to provide clear guidelines for diagnosis
and management of uterine hemangioma in pregnant women. It is also
unclear whether additional imaging beyond standard 2D ultrasound adds
any value. Therefore, we strongly recommend the establishment of an
international registry for uterine hemangioma in pregnancy to obtain
better knowledge on this subject.

\textbf{Conclusion}

Although our current knowledge on uterine hemangioma during pregnancy is
limited to 15 case reports, the condition seems to hold substantial
risks for both mother and child. Therefore, these pregnancies should
ideally be followed-up and cared for in centers of expertise. Routine
screening for this clearly visible condition is feasible and possibly
sufficient at the standard mid trimester anomaly scan. We feel all
obstetricians and sonographers should at least eyeball the uterus during
this evaluation. An international registry for uterine hemangioma in
pregnancy would be of great value to obtain better knowledge on this
subject and could serve as a basis for the development of clinical
management guidelines.

\textbf{Funding Details}

The author(s) received no specific funding for this work.

\textbf{Declaration of interest statement}

No potential competing interest was reported by the authors.

\textbf{Author contribution}

All authors have contributed to the writing of this paper. EB and JvdM
performed the literature search, extracted the data and merged corrected
work.



\textbf{References}

1. Bhavsar T, Wurzel J, Duker N. Myometrial cavernous hemangioma with
pulmonary thromboembolism in a post-partum woman: A case report and
review of the literature. J Med Case Rep 2012;6:397.

2. Aka KE, Horo GA, Fomba M, Kouyate S, Koffi AK, Konan S et al. A rare
case of important and recurrent abnormal uterine bleeding in a post
partum woman caused by cavernous hemangioma: A case report and review of
literature. Pan Afr Med J 2017;28:130.

3. Chou WY, Chang HW. Uterine hemangioma: A rare pathologic entity. Arch
Pathol Lab Med 2012;136(5):567--71.

4. Virk RK, Zhong J, Lu D. Diffuse cavernous hemangioma of the uterus in
a pregnant woman: Report of a rare case and review of literature. Arch
Gynecol Obstet 2009;279(4):603--5.

5. Comstock CH, Monticello ML, Johnson TW, Wechter D. Cavernous
Hemangioma: diffuse enlarged venous spaces within the myometrium in
pregnancy. Obstet Gynecol 2005;106(5 Pt 2):1212-4

6. Benjamin MA, Yaakub HR, Telesinghe PU, Kafeel G. A rare case of
abnormal uterine bleeding caused by cavernous hemangioma: a case report.
J Med Case Rep 2010;4:136.

7. Djunic I, Elezovic I, Ljubic A, Markovic O, Tomin D, Tadik J. Diffuse
cavernous hemangioma of the left leg, vulva, uterus, and placenta of a
pregnant woman. Int J Gynecol Obstet 2009;107(3):250-1.

9. Thanner F, Suetterlin M, Kenn W, Dinkel HP, Gassel AM, Dietl J et al.
Pregnancy-associated diffuse cavernous hemangioma of the uterus. Acta
Obstet Gynecol Scand 2001;80(12):1150--1.

10. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting
items for systematic reviews and meta-analyses: The PRISMA statement.
BMJ 2009; 339:b2535

11. Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan-a web and
mobile app for systematic reviews. Syst Rev 2016; 5(1):210..

12. Dawood MY, Teoh ES, Ratnam SS. Ruptured haemangioma of a gravid
uterus. J Obstet Gynaecol Br Commonw 1972;79(5):474-5.

13. Gallegos SA, Gaona JMG, Torres BV, Sosa SEI, P\selectlanguage{ngerman}érez MÁS, Huerta MEG.
{[}Diffuse cavernous hemangioma of the uterus diagnosed during
pregnancy. Case report{]} Ginecol Obstet Mex 2011;79(7):447--51.

14. Lotgering FK, Pijpers L, van Eijck J, Wallenburg HCS. Pregnancy in a
patient with diffuse cavernous hemangioma of the uterus. Am J Obstet
Gynecol 1989;160(3):628--30.

15. Milton PJ, Thonet RG. Myometrial Haemangioma a Rare Cause of Severe
Menorrhagia Case Report. Br J Obstet Gynaecol 1981;88(10):1054-5.

16. Reiffenstuhl G. {[}Diffuse cavernous myometric angiomatosis of the
pregnant uterus and its clinical significance{]}. Geburtshilfe
Frauenheilkd 1984;44(9):579--82.

17. Sütterlin MW, Müller T, Rehn M, Rempen A, Dietl J. Successful
abdominal delivery in a woman with sonographic diagnosis of diffuse
cavernous hemangioma of the uterus. Am J Perinatol 1998;15(7):423--5.

18. Uotila J, Dastidar P, Martikainen P, Kirkinen P. Massive multicystic
dilatation of the uterine wall with myometrial venous thrombosis during
pregnancy. Ultrasound Obstet Gynecol 2004;24(4):461--3.

19. Weissman A, Talmon R, Jakobi P. Cavernous hemangioma of the uterus
in a pregnant woman. Obstet Gynecol 1993;81(5):825--7.\selectlanguage{english}
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