Italian Journal of Gynaecology & Obstetrics · Circulating cell-free DNA in cancer management...

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GynaecologyItalian Journal

of

The Official Journal of theSocietà Italiana di Ginecologia e Ostetricia

(SIGO)

Quarterly

& Obstetrics

Partner-Graf

Dec

embe

r 201

7 - V

ol. 2

9 - N

. 4 -

ISSN

238

5 - 0

868

Gynaecology

Italian Journalof

The Official Journal of theSocietà Italiana di Ginecologia e Ostetricia

(SIGO)

Quarterly

& Obstetrics

Partner-Graf

Editor in Chief

Vizza Enrico, Roma

Editors

Ghezzi Fabio, VareseParazzini Fabio, Milano

Editorial Board

Chiantera Vito, PalermoChiofalo Benito, MessinaCorrado Giacomo, RomaDe Franciscis Pasquale, NapoliErcoli Alfredo, NovaraFanfani Francesco, ChietiFerati Maurizio, VareseGallotta Valerio, RomaGambacciani Marco, PisaJorizzo Gianfranco, VicenzaMeroni Mario, MilanoRossitto Cristiano, RomaScibilia Giuseppe, CataniaSoligo Marco, Milano Solima Eugenio, MilanoSurico Daniela, NovaraSvelato Alessandro, MilanoTrojano Giuseppe, BariVignali Michele, Milano

Editorial Staff

Zerbinati Roberto Zerbinati Serena

Management, Administrative officePartner-Graf Srl - Via F. Ferrucci, 73 - 59100 PratoTel 0574 527949 - Fax 0574 636250E-mail: [email protected]

The Italian Journal of Gynaecology & Obstetrics is a digital magazine.You can download it freely from:www.italianjournalofgynaecologyandobstetrics.comor www.italianjog.com

It. J. Gynaecol. Obstet.2017, 29: N.4

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Table of contents

EditorialCirculating cell-free DNA in cancer managementEnrico Vizza

Heterotopic pregnancy: intrauterine and omental implantation. Case reportNicola De Frenza, Giovanni Magnifico

Quadruplet pregnancy after ovarian stimulation: the role of the counseling program to avoid dangerous pregnanciesMichele Fichera, Gaetano Valenti, Simona Taschetta, Marta Grazia Li Destri, Serena D’Amico,Lisa Caldaci, Martina Ferrara, Fabrizio Sapia, Marco Marzio Panella

Otocephaly: a case postnatal diagnosedAstrit M. Gashi, Jakup Ismajli, Curr Gjocaj, Xhevdet Gojnovci

Restless legs syndrome in pregnancy and risk of gestational hypertension in a low risk populationGiovanna Esposito, Francesca Chiaffarino, Vanessa Odelli, Lucrezia Romiti,Mirella Di Martino, Fabio Parazzini

Guidelines for diagnosis and treatment of fibromyomatosisGiancarlo Conoscenti, Attilio Di Spiezio Sardo, Caterina Exacoustos, Antonio Maiorana,Lucia Manganaro, Yoram Jacob Meir, Fabio Parazzini, Sergio Schettini, Michele Vignali,Enrico Vizza, Fulvio Zullo, Errico Zupi

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It. J. Gynaecol. Obstet.2017, 29: N. 4

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Editorial

Circulating cell-free DNA in cancer management

Circulating cell-free DNA (cfDNA) is defined as extracellular DNA occurring in blood serum or plasma. CfDNA provides rapid, cost-effective, and non-invasive “liquid biopsy” surrogates, and is considered as a potential biomarker for the detection and monitoring of various human diseases, such as stroke, myocardial infarction, sepsis, as well as some chronic conditions such as cancer. CfDNA molecules are double-stranded molecules with low molecular weight than genomic DNA, in the form of short fragments (between 70 and 200 base pairs in length) and/or long fragments up to 21 kb. Cell death is suggested to be the major source of cfDNA. Under normal physiologic circumstances, apoptotic and necrotic cells are cleared by infiltrating phagocytes and cfDNA levels are relatively low. Usually, cfDNA is removed from blood by liver and kidney, and its half-life is 10 to 15 min. Nevertheless, not all cfDNA originates from cell death. Live cells spontaneously release newly synthesized DNA as part of a homeostatically regulated system.

Cancer patients generally have much higher levels of cfDNA than healthy individuals, but the levels vary widely, from 0.01% to more than 90%. CfDNA content rapidly increased accumulation in blood during tumor development is caused mainly by an excessive DNA release by apoptotic and necrotic cells. The variability of cfDNA levels in cancer patients likely associates with tumor burden, stage, vascularity, cellular turnover, and response to therapy. It is worth to note that cfDNA content is elevated in various other disorders, such as infectious and autoimmune diseases, stroke, infarction and trauma, thus specific approaches and accurate methodologies are needed to discriminate the source of cfDNA.

For blood-based genomic profiling and detection of minute amounts of cfDNA deriving specifically from tumour tissues new technologies have been developed, such as Next Generation Sequencing (NGS) and Droplet Digital PCR (ddPCR), but these require proof-reading measures to avoid artefacts and needs to be controlled very well to minimize bias. However, the presence of very low amounts of cfDNA in blood samples from early-stage cancer patients, and assessment of the possible clinical significance of the resulting data, is still a challenge. There are also several technical difficulties challenging the practical application of kind of analysis in cancer screening, mainly because of the technical complexity and high cost associated.

Recently, new methodologies for accurate cfDNA measurements directly from plasma or serum have been developed, such as the cfDNA staining using specific fluorochromes and Alu-quantitative real-time PCR (qPCR). These methods do not require prior DNA purification, overcoming artifacts associated with DNA isolation, and may represent simple and not expensive novel clinical tools for routine patient management.

Challenges for routine implementation of liquid biopsy tests include the necessity of development of a multi-marker approach that takes into account the source of cfDNA and the correlation between the quality and the quantity of cfDNA, and clinic-pathological features of cancer patients. Further analysis are needed in order to better optimize the accuracy and reliability of cfDNA measurements and validate it as a useful, non-expensive and non-invasive tool for guiding personalized cancer therapy.

Finally, future orientations should include the cost assessment, the accuracy and reproducibility of liquid biopsy in comparison with current “solid biopsy” performance to provide clinically important actionable information for precision oncology approaches.

Prof. Enrico VizzaEditor in Chief

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Heterotopic pregnancy: intrauterine and omental implantation.Case reportNicola De Frenza1, Giovanni Magnifico1

1 Department of Obstetrics & Gynecology Madonna delle Grazie Hospital, Matera, Italy

ABSTRACTHeterotopic pregnancy (HP) is defined as the simultaneous presence of intrauterine and extrauterine pregnancy. This is a rare obstetrical condition, first described by Duverney in 1708, potentially very dangerous for mother and for pregnancy. The incidence of HP, in spontaneous pregnancies, is around 1:15000 to 1:30000 but it is higher in assisted pregnancy. 98% of all extrauterine pregnancy are intratubal, 1% is ovarian, the rest are primary or secondary peritoneal implantations. The implantation can occur anywhere in the abdomen including ligaments, liver, omentum, spleen. Omental pregnancy is the least common form of abdominal pregnancy. More than 50% of all HP cases can remain totally asymptomatic till it is discovered occasionally by a routine first trimester ultrasound. The most important risk factors are assisted pregnancy, previous tubal pregnancy and pelvic inflammatory disease. We report a very rare case of HP with primary omental implantation of the extrauterine pregnancy after spontaneous conception. We performed a laparoscopy to diagnose and treat the HP and then obtaining, for the intrauterine pregnancy, a term live baby born by spontaneous vaginal delivery. We suggest, after a discussion on physiopathology and diagnosis, the laparoscopic management of HP especially in early abdominal implantation: in this case the mininvasive approach is safe and feasible permitting to preserve mother health and intrauterine fetus.

Key words: heterotopic pregnancy, abdominal pregnancy, diagnosis, laparoscopic surgery.

Corresponding Author: Dr. Nicola De [email protected] 2017, Partner-Graf srl, PratoDOI: 10.14660/2385-0868-76

Gynaecology & ObstetricsItalian Journal of

December 2017 - Vol. 29 - N. 4 - Quarterly - ISSN 2385 - 0868

SOMMARIOPer gravidanza eterotopica (GE) si intende una gravidanza insorta simultaneamente in sede intra ed extrauterina. Si tratta di una rara condizione ostetrica, descritta per primo da Duverney nel 1708, potenzialmente molto pericolosa per la madre e per la gravidanza stessa. L’incidenza di GE, in gravidanze spontanee, è compresa tra 1: 15000 e 1: 30000 ma è ben più elevata nelle gravidanze assistite. Il 98% di tutte le gravidanze extrauterine è in sede intratubarica, 1% in sede ovarica, le restanti sono impianti peritoneali primari o secondari. L’impianto può verificarsi in qualsiasi parte dell’addome compresi legamenti, fegato, omento e milza. La gravidanza omentale è la forma meno comune di gravidanza addominale. Più del 50% di tutti i casi di GE decorre in modo totalmente asintomatico sino a quando non è diagnosticata occasionalmente durante una ecografia di routine del I trimestre. I più importanti fattori di rischio sono una gravidanza assistita, una precedente gravidanza tubarica e la malattia infiammatoria pelvica. Riportiamo un caso molto raro di GE con impianto primitivo omentale della gravidanza extrauterina dopo concepimento spontaneo. Abbiamo eseguito una laparoscopia per diagnosticare e trattare la GE ottenendo poi, per la gravidanza intrauterina, la nascita, con parto spontaneo, di un neonato vivo a termine. Dopo una discussione su fisiopatologia e diagnosi della GE, proponiamo un approccio laparoscopico per questa patologia, soprattutto negli impianti precoci, in cui la gestione minivasiva si è dimostrata sicura e fattibile permettendo la preservazione della salute della madre e del feto in sede intrauterina.


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Heterotopic pregnancy: intrauterine and omental implantation. Case report.

INTRODUCTIONHeterotopic pregnancy (HP) is defined as

the simultaneous intrauterine and extrauterine pregnancy. HP is a rare obstetrical condition first described by Duverney (1) in 1708 during an autopsy on a patient who had died of a ruptured ectopic pregnancy. DeVoe and Pratt (2) were the first to determine the incidence of this pathology: it was, in spontaneous pregnancies, around 1:15000 to 1:30000. In the western world, the incidence was increased to 1:10000 due to ovulation-induction therapy and medical assisted procreation (MAP) with superovulation and relative increased incidence of ectopic pregnancies (3).

The incidence of HP is 400 times greater in assisted pregnancy than in natural pregnancies (4). In the last decades a 3-fold increase of incidence of bilateral tubal pregnancy as well as HP has been observed mainly related to assisted reproduction technique (5). In 2015, Perkins and Al. (6) believed in an incidence up to 1:100 in patients who have MAP. In assisted pregnancy with unreasonable transfer of more then four embryos, the risk of HP has been reported as high as 1:45 (7,8). 98% of all extrauterine pregnancy are intratubal, 1% is ovarian, the rest are primary or secondary peritoneal implantations. Implantation can occur anywhere in the abdomen including ligaments, liver, omentum, spleen. The omental pregnancy is the least common form of abdominal pregnancy.

A review of literature based on medline search for period 1958-2012 reported 16 cases of omental pregnancy (9) and for period 2013-2016 we founded only 8 new cases. Very few of all reported cases have been treated using laparoscopy (10). Secondary peritoneal ectopic pregnancy implantation can occur not only after tubal rupture or expulsion of tubal ectopic pregnancy but also after primary implantation (10).

General agreement exists as the possibility of human superfecundation (two ovulations and conceptions in the same menstrual cycle) and superfetation (two conceptions in two different cycles). Winer et Al. (11) suggested that the pathogenesis of HP could be due to modification of tubal peristalsis caused by hormonal changes. Another possibility mentioned by the same Authors was a transperitoneal migration due to the condition that the impregnated ovum becomes too large for the tubal lumen. Pelvic inflammatory disease (PID) and its sequelae can play an important role in the etiology of HP, particularly Chlamydia infection as well as the widespread use of IUD, because PID can change the tubal lumen and tubal peristalsis and can stop the

ovum progression. Black women have more risk of HP probably because of their high incidence of ectopic pregnancy and more frequent occurence of twin pregnancies. The high incidence of PID in this population group can play also a role in the higher occurance rate. Other important risk factors are previous tubal pregnancy, tubal sterilization, tubal infertility, tubal reconstructive surgery and progesterone contraceptive pill. Endometriosis has also been associated with the development of HP because it can inhibit tubal motility, it can cause adhesions and persistent endometrial deposits. High estrogen concentrations after ovulation induction may also disturb the tubal transport.

Ectopic pregnancy remains the leading cause of maternal death in the first trimester and accounts for 10% to 15% of all maternal deaths (12) but, in abdominal pregnancy, maternal mortality is higher with a range between 0.5 and 30% and with a significant fetal morbidity and mortality (13). The risk of maternal death in an abdominal pregnancy (AP) is 7.7 times higher than tubal pregnancy and 90 times higher than intrauterine pregnancy (14,15) and this is principally because of the risk of massive hemorrhage from incomplete or entire placental separation.

Nowadays in AP the maternal mortality rate has decreased due to earlier diagnosis of HP instead of the perinatal mortality that registers a higher value of about 40% up until 83-95%. However, with advanced pregnancy and if the fetus is surrounded by a normal volume of amniotic fluid, fetal outcome tends to be better and thanks to the progress of neonatology, the survival rate of fetuses over 30 weeks has grown at about 78-80% (13,16). The most common cause of fetus death is massive hemorrhage caused by partial or total placental separation which can occure anytime during pregnancy. Furthermore, in AP there is a very high percentage of fetal malformations, retarded physical and mental development. A literature review of HP showed a survival rate of 50 to 66% for intrauterine fetus (16).

CASE REPORTA 29-year-old black women, coming from

Nigeria, was admitted to our Emergency Department of Obstetrics & Gynaecology for persistent abdominal pain. She was gravida 5, para 3013, at 7 weeks and 5 days of gestation. She came ten days early to our Department for pelvic pain and she has been diagnosed with

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Nicola De Frenza et al.Heterotopic pregnancy: intrauterine and omental implantation. Case report.

intrauterine pregnancy corresponding to period of amenorrhea.

When the patient was admitted to the Hospital, she was in stable condition: blood pressure was 120/80 mmHg, heart frequency was 80 beats/minute, temperature was 36.5°C, hemoglobin was 11.5 g/dl, white blood cells were 6.51 x 10^3/ml. Abdominal examination revealed pain in the sovrapubic region with a Blumberg sign ++- and, during vaginal examination, the patient felt pain at pouch of Douglas. No adnexal masses were appreciated, no pain revealed at cervical mobilization and vaginal bleeding was absent. Transvaginal ultrasonography showed an HP with a vital intrauterine pregnancy (crown rump length 14 mm.) and an ectopic empty gestational sac (mean diameter 28 mm.) probably located in the right Fallopian tube. Free liquid fluid was also seen in the pouch of the Douglas. 45 minutes after hospital admission, the patient underwent to a laparoscopy. The intraoperative vision (Figure 1) showed about 400cc. of hemoperitoneum, both ovaries and Fallopian tubes were normal without any sign of ectopic pregnancy and the uterine size was corresponding to amenorrhea but on the omental border we founded a dark bleeding mass of 4 cm. in size: the ectopic pregnancy! (Figure 2).

We performed, after the aspiration of hemoperitoneum, a partial omentectomy using harmonic scalpel. The specimen was extracted with an endobag and a Jackson-Pratt drainage was placed into the Douglas pouch. The total operative time was 47 minutes (Figure 3).

After the surgery, an ultrasound examination was performed to evaluate fetal viability and placenta status of the intrauterine pregnancy.

The postoperative course of the patient was uneventful: she was always apyretic and blood transfusion wasn’t necessary. 12 hours after laparoscopy we removed the Foley catheter. The patient was discharged 3 days later. The hysto-pathological examination of the partial omentectomy specimen confirmed the diagnosis of primary omental ectopic pregnancy with trophoblastic cells invasion into omental tissue (Figure 4).

With regards to the intrauterine pregnancy, the patient has delivered vaginally a healthy live baby at term.

Figure 1. Intraoperative view.

Figure 3. Postoperative view.Detail of intact right tube and residual omentum.

Figure 4.Histo-pathological examination of omental tissue showed trophoblastic cells implantation.

Figure 2. Omental heterotopic pregnancy.


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DISCUSSIONIn 1942 Studdiford (17) defined the criteria

for primary diagnosis of abdominal pregnancy: normal bilateral fallopian tubes and ovaries, absence of uteroperitoneal fistula and presence of a pregnancy on peritoneal surface exclusively. In 1968 Friedrich and Rankin (18) proposed modifying Studdiford’s criteria to a presence of a pregnancy of less than 12 histological gestational week (g.w.) in order to limit the cases of primary abdominal pregnancy.

The diagnosis of early HP remains nowadays a clinical problem. Most cases of HP are diagnosed between the 5th and 34th g.w.: 70% of cases are diagnosed between the 5th and 8th g.w., 20% between 9th and 10th g.w. and the remaining 10% after 10th g.w. (19,20). More than 50% of all HP cases can remain totally asymptomatic till it is discovered occasionally by a routine first trimester ultrasound. Early diagnosis is very difficult and it can happen more frequently if the clinician has a high index of suspicion (5). Reece et Al. (3) defined four common symptoms and findings: abdominal pain, adnexal mass, peritoneal irritation and increase size of uterus. The symptoms of HP are various and not pathognomic: the pre-operative diagnosis was made only in 2.6 – 9.9% of all cases (13,21). Vaginal bleeding is more frequent in tubal pregnancy versus HP due of intact endometrium of intrauterine pregnancy (21).

We can observe four main clinical situations:1) the diagnosis of HP is made during thesurgery or later;2) after an abortion we have an unexpectedrupture of an ectopic pregnancy, verydangerous group;3) simultaneous interruption of both extraand intrauterine pregnancy and in this case, theabortion symptoms are dominant;4) both pregnancies grow up, very rare.

B-hcg serum level measurement is not useful for diagnosis because the intrauterine pregnancy will be producing normal and increasing levels of serum B-hcg and then, the B-hcg serum level, can be unreliable and mislead the diagnosis (4,5,22). A higher than expected level of serum B-hcg, in relation to gestational age, may be suspicious of HP although the presence of a complete or partial mole must also be considered.

For an early diagnosis of HP we suggest to make a careful anamnesis in order to highlight risk factors (black race, previous ectopic pregnancy, PMA, etc.) and to perform an accurate

abdominal and vaginal examination and also an ultrasonography with abdominal and vaginal probes. Ultrasound when coupled with clinical evaluation has approximately a 50% success rate in the diagnosis (23). Transvaginal pelvic ultrasonography makes a correct diagnosis in 88.9% of cases and differential diagnosis should be made with ovarian cyst, pedunculated uterine fibroid undergoing necrobiosis, hydrosalpinx, twisted adnexa, ovarian tumor or hemorrhagic corpus luteum. The ultrasound diagnosis of early abdominal pregnancy is more difficult versus tubal pregnancy and the reported diagnostic error rates, in different series, have ranged from 50 to 90% (24). The abdominal localization of the ectopic pregnancy is very rare, particularly on the omental site, and it is very difficult to diagnose only with abdominal ultrasound examination especially if it is in an early gestational age. It can be useful to perform a computed tomography (CT) or a magnetic resonance (MR) scan. Pregnant women generally do not undergo CT examination due to radiation. On CT scan, an intrabdominal extrauterine gestational saclike structure with an enhancing rim can be seen but, in any case, CT generally provides a less detailed placental evaluation (25). MR can be more useful because it can diagnose an abdominal pregnancy but also locate the position of the placenta and it can assess placental adherence to surrounding organs which will significantly contribute to the development of treatment plan (26,27). MR, also, has many advantages over ultrasound as bone, gas-filled structures and maternal obesity provides no hindrance to imaging.

Whenever a diagnosis remains unclear, laparoscopy is very useful for a correct diagnosis of HP with a low risk for the intrauterine pregnancy permitting, in the same time, the treatment of the pathology. Clinicians should mantain a high index of suspicion in all patients presenting amenorrhea, abdominal pains, adnexal mass, peritoneal irritation, enlarged uterus and suspicion of HP should be higher in women with risk factors and/or MAP. A delayed diagnosis could cause serious complications for both women and pregnancy.

The goal of any treatment of HP is preserving mother health and intrauterine fetus. In the management of HP, particularly in the abdominal pregnancy, we must consider many factors such as maternal hemodynamic status, fetal viability or congenital abnormality, gestational age and the wish of the woman regarding its final outcome (18). Expectant management is an option

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Nicola De Frenza et al.Heterotopic pregnancy: intrauterine and omental implantation. Case report.

in HP where the ultrasound findings are of a non viable pregnancy. Various clinicians recommend a period of observation of 3 to 8 weeks to allow atrophy of placental vessels (28). For Shafi et Al. (29), if the extrauterine fetus is dead, surgical intervention is generally indicated owing the risk of infection and/or disseminated intravascular coagulation. If the fetus is alive, regardless gestational age and fetal condition, a laparotomy should be performed. An alternative management is a medical treatment using local injection of potassium chloride or hyperosmolar glucose into the gestation sac either during laparoscopy or under ultrasound guidance. This approach has been described also for cervical, interstitial and caesarean scar pregnancies. Goldstein et Al. (30)

reviewed 11 cases of heterotopic pregnancies treated with potassium chloride injection and reported that 6 of the 11 cases failed to respond to treatment and required a surgical intervention. Systemic methotrexate (MTX) or local injection of MTX cannot be used in a heterotopic pregnancy owing to its toxicity although some Authors have used instillation of a small dose (31).

In the surgical management of HP, laparoscopy is preferable to laparotomy because of minimal manipulation of uterus and drying from open exposure which can cause uterine irritability and postoperative abortion. Furthermore the laparoscopic approach resulting in less blood loss, less postoperative pain, lower analgesic requirements, shorter hospital stay. To reduce the risk of persistent HP during laparoscopy it’s advisable aspiration of all the blood clots and tissue fragments, minimize the degree of the Trendelenburg position, perform a meticulous extraction of the trophoblastic tissue from the

Fallopian tube in case of salpyngotomy and use of a tissue retrieval bag. We can preserve intrauterine pregnancy also by shortest time under general anesthesia, appropriate handling of the uterus during surgery and supplementation with progesterone after surgery.

In the omental HP, the least common form of abdominal pregnancy, especially in the early g.w., we can perform a total or partial omentectomy. Everden et Al. (32) treated an omental HP by a transvaginal endoscopic approach (Natural Orifice Translumenal Endoscopic Surgery: NOTES) with a partial omentectomy. In early abdominal HP laparoscopic approach is safe and feasible obtaining a good intraoperative hemostasis and a good prognosis for the mother and for the intrauterine pregnancy (10,33,34). Patient should be advised that the incidence of recurrent ectopic pregnancy is similar (about 10%) to other forms of ectopic pregnancy.

In conclusion, heterotopic pregnancy (HP), especially omental implantation of the ectopic pregnancy, is a rare obstetrical condition potentially very dangerous to the mother and to the intrauterine pregnancy. It is important to remember the population at risk for HP and we also should be kept in mind the HP in differential diagnosis of any patient with an intrauterine pregnancy with abdominal pain and/or free fluid in the abdominal cavity. It is very useful for early diagnosis of HP to perform an ultrasonography and/or magnetic resonance and/or a laparoscopy. In abdominal-omental ectopic pregnancy, especially at low gestational age, we suggest a laparoscopic approach because it is safe and feasible preserving mother health and intrauterine fetus.


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REFERENCES1) Duverney JG. Oeuvres anatomiques. In: Jombert CA (ed) Oeuvres Anatomiques, Paris Bailliere; 1899: 355.2) De Voe RW, Pratt JH. Simultaneous extra and intrauterine pregnancy. Am J Obstet Gynecol 1948; 56 (6):1119-26.3) Reece EA, Petrie RH, Sirmans MF, Finster M, Todd WD. Combined intrauterine and extrauterine gestations: a review. Am J Obstet Gynecol 1983; 146 (3):323-30. 4) Walker DD, Clarke TC, Kennedy EC. Heterotopic ectopic and intrauterine pregnancy after embryo replacement. Br J Obstet Gynecol 1993; 100:1048-49.5) Calagna G, Rossi C, Adile G, Manzone M, Perino A, Cucinella G. Spontaneous bilateral tubal pregnancy in a nulliparous woman. Laparoscopic diagnosis and treatment. It J Obstet Gynecol 2015; 27 (4):137-40.6) Perkins KM, Boulet SL, Kissin DM, et Al. Risk of ectopic pregnancy associated with assisted reproductive technology in the United States, 2001–2011. Obstet Gynecol 2015; 125:70-78.7) Dor J, Seidman DS, Levran D, Ben-Rafael Z, Ben-Shlomo I, Mashiach S. The incidence of combined intrauterine and extrauterine pregnancy after in vitro fertilization and embryo transfer. Fert Steril 1991; 55: 4833-34.8) Thakur R, El-Menabawey M. Combined intrauterine and extrauterine pregnancy associated with mild hyperstimulation syndrome after clomyphene ovulation induction. Hum Reprod 1996; 11(7):1583-84.9) Maiorana A, Incandela L, Giambanco L, Alio W, Alio L. Omental pregnancy: case report and review of letterature. Pan Afr Med J 2014; 19:244.10) Watrowski R, Lange A, Mockel J. Primary Omental Pregnancy With Secondary Implantation Into Posterior Cul-de-sac: Laparoscopic Treatment Using Hemostatic Matrix. J Minim Invas Gyn 2015; 22(3):501-03.11) Winer EA, Bergman WD, Fields C. Combined intra and extrauterine pregnancy. Am J Obstet Gynecol 1957; 74:170-78.12) Lozeau AM, Potter B. Diagnosis and management of ectopic pregnancy. Am Fam Physician 2005; 72:1707-14, 1719-20.13) Martin JN, McCaul JF. Emergent management of abdominal pregnancy. Clin Obstet Gynecol 1990; 33:438-47.14) Atrash HK, Friede A, Hogue CJ. Abdominal pregnancy in the United States. Frequency and maternal mortality. Obstet Gynecol 1987; 69:333-37.15) Poole A, Haas D, Magann EF. Early abdominal ectopic pregnancies: a systematic review of the literature. Gynecol Obstet Invest 2012; 74:249-60.16) Noor N, Bano I, Parveen S. Heterotopic pregnancy with successful pregnancy outcome. J Hum Reprod Sci 2012; 5(2):213-14.17) Studdiford WE. Primary peritoneal pregnancy. Am J Obstet Gynecol 1942; 44(3):487-91.18) Friedrich EG Jr, Rankin CA Jr. Primary pelvic peritoneal pregnancy. Obstet Gynecol 1968; 31(5):649-53.

19) Talbot K, Simpson R, Price N, Jackson SR. Heterotopic pregnancy. J Obstet Gynaecol 2011; 31:7-12.20) Tal J, Haddad S, Gordon N, Timor-Tritsch I. Heterotopic pregnancy after ovulation induction and assisted reproductive technologies: a literature review from 1971 to 1993. Fertil Steril 1996; 66:1-12.21) Tummon IS, Whitmore NA, Daniel SAJ, Nisker JA, Yuzpe AA. Transferring more embryos increases risk of heterotopic pregnancy. Fertil Steril 1994; 61:1065-67.22) Roy M, Adrian S. Controversies and problems in the current management of tubal pregnancy. Hum Reprod Update 1996; 2:541-51.23) Costa SD, Presley J, Bastert G. Advanced abdominal pregnancy. Obstet Gynecol Surv 1991; 46:515-25.24) Allibone GW, Fagan CJ, Porter SC. The sonography features of intrabdominal pregnancy. J Clin Ultrasound 1981; 9:383-87.25) Chen L, Qiu L, Diao X, Yue Q, Gong Q. CT findings of omental pregnancy: a case report. Jpn J Radiol 2015; 33(8):499-502.26) Kao LY, Scheinfeld MH, Chernyak V, Rozenblit AM, Oh S, Dym RJ. Beyond ultrasound: CT and MRI of ectopic pregnancy. Am J Roentgenol 2014; 202(4): 904-11. doi: 10.2214/AJR.13.10644.27) Lockhat F, Corr P, Ramphal S, Moodley J. The value of magnetic resonance imaging in the diagnosis and management of extra-uterine abdominal pregnancy. Clin Radiol 2006; 61:264-69.28) Meinert J. Advanced ectopic pregnancy including combined ectopic and intrauterine pregnancy. Geburtshilfe Frauenheilkd 1981; 41:490-95.29) Shafi SM, Malla MA, Salaam PA, Kirmani OS. Abdominal pregnancy as a cause of hemoperitoneum. J Emerg Trauma Shock 2009; 2(3):196-98. doi: 10.4103/0974-2700-55342.30) Goldstein JS, Ratts VS, Philpott T, Dahan MH. Risk of surgery after use of potassium chloride for treatment of tubal Heterotopic pregnancy. Obstet Gynecol 2006; 107:506-08.31) Oyawoyea S, Chander B, Pavlovic B, Hunter J, Gandir AA. Heterotopic pregnancy: successful management with aspiration of cornual/interstitial gestational sac and installation of small dose of methotrexate. Fetal Diagn Ther 2003; 18:1-4.32) Everden C, El Sayed W, Sankaran S, Beynon DWG. Rare case of primary omental ectopic pregnancy treated by transvaginal endoscopic appproach.; E.P.U. conferences 2014. com/Abst/2014/OP24.33) Chadee A, Rezai S, Kirby C, Chadwick E, Gottimukkala S, Hamaoui A, et Al. Spontaneous Heterotopic Pregnancy: Dual Case Report and Review of Literature. Case Rep Obstet Gynecol 2016. doi: 10.1155/2016/2145937.34) Yu Y, Xu W, Xie Z, Huang Q, Li S. Management and outcome of 25 heterotopic pregnancies in Zhejiang, China. Eur J Obstet Gynecol Reprod Biol 2014; 180: 157–61. doi: 10.1016/j.ejogrb.2014.04.046.


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Quadruplet pregnancy after ovarian stimulation: the role of the counseling program to avoid dangerous pregnanciesMichele Fichera1, Gaetano Valenti1, Simona Taschetta1, Marta Grazia Li Destri1, Serena D’Amico1, Lisa Caldaci1, Martina Ferrara1, Fabrizio Sapia1, Marco Marzio Panella1

1 Department of General Surgery and Medical Surgical Specialties, University of Catania, Catania, Italy

ABSTRACTThe incidence of high-order multiple gestation (HOM) (triplet and quadruplet pregnancies) has increased noticeably in the last few years due to the increase of medically assisted reproduction techniques. In order to reduce these generally unsafe pregnancies, different solutions are available such as embryo reduction. However, the best and most ethical method is prevention. It is strongly suggested to assign these procedures to a fertility specialist with experience in preconception counseling in order to establish a good relationship between the physician and the couple. When HOM occurs, identifying the optimal gestational age for delivery becomes a mandatory goal for its management. We describe a case of a woman with a history of infertility who had ovarian hyper stimulation and, as a consequence of an inadequate medical compliance, a quadruplet pregnancy.

Key words: high-order multiple gestation, cesarean section, ovarian hyperstimulation, quadruplet gestations.

Corresponding Author: Dr. Gaetano [email protected] 2017, Partner-Graf srl, PratoDOI: 10.14660/2385-0868-77



SOMMARIOIl numero di gravidanze multiple con un numero di feti superiore a due (HOM) è aumentato sensibilmente negli ultimi anni a causa dell’incrementato uso di tecniche di riproduzione medicalmente assistita. Al fine di ridurre queste gravidanze potenzialmente pericolose, diverse soluzioni possono essere valutare, tra le quali la discutibile embrio riduzione. Tuttavia la prevenzione rappresenta la scelta più etica e sicura. Al fine porre la donna a un simile rischio, è molto consigliabile assegnare queste procedure a uno specialista con esperienza nel campo dell’infertilità e che, durante il counseling preconcezionale, sia capace di istaurare una fiduciosa collaborazione tra il medico e la coppia. Quando tuttavia la HOM si verifica, individuare l’età gestazionale ottimale per il parto diventa un obiettivo essenziale. Qui di seguito riportiamo il caso clinico di donna con storia d’infertilità che a seguito di un’inappropriata gestione e counseling preconcezionale è andata incontro a una gravidanza quadrigemina insorta su un quadro d’iperstimolazione ovarica.

INTRODUCTIONThe incidence of high-order multiple gestation

(HOM) has increased drastically in the last few years. Spontaneous twin pregnancy occurs with a frequency of 1:90. According to Hellen’s rule, it is possible to estimate that quadrigeminal

gestation occurs with a frequency of 1:833 (1,2). Between 1980 and 2009 epidemiological reports showed an increase in multifetal pregnancies of 76% for twin pregnancies and 400% for more than two pregnancies (3). HOM is correlated with several maternal and fetal negative outcomes. Firstly, triplet and quadruplet pregnancies are affected by a higher perinatal mortality because of an unavoidable higher rate of pre-term delivery (mean gestational age of 31 + 5 and 29 + 5 weeks,


14

respectively) and intra uterine growth restriction

(4,5). The intrauterine death rate increase for HOM from 1% in singleton pregnancies to 5%, and neonatal morbidity, neonatal and perinatal mortality is significantly higher in quadruplets compared to triplets and twins (6). Respiratory distress syndrome has a rate of 23% for triplet pregnancies and 65% for quadruplet pregnancies. Other adverse outcomes such as intracranial hemorrhage, retinopathy of prematurity and feto-fetal transfusion syndrome (FFTS) are correlated with the number of fetuses and occur more frequently in a quadruplet pregnancy (7,8). The most common maternal adverse events are: preeclampsia 32%, anemia 25%, postpartum hemorrhage 21% with a higher risk of emergency cesarean hysterectomy (8-10). Several measures could be adopted to reduce these unsafe pregnancies: for example the use of specific markers for early prediction of high-risk pregnancy such as preeclampsia is reasonable (11) or in “extrema ratio” embryo reduction. Periti et al. have shown that embryo reduction performed in trichorionic triplet pregnancies does not influence the rate of miscarriages, whereas the rate of pre-term delivery (before 32 weeks) is higher in women managed expectantly (12). Embryo reduction (ER) is undertaken with the aim of reducing maternal morbidity and mortality and improving fetal outcome but is not appropriate for all multiple pregnancies, and also it is forbidden in several countries causing many ethical controversies (13). Certainly, the best ethical modality to avoid an HOM secondary to medical treatment is prevention. Fertility preservation is a crucial aspect of the psychological, social and physical wellness of a woman and this aspect must be considered in all gynecological disorders (14-21). However, especially in an infertile couple and/or in a nulliparous women, fertility preservation and reproductive care must be absolutely warranted by the presence of a fertility specialist team that work in an approved reproduction center, with good experience in preconception counseling and are capable of reaching a straightforward collaboration and a complete compliance with medical advices (22). In fact, the Health Council of Italy has defined the role of psychological support and counseling for couples with infertility problems. In specific guidelines published in 2008, the necessity to offer psychological support to all couples from the early stages of the diagnostic and therapeutic process of infertility has become obligatory (23). Herein we report a case of a spontaneous HOM as a consequence of

incomplete preconception counseling performed in an unapproved reproduction center.

We also discuss our clinical management of this quadruplet pregnancy from a hyper stimulation syndrome.

CASE REPORTA 31-year-old Caucasian woman, parity 0030.

was referred to our department secondary to an ovarian hyper stimulation syndrome (OHSS) where, successively, there was a spontaneous quadruplet pregnancy. As standard protocol of the university hospital in which the case was reported, the patient was informed and signed a consent allowing data collection for research purposes.

This case report is in accordance with the Helsinki Declaration, conforms to the Consensus-based Clinical Case Reporting Guideline Development (http://www.equator-network.org/) the Committee on Publication Ethics (COPE) guidelines (http://publicationethics.org/) and was approved by the Institutional Review Board (IRB) of the university hospital in which it was carried out. Her medical history was remarkable for the presence of heterozygous mutation of methylenetetrahydrofolate reductase (MTHFR), polycystic ovarian syndrome (PCOS), obesity (BMI: 34) and recurrent abortions. She was referred to an external reproduction center to have a first line ovarian stimulation and underwent 3 cycles of clomiphene citrate and menotrophin without a positive response. After the last cycle, the patient developed OHSS. She was not well informed about her situation and the fertility specialist team probably underestimated the social-cultural limits of the couple in understanding the risk of a potential pregnancy arising from this clinical condition. Despite the interruption of stimulation and the medical advice, they voluntarily decided to ignore it and had unprotected sexual intercourse. After 6 weeks she was referred to our department for moderate OHSS (ovarian size > 8 cm, <12 cm, moderate abdominal pain, and ascites) (24,25) and hospitalization was required. During the early standard evaluations a vital quadruplet monochorionic monoamniotic pregnancy was diagnosed. The fluid balance, the amount of abdominal ascites and the hematocrit level was monitored daily. Low molecular weight heparin (LMWH) for thrombosis prophylaxis was administered for the entire hospitalization period. Hospital discharge was 10 days later because of spontaneous OHSS regression.

A complication of ovarian stimulation

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After hospital discharge she was periodically evaluated to check pregnancy status. Periodical physical examinations, vital sign collection, ultrasound scan (US) (including biometric measurement, placental evaluation, amniotic fluid index, Doppler velocimetry of the umbilical artery and the middle cerebral artery), and gestational diabetes screening, were performed according to the international guidelines for twin prenatal care (26). Prophylaxis for infant respiratory distress syndrome (IRDS) was made at 24 weeks. At the 26th week, after a negative screening for gestational diabetes mellitus, she was admitted to hospital again because of the IUGR of one fetus and altered Doppler velocimetry: Pulsatility Index (PI) UA 1.55; PI MCA 1.95. We decided to perform a careful wait-and-see management with periodical (every 6 days) full US evaluation until the 30th week, when worsening velocimetry values of the IUGR fetus (PI UA 1.93; PI MCA 1.09) were seen. A single dose of betamethasone 12 mg was administered and 12 h later a cesarean section (CS) was performed. Four vital fetuses were born (I, III, IV fetuses in cephalic presentation, II fetus in breech presentation): two male and two female monochorionic monoamniotic twins (Figure 1), weighing 1,560 gr, 1040 gr, 930 gr and 1300 gr, respectively. The Apgar score at 5 min was 7/10, 8/10, 7/10 and 9/10, respectively. All babies had respiratory distress syndrome (RDS) treated with intubation surfactant extubation (INSURE).

One baby had an intra-ventricular hemorrhage (IVH) and the smaller female also had grade III premature retinopathy (ROP) treated with laser-therapy. The patient had no complications and was discharged from hospital after 5 days. All babies were discharged separately from the intensive neonatal care unit from 4 to 28 days after birth.

DISCUSSIONDespite the rarity of spontaneous trigeminal

and quadrigeminal gestations, these overall rates of HOM have increased due to the escalation of medically assisted procreation (MAP) techniques, which account for more than 90% (27). Clomiphene citrate, usually associated with other drugs and nutraceutical agents (28-35), is one of the most common first line treatment in women with anovulatory infertility (AI) (36). Ever more women undergo medical treatment for AI due to polycystic ovarian syndrome (PCOS), the main cause of AI, which affects 4%-8% of women in reproductive age and is not always properly diagnosed and treated (37-41). Moreover, in our case, the administration of clomiphene was not completed properly. It has been shown that the use of metformin in association with clomiphene or letrazolo is associated with a lower risk of multiple pregnancies, especially in women with metabolic dysfunctions (41-44). The risk of an HOM as a consequence of medical stimulation is notable and physicians have to consider these metabolic alterations to prevent adverse effects including OHSS (45,46). When OHSS occurs, pregnancy should be avoided because the rising level of human chorionic gonadotrophin (hCG) can worsen the syndrome (47). As highlighted in our case, counseling and patient compliance are important factors that should not be underestimated, particularly when complex therapies are commenced.

Nevertheless, pregnancy can begin from an OHS scenario. When it happens, the main efforts required are: treat OHSS until complete regression (therapeutic abortion is contemplated); considering the pregnancy as a high-risk pregnancy and consequentially properly checked using standard guidelines; define the best time and modality for delivery (24,48). According to these notions, we admitted the woman to our department for a short preliminary hospitalization to monitor the mother’s condition in order to

Figure 1. Postpartum chorionic evaluation.

Michele Fichera et al.A complication of ovarian stimulation


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avoid an escalation to severe OHSS. Successively, when a safe maternal-fetal condition was assured, the identification of the optimal gestational age for delivery, considering the balance between preterm complications and intrauterine adverse conditions, was the main target for the correct management of an HOM. The significant perinatal mortality is caused by the high incidence of small for gestational age (SGA), low birth weight and intrauterine grow restriction (IUGR), which correlates with prematurity and occurs in 40% of two-multifetal gestations and in approximately 100% of higher than two-multifetal gestations. Long-term consequences and disability, especially cerebral palsy, are more common among newborns of multiple pregnancies (49,50). Intrauterine death of one twin has an incidence of 0.5% - 6.8%, although an exact estimation of intrauterine death in quadrigeminal pregnancy cannot be deduced from the current literature. Furthermore, monochorionic twin pregnancy doubles the probability of intrauterine death and increases the probability of contemporary cerebral palsy in the surviving twin. In addition, disseminated intravascular coagulation (DIC) has a higher incidence in multifetal pregnancy when compared to normal pregnancy (51).

A retrospective study based on 100 women with multifetal gestation pregnancy showed that the average gestational age for delivery in quadrigeminal pregnancy was 29 weeks and 5 days

and the perinatal mortality, hyaline membrane disease (RDS) and intracranial hemorrhage were, respectively, 36%, 65% and 15% (7). The same authors also showed a significant high rate in morbidity, despite the relative low rate in mortality; furthermore, they underlined that reaching a gestational age ≥ 30 weeks appears to be a protective factor, capable of lowering the neonatal complication rate. Considering this literature evidence and the worsening flowmetry values of the smaller fetus, we decided to perform a CS at the 30th week. Despite the fact that CS is not mandatory for HOM, no robust data have been gathered for neonatal outcomes and mortality in quadruple pregnancies, especially when concomitant IUGR of one or more fetuses occurs.

DECLARATION OF INTERESTThe authors report no conflicts of interest. The

authors alone are responsible for the content and writing of the paper. No specific funding was obtained.

ACKNOWLEDGMENTSThe authors wish to thank The Scientific Bureau

of the University of Catania for language support.

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Otocephaly: a case postnatal diagnosedAstrit M. Gashi¹, Jakup Ismajli², Curr Gjocaj³, Xhevdet Gojnovci4

1 Department of Obstetrics and Gynecology, University Clinical Centre of Kosovo, Pristine2 Chief of Emergency Department at Obstetrics and Gynecology Clinic, University Clinical Centre ofKosovo, Pristine

3 Director of the Hospital and University Clinical Service of Kosovo4 Director of Neonatology Clinic, University Clinical Centre of Kosovo, Pristine

ABSTRACTOtocephaly is characterized by agenesis or severe hypogenesis of the mandible or agnathia, synotia (the external ears horizontally placed and/or fused), microstomia (“small mouth”), aglossia (congenital absence of the tongue). This anomaly is often associated with other malformations as; Holoprosencephaly, anencephaly, congenital heart disease, tracheoesophageal fistula etc. The etiology is unknown. The pathogenetic mechanism seems to be related to a complete failure of the mandibular development, possibly associated with inhibited or arrested migration of neural crest cells. Three-dimensional ultrasound is often the only way to obtain an overall idea of the anomaly. The virtually all views of the fetal face are abnormal, due to the complete distortion of the facial anatomy. Otocephaly has been always lethal, so when detected, an accurate counseling of pregnancy should be offered at parents with also the possibility to offer termination of pregnancy. We report the case of a fetus, who was born on the 30th week of pregnancy, and was diagnosed with otocephaly, after birth.

Keywords: otocephaly, agnathia, synotia, microstomia, Aglossia

Corresponding Author: Dr. Astrit M. [email protected] 2017, Partner-Graf srl, PratoDOI: 10.14660/2385-0868-78



SOMMARIOOtocefalia è caratterizzato da agenesia o ipogenisia severa della mandibola o agnatia, sinotia (gli orecchi esterni sono messi orizzontalmente), microstomia (piccola bocca), aglossia (l’assenza congenita della lingua), questa anomalia è associata speso con le altre malformazioni, come; oloprosencefalia, fistola tracheoesofagea, ecc. L’ezilogia di questo malformazione è ingnota. II meccanismo di patogenesa sembra essere riferito ad un fallimento completo dello sviluppo della mandibola, possibilmente associato con migrazione inibita o arrestata di celule di creste neurali. L’ecografia tridimensionale è l’unico modo di ottenere un idea complessiva dell anomalia stressa. Virtualmente tutte prospettive della faccia fetale sono anomalia, a causa della distorsione completa dell’anatomia facciale. Otocefalia è un anomalia letale. L’interruzione della gravidanza può essere proposta nei termini di legge. Noi riportiamo il caso di un feto che nascerva nella 30 settimana di gravidanza, e fu diagnosticato con otocefalia dopo nascita.

Parole chiave: otocefalia, agnatia, sinotia, microstomia, aglossia

CASE PRESENTATIONA 21-year-old G2P1A0 patient presents at 30

weeks gestation for labor with uterine contractions, and is found to be in active labor with the fetus in breech presentation. Clinical assessment of the maternal pelvis is determined to be adequate for a fetus of this estimated weight.


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The cervix is 10 cm dilated, 100% effaced and the fetal pelvic are at -3 station. Ultrasound examination reveals of polyhydramnios, was reconfirmed afterwards with rupture of membrane he had approximately 5 L amniotic fluid. The patient had no medical and family history of any congenital anomalies, and likewise had no antenatal history of infection/radiation or toxin exposure. She has had a non-good prenatal care, including lack of one anatomy scans in the second trimester. Her prior infant, weighing approximately 3500 g, was delivered vaginally without complications. He was completely healthy. After 30 minutes, the patient with vaginal delivery, with manual assistance, according to Bracht maneuver, gave birth to a male baby with body weight 900 g and Apgar score 4/5. The macroscopic placenta was normal, and the umbilical cord with central insertion and that had three vessels. A detailed examination showed multiple anomalies of face as; Synotia (the external ears horizontally placed and/or fused), Agnathia (agenesis or severe hypogenesis of the mandible), Microstomia (“small mouth”), Aglossia (congenital absence of the tongue), (Figure 1, 2). Based on these components was diagnosed as an otocephaly. Six hours after delivering the baby, he dies.

DISCUSSIONOtocephaly is characterized by agenesis or

severe hypogenesis of the mandible (agnathia). The temporal bones are juxtaposed and the external ears are horizontally placed and/or fused. Different degrees of severity have been described (synotia, agnathia, microstomia, aglossia etc.). This anomaly is often associated with other malformations as; holoprosencephaly, anencephaly, congenital heart disease, tracheoesophageal fistula etc. The etiology is unknown. Some report’s emphasis to the role of autosomal recessive inheritance and drugs as possible causes (1-4). Otocephaly is an anomaly that has not been reported to be associated with trisomy 13 (5,6). The incidence of the otocephaly is around 1 in 70,000 births (2). The pathogenetic mechanism seems to be related to a complete failure of the mandibular development, possibly associated with inhibited or arrested migration of neural crest cells. Three-dimensional ultrasound is often the only way to obtain an overall idea of the anomaly (7).

Otocephaly ultrasound diagnosis can be made on the midsagittal view of the profile, where to all views of the fetal face are abnormal, due to the complete distortion of the facial anatomy. The fetal face represents an extremely irregular region to explore with ultrasound. This is why ultrasound examination of the fetal face has always posed great difficulty during the examination. We have some scanning planes, classified as axial, coronal, sagittal, and oblique, and the anatomic structures assessable in each of these views. In an axial view are usually seen; tongue, pharynx, Mandible, inferior alveolar ridge, mandibular bone etc. In a sagittal view are usually seen; facial profile (midline sagittal) and ear—parasagittal

Otocephaly: a case postnatal diagnosed

Figure 1. Otocephaly

Figure 2. Otocephaly and components such as; Microstomia, Aglossia, Agnathia, Synotia

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(lateral). The final scanning planes to complete the evaluation of the splanchnocranium are as follows:

1) The coronal view of the face and palate;2) The oblique view of the upper lip;3) The coronal/oblique view of the palate (7).

Scanning for fetal anomaly is usually performed between 18 and 22 weeks’ gestation. Otocephaly has been always lethal, so when detected, an accurate counseling of pregnancy should be offered at parents with also the possibility to offer termination of pregnancy. In such cases, postnatal treatment is not possible. Our case was a malformation of order that consisted of synotia, agnathia, microstomia, aglossia. A case that after six hours end to death.

In the pathogenic aspect , during the 4th weeks gestation, the mesoderm lateral plate of the ventral foregut region becomes segmented to form a series of five distinct bilateral mesenchyme swellings called the pharyngeal (branchial) arches. Ventrally migrating neural crest cells interact with lateral extensions of the pharyngeal endoderm, surround the six aortic arch arteries, and initiate pharyngeal arch development. The initial mesodermal core of each arch is augmented by neural crest tissue that surrounds the mesodermal core. The mesoderm will give rise to muscle myoblasts while the neural crest cells give rise to skeletal and connective tissues.

Otocephaly: a case postnatal diagnosed Astrit Gashi et al.

The pharyngeal arches are separated by pharyngeal grooves on the external aspect of the embryo, which correspond internally with five outpouchings of the elongated pharynx of the foregut, known as the five pharyngeal pouches. Although derivatives of five or even six arches are described, only four arches appear externally. The first pharyngeal arch is the precursor of both the maxillary and mandibular jaws and appropriately bounds the lateral aspects of the stomodeum. Meckel’s cartilage arises at the 41st to 45th days post conception, provides a template for subsequent development of the mandible. Persisting portions of Meckel’s cartilage form the basis of major portions of two ear ossicles. Deficient development of the pharyngeal arches results in syndromes that are identified according to the arch involved. The syndromes become rarer as the number of the arch increases. Severe first-arch anomalies are: Agnathia, Synotia, Microstomia. Less severe are: Treacher Collins syndrome, Pierre Robin syndrome etc.

CONFLICT OF INTERESTSAll the authors do not have any conflict of

interests.

REFERENCES1) Gekas J, Li B, Kamnasaran D. Current perspectives on the etiology of agnathia-otocephaly. European journal of medical genetics. 2010 Dec 31;53(6):358-66.2) Faye-Petersen O, David E, Rangwala N, Seaman JP, Hua Z, Heller DS. Otocephaly: report of five new cases and a literature review. Fetal and pediatric pathology. 2006 Jan 1;25(5):277-96.3) Pauli RM, Pettersen JC, Arya S, Gilbert EF, Opitz JM. Familial agnathia-holoprosencephaly. American Journal of Medical Genetics Part A. 1983 Apr 1;14(4):677-98.4) Ibba RM, Zoppi MA, Floris M, Putzolu M, Monni G, Todde PF, Sardu G. Otocephaly: prenatal diagnosis of a new case and etiopathogenetic considerations.

American Journal of Medical Genetics Part A. 2000 Feb 28;90(5):427-9.5) Blaas HG, Eriksson AG, Salvesen KÅ, Isaksen CV, Christensen B, Møllerløkken G, Eik-Nes SH. Brains and faces in holoprosencephaly: pre-and postnatal description of 30 cases. Ultrasound in obstetrics & gynecology. 2002 Jan 1;19(1):24-38.6) Cohen MM. Perspectives on holoprosencephaly: Part I. Epidemiology, genetics, and syndromology. Teratology. 1989 Sep 1;40(3):211-35.7) Chaoui R, Heling KS, Thiel G, Karl K. Agnathia-otocephaly with holoprosencephaly on prenatal three-dimensional ultrasound. Ultrasound in Obstetrics & Gynecology. 2011 Jun 1;37(6):745-8.

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Restless legs syndrome in pregnancy and risk of gestational hypertension in a low risk populationGiovanna Esposito1, Francesca Chiaffarino2, Vanessa Odelli1, Lucrezia Romiti1, Mirella Di Martino1, Fabio Parazzini1-2

1 Dipartimento di Scienze Cliniche e di Comunità, Università di Milano2 Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy

ABSTRACTIt has been reported a relationship between Restless Legs Syndrome (RLS) and pregnancy-induced hypertension (PIH). In this brief paper we report the association between RLS and PHI observed in a study conducted in Italy. This is a cross sectional study. Eligible for the study were women aged >18 years who delivered in randomly selected days to the Department of Obstetrics of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, the largest maternity hospital in Milan, Italy during 3 bimonthly periods in 2013-2015. The study protocol did not include any exclusion criteria. The researchers identified eligible women in the obstetric wards on randomly selected days within 3 days from delivery. Each woman who met the inclusion criteria agreed to be interviewed. A total of 648 women (median age 35, interquartile range 32-38) were identified. A questionnaire was administered during a face-to-face interview. This questionnaire included information about demographic characteristics and personal behavior. Diagnosis of RLS was established on the basis of the International Restless Legs Syndrome Study Group criteria. Out of the 648 interviewed women, 132 (20,4%, 95% CI: 17.3-23.5) met the criteria for diagnosis of RLS. Considering the 132 with and the 516 without RLS, 7(5,3%) and 29(5,6%) respectively had diagnosis of PHI (Odds Ratio adjusted for age: 0.89, 95% confidence interval 0.38-2.10). In conclusion despite the limitations our study suggests that the relationship between RLS syndrome and gestational hypertension should be more careful analyzed in different populations.

Corresponding Author: Fabio [email protected] 2017, Partner-Graf srl, PratoDOI: 10.14660/2385-0868-79



SOMMARIOÈ stato segnalato un rapporto fra la Restless Legs Syndrome (RLS) e l’ipertensione gestazionale (PIH). In questo breve documento Analizziamo l’associazione tra RLS e l’ipertensione gestazionale osservata in uno studio condotto in Italia. Questo è uno studio trasversale. Ammissibili per lo studio sono state le donne di età > 18 anni che hanno partorito in giorni selezionati in modo casuale al dipartimento di ostetricia della Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico durante 3 periodi di due mesi tra il 2013 ed il 2015. Il protocollo di studio non prevedeva alcun criterio di esclusione. I ricercatori hanno identificato le donne ammissibili nei reparti ostetrici nei giorni scelti casualmente entro 3 giorni dal parto. Ogni donna che ha soddisfatto i criteri di inclusione ha accettato di essere intervistata. Sono state identificate complessivamente 648 donne (età media 35 anni, intervallo interquartile 32-38). Un questionario è stato somministrato durante l’intervista faccia a faccia. Delle donne intervistate 648, 132 (20, 4%, 95% CI: 17,3-23,5) ha soddisfatto i criteri per la diagnosi di RLS. Considerando le 132 con e le 516 senza RLS, rispettivamente 7 (5,5%) e 29 (5,6%) hanno avuto una diagnosi di ipertensione gestazionale (Odds Ratio aggiustato per età 0,89, 95% intervallo di confidenza 0.38-2.10). In conclusione malgrado le limitazioni il nostro studio non conferma la possibile relazione tra la RLS ed il rischio di ipertensione gestazionale.


24

Restless legs syndrome in pregnancy and risk of gestational hypertension

INTRODUCTIONRestless legs syndrome (RLS) is a common,

distressing movement disorder. It is characterised by discomfort of, and urge to, move the legs, primarily during rest or inactivity (1). RLS has been associated with cardiovascular disease (CVD), hypertension, diabetes, and related disorders. A systematic review (2) has found that over half of the existing studies supported a positive association between RLS and hypertension, and that the variation in findings was primarily due to differences in participant demographics and disease assessment.

In etiologic terms, it has been suggested that individuals with RLS are more likely to develop hypertension because of the presence of periodic limb movements of sleep (PLMS) (3), thus underlining the association between sleep disorders, and RLS. Recently, it has been reported a relationship between RLS and pregnancy-induced hypertension (PIH) (4,5), a predictor of subsequent CVD and diabetes. However, the association between RLS and gestational hypertension remains little explored.

Pregnancy is a well recognized risk factor for the development of RLS and sleep disorders (6-8). Thus in consideration of the contribution to maternal and perinatal morbidity and mortality of hypertension in pregnancy, the potential association bertween RLS ad hypertensive disorders in pregnancy deserves attention.

In this brief paper we report the association between RLS and gestational hypertension observed in a study conducted in an European Caucasian population, a population characterized by a lower rate of hypertensive disorders in pregnancy (9) and not considered in the previous published studies on the association between RLS and hypertension in pregnancy.

METHODSThis is a cross sectional study.Eligible for the study were women aged >18

years who delivered in randomly selected days to the Department of Obstetrics of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, the largest maternity hospital in Milan, Italy, during 3 bimonthly periods in 2013-2015. The study protocol did not include any exclusion criteria.

The researchers identified eligible women in the obstetric wards on the randomly selected days within 3 days from delivery. Each woman who met the inclusion criteria agreed to be interviewed.

A total of 648 women (median age 35, interquartile range 32-38) were identified.

A questionnaire was administered during a face-to-face interview. This questionnaire included information about demographic characteristics (age, height, body weight, education, number of previous pregnancies), personal behavior (physical activity, smoking, alcohol drinking) and information on the newborn including centiles of weight according to Parazzini et al (10).

Diagnosis of RLS was established on the basis of the International Restless Legs Syndrome Study Group criteria (1). Gestational hypertension was defined according to the ACOG criteria (11).

Odds ratios (OR) and corresponding 95% confidence interval (CI) of gestational hyperthension were computed. We used unconditional multiple logistic regression, with maximum likelihood fitting including terms for age and parity.

This study was approved by the Institutional Review Board. Informed consensus was obtained.

RESULTSOut of the 648 interviewed women, 132 (20,4%,

95% CI: 17.3-23.5) met the criteria for diagnosis of RLS. The risk of RLS increased with age (Table 1).

Considering the 132 with and the 516 with and without RLS, 7 (5,3%) and 29 (5,6%) respectively had diagnosis of PHI (Odds Ratio adjusted for age: 0.89, 95% confidence interval 0.38-2.10).

This finding was consistent strata of age: the corresponding OR estimates were: 1.1, 0.9 respectively in women aged <35 and ≥ 35.

DISCUSSIONFew previous studies have suggested a possible

link between RLS and hypertensive disorders in pregnancy. In a study conducted in Peru and including 218 consecutive expectant mothers preeclampsia was more common in women with RLS (4). In a large Chinese study including 3,781 pregnant women PHI was more common among the 453 patients with RLS (5). However no difference was observed in the prevalence of chronic hypertension in pregnancy between women with and without RLS.

Further, it has been shown that a history of PIH was positively related to RLS later in life in a study of primary care patients (12).

25

Restless legs syndrome in pregnancy and risk of gestational hypertension Giovanna Esposito et al.

We did not confirmed this association. Potential limitations of our study could explain the lack of association between RLS and gestational hypertension observed in this study.

First of all, the limited numbers may explain our findings. Further, interviewed women were a sample of all women who delivered in the study period in the study center and not a random sample of all pregnancies in the study area. The interviewers identified the subjects in random sampled days during all the study period. Major selection bias, however, should not act in the identification of study subjects: the observed prevalence of RLS in our population is largely consistent with that reported in another Italian study (6). The information were collected in a vis a vis interview and the potential association between gestational hypertension and RLS was not known to the pregnant women and the diagnosis of gestational hypertension was checked with clinical records.

Among other limitations we have to

consider that we did not analyze the severity of hypertension. Among the strengths of the study we have to include the fact that we considered the main potential confounding.

However, some differences among published studies should also be discussed. We have considered only gestational hypertension. The South American study (4) considered preeclampsia and not hypertension. In preeclamptic women renal impairment may play a role and some studies have suggested that RLS is associated with renal diseases.

Further, in the largest study conducted in China (5) the prevalence of gestational hypertension was slightly higher than in our population and in that study an association (OR 1,35) between RLS and gestational hypertension, but not chronic hypertension was observed.

In conclusion despite the limitations our study suggests that the relationship between RLS syndrome and gestational hypertension should be more careful analyzed in different populations.

Table 1.Distribution of interviewed women according to diagnosis of RLS and selected characteristics.

OR odds ratio; CI Confidence interval*Multivariate estimates adjusted for age° Reference category °°Reference category: noIn some cases the sum does not add up to the totl due to missing values

Rest Legs SyndromeYes No OR* 95% CI

No.+ (%) No. (%)Age (years)< 35 47 (35.6) 249 (48.3) 1°≥ 35 85 (64.4) 267 (51.7) 1.69 (1.14–2.51)Pre-conception BMI (kg/m2)≤ 20.2 42 (31.8) 167 (32.7) 1°20.3-23.0 44 (33.3) 170 (33.3) 0.99 (0.62-1.60)≥ 23.1 46 (34.8) 174 (34.1) 1.02 (0.64-1.64)Education (years)≤ 13 73 (55.3) 253 (49.0) 1.36 (0.92-2.00)≥ 14 59 (44.7) 263 (51.0) 1°Weight gain in pregnancy(kg)≤ 15 99 (75.0) 408 (79.1) 1°> 15 31 (23.5) 103 (20.0) 1.24 (0.78-1.97)Parity0 69 (52.3) 282 (54.7) 1°1 49 (37.1) 201 (39.0) 1.03 (0.72-1.51)≥ 2 14 (10.6) 33 ( 6.4) 1.61 (0.81-3.19)Smoking No 109 (82.6) 426 (82.6) 1°Yes 23 (17.4) 90 (17.4) 1.06 (0.64-1.77)Alcohol drinking in pregnancyNo 100 (75.8) 397 (76.9) 1°Yes 32 (24.2) 119 (23.1) 1.02 (0.65-1.60)


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REFERENCES1) Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi J, Restless Legs Syndrome Diagnosis Epidemiology workshop at the National Institutes of Health International Restless Legs Syndrome Study Group (2003) Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med 4 (2):101-1192) Innes KE, Selfe TK, Agarwal P (2012) Restless legs syndrome and conditions associated with metabolic dysregulation, sympathoadrenal dysfunction, and cardiovascular disease risk: a systematic review. Sleep Med Rev 16:309–3393) Ohayon MM, Roth T (2002) Prevalence of restless legs syndrome and periodic limb movement disorder in the general population. J Psychosom Res 53:547–554Ohayon MM, O’Hara R, Vitiello MV (2012) Epidemiology of restless legs syndrome: a synthesis of the literature. Sleep Med Rev 16 (4):283-295. doi:10.1016/j.smrv.2011.05.0024) Ramirez JO, Cabrera SA, Hidalgo H, Cabrera SG, Linnebank M, Bassetti CL, Kallweit U. Is preeclampsia associated with restless legs syndrome? Sleep Med. 2013 Sep;14(9):894-6. doi: 10.1016/j.sleep.2013.03.013. Epub 2013 Jul 23 5) Ma S, Shang X, Guo Y, Liu G, Yang J, Xue R. Restless legs syndrome and hypertension in Chinese pregnant women. Neurol Sci. 2015 Jun;36(6):877-81. doi: 10.1007/

s10072-015-2094-4. Epub 2015 Feb 36) Manconi M, Govoni V, De Vito A, Economou NT, Cesnik E, Mollica G, Granieri E (2004) Pregnancy as a risk factor for restless legs syndrome. Sleep Med 5 (3):305-308. doi:10.1016/j.sleep.2004.01.0137) Yeh P, Walters AS, Tsuang JW (2012) Restless legs syndrome: a comprehensive overview on its epidemiology, risk factors, and treatment. Sleep Breath 16 (4):987-1007. doi:10.1007/s11325-011-0606-x8) Alves DA, Carvalho LB, Morais JF, Prado GF (2010) Restless legs syndrome during pregnancy in Brazilian women. Sleep Med 11 (10):1049-1054. doi:10.1016/j.sleep.2010.06.0069) Shen JJ, Tymkow C, MacMullen N. Disparities in maternal outcomes among four ethnic populations. Ethn Dis. 2005 Summer;15(3):492-710) Parazzini F, Cipriani S, Bulfoni G, Mauri PA, Carraro G, Mastrolia, Busacca M, Trojano G. Centiles of weight at term birth according to maternal nationality in a Northern Italian region. It. J. Gynaecol. Obstet. 2016, 28: N.211) Acog Committee on Practice Bulletins (2001) ACOG Practice Bulletin. Chronic hypertension in pregnancy. ACOG Committee on Practice Bulletins. Obstet Gynecol 98 (1):suppl 177-18512) Innes KE, Kandati S, Flack KL, Agarwal P, Selfe TK. The Relationship of Restless Legs Syndrome to History of Pregnancy-Induced Hypertension. J Womens Health (Larchmt). 2016 Apr;25(4):397-408. doi: 10.1089/jwh.2015.5484. Epub 2016 Feb 25).

Restless legs syndrome in pregnancy and risk of gestational hypertension

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Guidelines for diagnosis and treatment of fibromyomatosisGiancarlo Conoscenti1, Attilio Di Spiezio Sardo2, Caterina Exacoustos3, Antonio Maiorana4, Lucia Manganaro5, Yoram Jacob Meir6, Fabio Parazzini7, Sergio Schettini8, Michele Vignali9, Enrico Vizza10 (coordinator), Fulvio Zullo11, Errico Zupi3

1 Department of Obstetrics and Gynaecology, Cannizzaro Hospital, Catania 2 Department of Public Health, Federico II University of Naples3 Department of Biomedicine and Prevention. Obstetric and Gynaecological Clinic, “Tor Vergata”

University, Rome4 Complex Operating Unit of Gynaecology and Obstetrics, Palermo Civic Hospital5 Department of Radiological, Oncological, Anatomical and Pathological Sciences, La Sapienza Universityof Rome

6 Meir Y.J. Maternal-Infant Department, U.O.C. of Obstetrics and Gynaecology, Bassano del GrappaHospital

7 Department of Clinical and Community Sciences, Mangiagalli Clinic, University of Milan8 Obstetrics and Gynaecology Operating Unit, San Carlo Regional Hospital, Potenza9 Department of Obstetrics and Gynaecology, Macedonio Melloni Hospital, University of Milan.10 Department of Oncological Surgery, Oncological Gynaecology UOC, “Regina Elena” National Cancer

Institute, Rome11 Department of Obstetrics and Gynaecology, Magna Graecia University, Catanzaro

TABLE OF CONTENTS

- INTRODUCTION- METHODS- RECOMMENDATIONSBACKGROUNDSECTION 1: DIAGNOSTIC FRAMEWORK1.1 Ultrasound1.2 MRI1.3 HysteroscopySECTION 2: MEDICAL TREATMENTS2.1 SPRMS (Selective Progesterone Receptor Modulators)2.2 GnRH analogues2.3 GnRH antagonists2.4 Oral contraceptives2.5 Oral progestins and Levonorgestrel-releasing IUS

Copyright 2017, Partner-Graf srl, PratoDOI: 10.14660/2385-0868-80



2.6 Androgens2.7 Aromatase inhibitors2.8 Antagonists of estrogen receptors and SERMs (Selective Estrogen Receptor Modulators)SECTION 3: SURGICAL TREATMENTS3.1 Hysteroscopic Surgery 3.2 Laparoscopy3.3 Hysterectomy3.4 LaparotomySECTION 4: ALTERNATIVE TREATMENTS4.1 Uterine Artery Embolization (UAE)4.2 Thermal ablation4.3 Uterine artery occlusion

Annex 1 Clinical questionsAnnex 2 Summary of Recommendations

FONDAZIONECONFALONIERIR A G O N E S E


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INTRODUCTIONAUTHORS: These Recommendations have

been written by a group of medical professionals (Drafters) identified by SIGO, AOGOI and AGUI Scientific Committees with the organisational support of the Confalonieri-Ragonese Foundation.

RECIPIENTS: These Recommendations are addressed to all professionals who deal with the diagnosis and treatment of the diseases covered by these guidelines.

ACKNOWLEDGMENTS: A sincere thanks to dr. Benito Chiofalo (Gynecologic Oncology - “Regina Elena” National Cancer Institute of Rome) for the valuable support in draft, reformat and translation of the text.

METHODSWriting medical Recommendations is a

complex activity in terms of methods, and requires advanced technical skills, resources and time that companies usually are not able to provide. These recommendations are based on systematic reviews. Today, however, acquiring the critical skills required to assess the extent to which systematic reviews (or already existing Guidelines/recommendations produced in Italy or in other countries) are sufficiently valid from a scientific point of view to be taken into account for their application in Italy is the priority, and not writing new systematic reviews.

Based on these considerations, the production of these Recommendations included the following operational phases:

• Identification of expert drafters• Identification of systematic reviews and

the most recent guidelines published on the topic

• Formulation of clinical themes (Annex 1) used to develop the guidelines

• Definition of recommendations by individual drafters through their response to the identified clinical themes

• Definition of the recommendations grading by the group of expert drafters

Specifically, the Quality Level and the strength of these recommendations were graded and expressed in Roman numerals (I to VI) and in letters (A to E). The Quality Level refers to the likelihood that a certain amount of knowledge derives from studies planned and conducted in such a way as to produce valid information without systematic errors, while the Strength of

Recommendation refers to the likelihood that the practical application of a recommendation will lead to an improvement in the health status of the target population to which the recommendation is addressed.

The Level of Quality and Strength of Recommendations were defined according to the criteria suggested by the Methodological Manual of the National Guidelines System (table 1).

To develop these phases, an operational meeting was organised during the SIGO-AOGOI-AGUI National Congress, followed by an exchange of material and comments via email.

The Recommendations approved by a majority of the Group of Drafters have been revised by the Auditors appointed by the three Scientific Committees.

A summary of the Recommendations with the relevant level of quality and the strength of the recommendation is provided in Annex 2.

Table 1. Quality level and Strength of the Recommendations - Grading.From: ISS-PNLG 2002

Guidelines fot diagnosis and treatment of fibromyomatosis

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RECOMMENDATIONSBACKGROUNDUterine fibroids are benign, gynaecological

tumours with the greatest incidence and prevalence and are the main cause of hysterectomy.1 After the age of 50, it is believed that their prevalence is around 70 to 80%.2 They are caused by abnormal monoclonal growth of smooth muscle cells and connective matrix and respond to hormonal stimuli. They look like roundish, often poly-lobed fleshy masses, with a firm-elastic texture, and are separated from the surrounding myometrium by reactive connective tissue which is arranged to form a real pseudocapsule. The terms fibroids, myomas, leiomyomas or fibromas are used interchangeably. They do not respond to the rules of Mendelian inheritance, but a sort of inheritance for this pathology is well known; the etiopathogenesis remains unidentified, but known are risk factors, such as premature menarche, nulliparity, African ethnicity, obesity, polymenorrhea, arterial hypertension and diabetes.1,3 Symptoms are closely related to the number, position and size of fibroids. Small ones, especially isolated and subserosal, are often asymptomatic. The most common disorders include abnormal uterine bleeding, pelvic pain, infertility, urinary and intestinal disorders due to the compression on these regions.4 They can get larger under the action of ovarian steroids (estrogen and progesterone) or can be stable for all the woman life. The action of progesterone is mediated by estradiol which, through its ERα receptors, induces the expression of progesterone-specific receptors in smooth muscle cells, then progesterone regulates the genes involved in cell proliferation and apoptosis.5

Usually fibroids are divided into 3 classes, according to their position in the uterus: intramural fibroids, if they grow within the muscular uterine wall; submucosal fibroids, if they are on the inner surface of the uterus; and subserosal fibroids, if they modify the external profile of the uterus. These three classes are not

so well defined in clinical practice, and it is not rare to observe fibroids in intermediate positions. The recent FIGO classification system (figure 1) takes into account every kind of location and divides fibroids into 10 different classes.6 It is a common belief, even among specialists, that fibroids can grow rapidly during pregnancy, but the most numerous cases in the literature do not confirm this belief,7-8 indeed, according to them, there may even be a decrease in their diameter during gestation and, even in the presence of fibroids, the risk of possible obstetric complications can be considered as low.9 However, multiple and large fibroids can change the maternal-fetal outcome, since they increase the risk of fetal malposition, premature delivery, placental abruption, placenta previa, premature rupture of the membranes, retained placenta, post-partum haemorrhage, and caesarean section.10 Regarding the rate of neoplastic degeneration of fibroids, it is not yet well known whether leiomyosarcomas and muscle tumours with uncertain malignancy (STUMP) originate predominantly from fibroids. Their incidence, however, is very low (0.22-0.49%) and certain diagnostic criteria have not yet been identified.11-13

Figure 1.FIGO (International Federation of Gynecology and Obstetrics) leiomyoma subclassification system.Note: Reprinted from Int J Gynaecol Obstet. Vol 113 (1). Munro MG, Critchley HO, Brodes MS, Fraser IS, FIGO Working Group on Menstrual Disorders. FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age. pp.3-13. Copyright 2011, with permission from Elsevier1.

1) Wise LA, Laughlin-Tommaso SK. Epidemiology of Uterine Fibroids: From Menarche to Menopause. Clin Obstet Gynecol. 2016 Mar;59(1):2-24.2) Baird DD, Dunson DB, Hill MC, Cousins D, Schectman JM. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol. 2003 Jan;188(1):100-7.3) Flake GP, Andersen J, Dixon D. Etiology and

pathophysiology of uterine leiomyomas; a review. Environ Health Perspect 2003;111:1037–544) Buttram VC Jr, Reiter RC. Uterine leiomyomata: etiology, symptomatology, and management. Fertil Steril. 1981 Oct;36(4):433-45.5) Bulun SE, Moravek MB, Yin P, Ono M, Coon JS 5th, Dyson MT, Navarro A, Marsh EE, Zhao H, Maruyama T, Chakravarti D, Kim JJ, Wei JJ. Uterine Leiomyoma

Guidelines fot diagnosis and treatment of fibromyomatosis Enrico Vizza et al.


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Stem Cells: Linking Progesterone to Growth. Semin Reprod Med. 2015 Sep;33(5):357-65.6) Munro MG, Critchley HO, Broder MS, Fraser IS; FIGO Working Group on Menstrual Disorders. FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age. Int J Gynaecol Obstet. 2011 Apr;113(1):3-13. 7) Hammoud AO, Asaad R, Berman J, Treadwell MC, Blackwell S, Diamond MP. Volume change of uterine myomas during pregnancy: do myomas really grow? J Minim Invasive Gynecol. 2006 Sep-Oct;13(5):386-90.8) Neiger R, Sonek JD, Croom CS, Ventolini G. Pregnancy-related changes in the size of uterine leiomyomas. J Reprod Med. 2006 Sep;51(9):671-4.9) Stout MJ, Odibo AO, Graseck AS, Macones GA, Crane JP, Cahill AG. Leiomyomas at routine second-trimester

ultrasound examination and adverse obstetric outcomes. Obstet Gynecol. 2010 Nov;116(5):1056-63.10) Olive DL, Pritts EA. Fibroids and reproduction. Semin Reprod Med. 2010 May;28(3):218-27.11) Parker WH, Fu YS, Berek JS. Uterine sarcoma in patients operated on for presumed leiomyoma and rapidly growing leiomyoma. Obstet Gynecol 1994;83:414–8. 12) Leibsohn S, d’Ablaing G, Mishell DR Jr., Schlaerth JB. Leiomyosarcoma in a series of hysterectomies performed for presumed uterine leiomyomas. Am J Obstet Gynecol 1990;162:968–74; discussion 974–6.13) Peddada SD, Laughlin SK, Miner K, Guyon JP, Haneke K, Vahdat HL, Semelka RC, Kowalik A, Armao D, Davis B, Baird DD. Growth of uterine leiomyomata among premenopausal black and white women. Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19887-92.

SECTION 1: DIAGNOSTIC FRAMEWORK1.1 UltrasoundIn recent years, ultrasound, Colour-Power

Doppler Fluximetry and three-dimensional approaches have greatly improved the diagnosis of uterine fibroids, and consequently made a more targeted surgical management possible, also thanks to the contemporary development of minimally invasive surgery techniques.

In the common ultrasound practice, leiomyomas or uterine fibroids must be distinguished from adenomyosis and from rare myometrial malignant pathologies (leiomyosarcomas), which still poses considerable problems of differential diagnosis.

The ultrasound evaluation of a uterus with uterine fibroids can be performed either with transvaginal probe or with a transabdominal probe, or with both of them, depending on the size of the uterus that should be assessed before the ultrasound examination with a bimanual examination.

A transabdominal approach is recommended with 3.5 to 7.5 MHz Convex probes in case of large and/or uterine fundus fibroids; a full bladder examination may help, but is not essential. The transvaginal pathway is more useful in case of smaller intramural and submucosal fibroids; the current availability of multi-frequency probes (4.5 to 10 MHz) associated with the possibility of changing the position of the channel, allows a satisfactory evaluation of the majority of fibroids.

1.1.1 What are the ultrasound aspects of uterine fibroids and what are the methods used for a correct medical report?

The ultrasound appearance of uterine fibroids is a roundish mass, which can be hypoechoic or

hyperechoic, based on the amount of smooth or connective muscle component.1,2

Echogenicity is variable and there may be some hyperechogenicity within the lesion. The edges are usually clear, often hyperechoic, well differentiated from the surrounding myometrium. Using colour or power Doppler, a circumferential flow around the lesion can be observed.2 In the case of fibromatosis characterised by multiple nodes, the uterine body shows irregular contours and often not well recognisable edges. As for pedunculated fibroids, careful evaluation of the ipsilateral ovary and its anatomical integrity may aid the differentiation between them and solid neo-formations of ovarian origin. Leiomyomas positioned laterally, especially if in the cervico-isthmic region, may occur in relation to the broad ligament; to differentiate them from pedunculated subserosal fibroids, it may be useful to evaluate their mobility with respect to the probe and the surrounding tissues. Ultrasound examination of fibroids shall be used to assess: location, size, number, echo-structure and vascularity, growth and mobility and consistency of fibroids.2,3

LocationTo properly identify where fibroids are located,

the uterine version must be taken into account. Longitudinal scans of the uterine body allow to better assess the anterior or posterior position of fibroids, while transverse scans identify its lateral position.

The location of fibroids should be reported using the FIGO classification: 0= interstitial pedunculated; 1= submucous, < 50% intramural; 2= submucous, ≥ 50% intramural; 3= 100%


31

intramural, but in contact with the endometrium; 4= intramural; 5= subserous, ≥ 50% intramural; 6= subserous, < 50% intramural; 7= subserous pedunculated; 8= others (cervical, parasites).4 Subserosal fibroids usually deform the external uterine profile, while intramural fibroids, especially small in size, do not. Larger intramural fibroids frequently have a subserosal or submucosal position, or even both (transmural). Intramural fibroids in position 3 to 5 of the FIGO classification may deform the junctional area. The coronal section obtained with 3D ultrasound examination appears very useful for this evaluation.2

In case of submucosal position, the endometrium is dislocated and the image of the endometrial line is deformed; fibroids with a marked intracavitary component interrupt the ultrasound image of the endometrial line. The quantification of the intracavitary and intramural component of a submucous fibroid can be assessed with greater sensitivity by intracavitary saline infusion (sonohysterography).2

This method allows a better identification of submucous fibroids and by measuring the area of the intramural and intracavitary component of the fibroid, allows to accurately evaluate their grading (0, 1, 2 of the FIGO classification). In the case of submucous fibroids, the evaluation of the free myometrial margin behind the fibroid is also recommended, although according to some hysteroscopists, this measure is not always necessary.5,6

Size and numberTo measure the fibroids, it is necessary to

place gauges on the external contour of the formation (capsule) and the measurement should be performed on the three axes for volumetric assessment, which can be particularly useful to monitor fibroids growth during the follow-up.

It is advisable to specify the number of displayed nodes, even if in the presence of multiple, intramural or subserosal small fibroids, this data does not have particular clinical significance.

EchostructureThe echostructure of fibroids is quite variable,

sometimes less echogenic than the surrounding myometrium, but usually more echogenic, due to the presence of diffuse hyperechoic echoes. Fibroids have a hyperechoic pseudo-capsule, which is variable, depending on the amount of smooth and connective fibromuscular tissue. Echogenicity can be regular (homogeneous and/or characterised by a symmetrical pattern of echogenicity: hypoechoic, isoechoic or hyperechoic) or irregular (heterogeneous), due

to mixed echogenicity or due to the presence of echogenic areas or cystic areas (regular or irregular).2 Anechoic areas can be differentiated from large vessels using power Doppler ultrasound, in order to confirm the absence of blood flow. Some shadows can originate from the edges of the lesion, and in that case, they are reported as edge shadows, or originate within the lesion and in this case, they are called internal shadows.2,7 The shadow intensity is subjectively reported as mild, moderate or intense2. Fan-shaped shadow is defined by the presence of hypoechoic linear striae, sometimes alternating with hyperechoic linear striae. In the presence of calcific degeneration of the fibroid, the capsule can be very hyperechoic and/or the presence of internal hyperechoic areas with formation of back shadows can be observed. Sometimes the shadow can be so large that the back edges of the fibroid cannot be evaluated.2

Inside the fibroids, some anechoic areas with irregular contours can be observed, these are areas of colliquative necrosis. Spontaneous colliquative necrotic degeneration may occur in the case of rapid growth of the fibroid, red degeneration is the initial manifestation on the days following ischemia. The ultrasound appearance of red degeneration may not be consistent, although in some case it has been described as a homogeneous lesion characterised by low echogenicity, hyperechoic edges and by the absence of the internal vascularity.8,9 Haemorrhage and oedema, may appear with ultrasound in mixed echoic tumours. Hyaline degeneration with mixed echogenicity and a reduction of the consistency of fibroids, as well as in their volume, these characteristics can be observed during therapy with GNRH analogues or with Ulipristal Acetate. After ischemia induced by conservative treatments, fibroids are often homogeneous, hypoechoic and characterised by hyperechoic edges and acoustic shadows.10,11 Usually there is no internal vascularity, but few irregular vessels can be observed. Cystic or myxoid degeneration may develop resulting in a hypoechoic cystic area with a fluid or myxoid content.

VascularityColour or Power Doppler sonography should

evaluate the distribution, progression and number of fibroid vessels.

Power Doppler is usually preferred to Colour Doppler, because it allows to better identify small vessels with a low flow rate. Colour Doppler is used to assess the direction of blood flow. The Colour or Power Doppler box should include the whole fibroid. Magnification and setting should be



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adjusted to ensure maximum sensitivity and the Doppler spectral gain should be reduced until all artefacts disappear. Usually, the settings that allow to detect blood flow rates of 3 to 9 cm/s are ideal, but this may change based on the characteristics of the ultrasound device used. Fibroids can be characterised by circumferential, internal or mixed vascularity. The term “circumferential” refers to those vessels that surround a fibroid in the capsule, while the vessels located within the fibroid are defined as intralesional or central vessels.2,12,13

Usually, the vascularity of fibroids is greater in the capsule and less in the central region, with vessels radially arranged. The extent of vascularity is likely to vary according to the growth rate of the tumour. The degree of vascularity should be reported using a subjective colour scale, with a score of 1 representing the absence of colour and a score of 4 representing a remarkable colour signal. This score is based on a subjective assessment of both the lesion vascularity rate and the colour tone. The colour score can be assigned to the fibroid separately for the capsular and the central vascularity.2 For research purposes, the flow of colour within a lesion can be quantified using 3D ultrasound with virtual computer-aided analysis (VOCAL), in order to calculate 3D power Doppler indices: the vascularity index (VI, the number of voxels in the volume expressed as a percentage of the total number of voxels in the volume, potentially reflecting vascularity); the flow index (FI, the average colour value in the colour voxels expressed as a number from 0 to 100, potentially reflecting the flow rate); the vascularity flow index (VFI, calculated by multiplying the VI by the FI, reflecting the average colour of all voxels expressed as a number from 0 to 100 and potentially reflecting tissue perfusion).14 Since 3D vascular indices depend on ultrasound settings, their reproducibility in clinical practice remains doubtful and their use must be adequately studied. As long as these indices are not exceeded, we recommend using them only for specific research projects.15

Power Doppler may also help to better assess the direction of the vessels and therefore aid the differentiation between fibroids and adnexal masses. Usually, a solid adnexal neo-formation shows diffuse irregular vascularity, while fibroids, as previously described, are mainly characterised by peri-capsular vascularity. This distribution also aids differential diagnosis with endometrial polyps for which a vascular axis can be easily identified.16

1.1.2 What are the main aspect of differential diagnoses of uterine fibroids?

1.1.2.1 AdenomyosisDistinguish between fibroids and diffuse or

focal adenomyosis or adenomyomas is extremely important for the correct medical and surgical treatment. In addition to the symptoms, there are different ultrasound characteristics.

Adenomyosis is caused by the proliferation of endometrial glands and stroma that form a poorly defined lesion within the myometrium. On histological examination, adenomyosis is classified as diffuse when the endometrial glands and the stroma are widely distributed in the myometrium, while focal adenomyosis is when they are identified as nodular aggregates.17 Focal adenomyosis is different from adenomyoma. An adenomyoma is defined by pathologists as focal adenomyosis with compensatory hypertrophy of the myometrium surrounding the lesion.

The ultrasound characteristics of adenomyosis should be reported and quantified.

In particular, transvaginal ultrasonography shows that adenomyosis is characterised by:2,18-22

• Increased size of the uterus, without clear evidence of any formation, with poorly definable lesions, characterised by asymmetric thickening and globular shape of the organ;

• Diffuse heterogeneous myometrial echo-structure characterised by the presence of areas of increased or reduced echogenicity;

• Hypoechoic linear myometrial striae defined as subtle radial acoustic shadows that do not come from echoic areas or leiomyomas;

• Myometrial cysts defined as anechoic circular areas;

• Alteration of the junctional area assessed by 3D ultrasound.


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In particular, the presence of myometrial cysts in a poorly defined area has the highest specificity for diagnosis,18 however these are only present in 40 to 60% of cases.20 Furthermore, the combination of myometrial cysts and hypoechoic linear striae makes the ultrasound examination even more accurate.23

The use of the Power Doppler (PD) technique is also useful for diagnosis purposes and aids the differentiation between adenomyosis and uterine fibroids.2

Indeed, in case of adenomyosis, PD shows radially distributed vessels within the affected myometrium that follow their normal path perpendicular to the endometrial interface while, in case of fibroids, it shows a prevalently peripheral, capsular vascularity, with only a few vessels getting into the centre of the fibroid. Furthermore, for fibroids, ultrasound shows the presence of a pseudocapsule that separates them from the surrounding tissues, a characteristic that cannot be found in case of adenomyosis.2

1.1.2.2 Leiomyosarcoma There are few evidences related to a diagnosis

of uterine leiomyosarcoma with ultrasound examination and they mainly refer to numerically inconsistent retrospective studies, which make not possible to define final guidelines. There are also other rare uterine tumours deriving from smooth muscle other than leiomyomas but, to date, only limited informations on their ultrasound characteristics have been reported.13,24-26 However, this aspect has become incredibly relevant in view of the discussion about when, or whether, fibroids can be morcellated during laparoscopic surgery.

Uterine leiomyosarcomas are pure myometrial lesions and are typically single and large tumours. Macroscopically, leiomyosarcomas are very variable, being intra-myometrial formations consisting of a greyish parenchyma with many

haemorrhagic and necrosis areas, a formation that protrudes into the uterine cavity similar to a polypoid or, in the case of well-differentiated tumours, very similar to a leiomyoma. Histologically, the differential diagnosis between a well-differentiated leiomyosarcoma and a leiomyoma can be difficult, and is based on the degree of mitotic activity, cellularity and pleomorphism. Their ultrasound characteristics may not be distinguished from those of normal fibroids or may appear as an irregular vascular mass with a regular or irregular contour often with irregular anechoic areas caused by colliquative necrosis.12,13

Ultrasound elements for a possible diagnosis of leiomyosarcoma may be: the presence of a large single fibroid, the presence of many and large areas of colliquation and wide neovascularization especially at the central level.2,13,24-26 Other ultrasound elements may include rapid growth and invasion of the nearby organs.27

1) Mc Lucas B. Diagnosis, imaging and anatomical classification of uterine fibroids. Best Pract Res Clin Obstet Gynaecol 2008; 22: 627-642. 2) Van den Bosch T, Dueholm M, Leone FP, Valentin L, Rasmussen CK, Votino A, Van Schoubroeck D, Landolfo C, Installé AJ, Guerriero S, Exacoustos C, Gordts S, Benacerraf B, D’Hooghe T, De Moor B, Brölmann H, Goldstein S, Epstein E, Bourne T, Timmerman D. Terms, definitions and measurements to describe sonographic features of myometrium and uterine masses: a consensus opinion from the Morphological Uterus Sonographic Assessment (MUSA) group. Ultrasound Obstet Gynecol. 2015 ;46(3):284-98.3) Fascilla FD, Cramarossa P, Cannone R, Olivieri C,

Vimercati A, Exacoustos C. Ultrasound diagnosis of uterine myomas. Minerva Ginecol. 2016 ;68:297-312. 4) Munro MG, Critchley HO, Broder MS, Fraser IS. FIGO classification system (PALM- COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age. Int J Gynaecol Obstet 2011; 113: 3-13. 5) Yang JH, Lin BL. Changes in myometrial thickness during hysteroscopic resection of deeply invasive submucous myomas. J Am Assoc Gynecol Laparosc 2001; 8: 501-505.6) Casadio P, Youssef AM, Spagnolo E, Rizzo MA, Talamo MR, De AD, Marra E, Ghi T, Savelli L, Farina A, Pelusi G, Mazzon I. Should the myometrial free margin still be considered a limiting factor for hysteroscopic



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resection of submucous fibroids? A possible answer to an old question. Fertil Steril 2011; 95: 1764-1768. 7) Kliewer MA, Hertzberg BS, George PY, McDonald JW, Bowie JD, Carroll BA. Acoustic shadowing from uterine leiomyomas: sonographic-pathologic correlation. Radiology 1995; 196: 99-102.8) Ouyang DW, Economy KE, Norwitz ER. Obstetric complications of fibroids. Obstet Gynecol Clin North Am 2006; 33: 153-169. 9) Valentin L. Characterising acute gynaecological pathology with ultrasound: an overview and case examples. Best Pract Res Clin Obstet Gynaecol 2009; 23: 577-593.10) Allison SJ, Wolfman DJ. Sonographic evaluation of patients treated with uterine artery embolization. Ultrasound Clinics 2010; 5: 277-288.11) Nicholson TA, Pelage JP, Ettles DF. Fibroid calcification after uterine artery embolization: ultrasonographic appearance and pathology. J Vasc Interv Radiol 2001; 12: 443-446. 12) Szabo I, Szantho A, Csabay L, Csapo Z, Szirmai K, Papp Z. Color Doppler ultrasonography in the differentiation of uterine sarcomas from uterine leiomyomas. Eur J Gynaecol Oncol 2002; 23: 29-34.13) Exacoustos C, Romanini ME, Amadio A, Amoroso C, Szabolcs B, Zupi E, Arduini D. Can gray-scale and color Doppler sonography differentiate between uterine leiomyosarcoma and leiomyoma? J Clin Ultrasound 2007; 35: 449-457.14) Minsart AF, Ntoutoume SF, Vandenhoute K, Jani J, Van PC. Does three-dimensional power Doppler ultrasound predict histopathological findings of uterine fibroids? A preliminary study. Ultrasound Obstet Gynecol 2012; 40: 714-720. 15) Raine-FenningNJ,CampbellBK,ClewesJS,KendallNR,JohnsonIR. Thereliabilityof virtual organ computer-aided analysis (VOCAL) for the semiquantification of ovarian, endometrial and subendometrial perfusion. Ultrasound Obstet Gynecol 2003; 22: 633-639. 16) Leone FP, Timmerman D, Bourne T, Valentin L, Epstein E, Goldstein SR, Marret H, Parsons AK, Gull B, Istre O, Sepulveda W, Ferrazzi E, Van den Bosch T. Terms, definitions and measurements to describe

phenomena, can change with loss of the characteristic signal, making differential diagnosis of leiomyoma difficult, in particular between lesions such as mesenchymal mixed tumours (MMT), smooth muscle tumours of uncertain malignant potential (STUMP) and sarcomas.3

MRI is a second level diagnosis technique. The main indications are 1,2:

- Fibroids with atypical clinical or ultrasound features, such as rapid growth, blood loss, pain, echostructure or atypical vascularity, etc.;

- Voluminous lesions wich the origin is defined as

the sonographic features of the endometrium and intrauterine lesions: a consensus opinion from the International Endometrial Tumor Analysis (IETA) group. Ultrasound Obstet Gynecol 2010; 35: 103-112. 17) Ferenczy A. Pathophysiology of adenomyosis. Hum Reprod Update 1998;4:312-322. 18) Bazot M, Cortez A, Darai E, Rouger J, Chopier J, Antoine JM, Uzan S. Ultrasono- graphy compared with magnetic resonance imaging for the diagnosis of adenomyosis: correlation with histopathology. Hum Reprod 2001; 16: 2427-2433. 19) Reinhold C, Tafazoli F, Wang L. Imaging features of adenomyosis. Hum Reprod Update 1998; 4: 337-349. 20) Dueholm M. Transvaginal ultrasound for diagnosis of adenomyosis: a review. Best Pract Res Clin Obstet Gynaecol 2006; 20: 569-582. 21) Naftalin J, Jurkovic D. The endometrial-myometrial junction: a fresh look at a busy crossing. Ultrasound Obstet Gynecol 2009; 34: 1-11.22) Exacoustos C, Brienza L, Di GA, Szabolcs B, Romanini ME, Zupi E, Arduini D. Adenomyosis: three-dimensional sonographic findings of the junctional zone and correlation with histology. Ultrasound Obstet Gynecol 2011; 37: 471-479. 23) Kepkep K, Tuncay YA, Goynumer G, Tutal E. Transvaginal sonography in the diagnosis of adenomyosis: which findings are most accurate? Ultrasound Obstet Gynecol 2007; 30: 341-345. 24) Hata K, Hata T, Makihara K, Aoki S, Takamiya O, Kitao M, Harada Y, Nagaoka S. Sonographic findings of uterine leiomyosarcoma. Gynecol Obstet Invest 1990; 30: 242-245.25) Hata K, Hata T, Maruyama R, Hirai M. Uterine sarcoma: can it be differentiated from uterine leiomyoma with Doppler ultrasonography? A preliminary report. Ultrasound Obstet Gynecol 1997; 9: 101-104.26) Aviram R, Ochshorn Y, Markovitch O, Fishman A, Cohen I, Altaras MM, Tepper R. Uterine sarcomas versus leiomyomas: gray-scale and Doppler sonographic findings. J Clin Ultrasound 2005; 33: 10-13. 27) Vaquero ME, Magrina JF, Leslie KO. Uterine smooth-muscle tumors with unusual growth patterns. J Minim Invasive Gynecol 2009; 16: 263-268.

1.2 MRIMagnetic Resonance Imaging (MRI), thanks

to advancements in technology, has improved its diagnostic performance and tissue characterisation. Compared to medical ultrasound, MRI offers large fields of view (FOV), multiple planes, high contrast resolution of T2 mapping, multiple parameters and post-contrast graphic behaviour.1,2

Leiomyomas are generally observed as defined lesions with hypointense signal in T2-weighted sequences and isointensity images, compared to the myometrium, in T1- weighted images.

However, these aspects, in case of degenerative


35

uncertain after ultrasound examination;- Evaluation before and after treatment in patients

that must be treated with embolization or Focused Ultrasound (FUS)

1.2.1 MRI ProtocolMRI examination should be performed with

equipment equipped with a 1.5 T magnet and, using a multi-channel phased-array coil after intravenous administration of some antiperistaltic agents and after 6 hours of fasting.

The standard MRI protocol for the study of leiomyomas includes, as a first sequence, the acquisition on the coronal plane of a large field of view with T2-weighted sequences (which allows to evaluate the size of the uterus) the position of the fibroids, the type of fibroids and the presence of secondary signs, such as ascites effusion and/or hydroureteronephrosis, etc.

After an initial classification, a targeted study will be conducted with T1 and T2-weighted high resolution morphological sequences with and without Fat Saturation (FS), as well as a post-contrast graphic study, and Diffusion sequences have also been recently included (DWI).

The morphological study, and in particular T2 sequences, thanks to a high contrast resolution, allow to evaluate the site, the number, the involvement of the endometrial cavity and the adjacent organs and the presence of overlapping degenerative phenomena, such as cystic degeneration, hyaline and myxoid degeneration. Red degeneration is well visible in T1 sequences without and with abatement of the adipose signal.4

Diffusion sequences are expressed by the free movement of water molecules, the so-called Brownian motion, within the tissue. These sequences were mutated by neuroradiological imaging for the study of acute stroke, being able to identify the ischemic lesion early, when Computed Tomography (CT) is still negative. Diffusion sequences, in addition to offering a qualitative assessment (hypo-signal or hyper-signal) may also provide a quantitative parameter (Apparent Diffusion Coefficient or ADC).

In recent years, these sequences have also been used in body experience evaluation, in oncology, as they are able to reflect the cellularity of a tissue, and are used as a routine evaluation method for some lesions, such as such as prostate or cervical cancer, both for staging and for post-therapy re-evaluation. It is recommended to acquire DWI sequences with multiple values of b (b0, b1000), a factor that expresses the degree of diffusion and the following calculation of the ADC.

The use of an intravenous contrast medium, at a dose of 0.1 mmol/kg of gadolinium chelates, is a mandatory step for the evaluation of vascularity, type of enhancement, and to document any areas of necrosis and to identify the peripheral pseudocapsule.

Fibroids generally show a synchronous enhancement with the myometrium. This information is extremely important, for example in esophytic, voluminous lesions of uncertain origin. In this case, post-contrast graphic sequences help to assess the enhancement level and to identify the vascular peduncle. Fibroids, also in relation to the hormonal status of the patient and to any hormonal therapies, may show a hyper or hypo-vascularization and usually also a homogeneous impregnation of the contrast medium.1

The presence of large areas of necrosis is an important element for diagnosis because they are quite evident in lesions, such as STUMP or Sarcomas.

T1-weighted sequences with Fat Saturation (FS) on axial and/or sagittal planes are used. Currently, dynamic or perfusion studies have been suggested.

Dynamic studies provide important informations about post-contrast graphic behaviour.5 In this case, a sequence train is repeated for about 6 times with a total time of about 3 minutes, which may vary also based on the equipment used.

As for perfusion studies, these have not yet been employed in clinical practice and, at the moment, there are no literature data on their actual diagnostic performance unlike other segments such as the breast, the brain and the prostate.

1.2.2 Key MRI aspects of fibroid degeneration The signal of fibroids in MRI varies according

to their histological characteristics.Typical non-degenerated fibroids consist

of connective tissue and smooth muscle cells determining that typical hypo-intensity shown by T2-weighted images and isointensity in T1- weighted images with the myometrium, as already reported.

In the case of rapid growth, the lack of intralesional vascularity can cause a change in the structure with degenerative effects.4

Hyaline degeneration is the most common type of degeneration and is not always accompanied by a change in the signal described. In the presence of calcifications, there will be no enhancement in relation to the extent of the calcification rate.

Cystic degeneration leads to an increase in the



36

signal intensity of T2-weighted images, which will be directly proportional to the extent of inclusion cysts within the fibroid, and T1 basal images will show a consensual hypo-intensity. After administration of the contrast medium, the cyst does not show any enhancement.

Myxoid degeneration shows an increase in the fibroid signal strength and is associated with mild enhancement. Necrotic fibroids show a variable signal in T1 images, and generally hypo-intensity in T2 images; after administration of the contrast agent, total absence of impregnation is observed.

Red degeneration, which corresponds to haemorrhagic infarction, is characterised by an increase in signal intensity in T1 images with FS.

In some cases, leiomyomas can be surrounded by high T2 signal rims, which express a dilatation of the lymphatic and venous vessels, but are not pathognomonic.6

Typical fibroids identified by DWI usually have a characteristic effect called “black out effect”, characterised by hypo-intense signal in both, low b value images and high b value images, with a corresponding hypo-intensity in ADC.

The presence of areas of hyaline, myxoid or necrosis degeneration may lead to false shrinkage phenomena with consequent problems of differential diagnosis between hyper-cellular fibroids, STUMP and sarcomas. In fact, some components such as blood, fat, melanin and necrosis can determine Pitfalls. It should be pointed out that, in case of hyper-intense signal in DWI sequences with high b value (b1000), the image obtained must be compared to the ADC map. The presence of hyper-intensity on the map is an expression of the “T2 Shine Through” effect, while in the case of hypo-intensity on the maps, a quantification of the ADC should be considered. Some authors report suspected ADC values below 1.1 mm2/sec, but for such values there are fibroid overlaps.7 However, it should be emphasized that, for the characterisation of fibroids, all the parameters must be considered, including morphological aspects (T1 and T2), DWI sequences and type of enhancement, and must be correlated with clinical practice. Therefore, a non-homogeneous hyper-intense fibroid in T2 images, with signs of shrinkage in DWI and necrosis areas must be carefully evaluated together with further signs such as edges, relationships with surrounding structures, the presence of lymphadenopathy and the presence of ascites7.

Moreover, high b value DWI images, help detect lymph nodes and evaluate peritoneal carcinosis.

1.2.3 Lesions of uncertain originMRI indications for fibroid evaluation include

the classification of masses of uncertain origin. In this case, a multi-planar study finalised in a better investigation of the ovaries, the vascular peduncle, the relationship between the mass and the uterus with cleavage planes is always required.

1.2.4 Evaluation before and after treatment The assessment before and after treatment with

MRI-guided Embolization of the uterine arteries (EAU) and focused ultrasound (FUS) must focus on fibroid location, structure, size and involvement of the surrounding structures, with regard to FUS. Therefore, accurate mapping is necessary.

In the selection of patients to submit to FUS, ineligibility criteria include, in particular, pedunculated subserosal fibroids and high T2 signal fibroids. Evaluation in relation to the surrounding structures (intestinal loops and sacral promontory) is extremely important; fibroid size is not a contraindication, since even fibroids larger than 5 cm can be treated.8

After treatment with FUS, fibroids usually show a shrinkage ranging from 20 to 50%, and after administration of the contrast agent, absence of enhancement is reported in relation to coagulative necrosis. The non-perfused volume (VPN) of the myoma, then, proves that the treatment was successful. The persistence of fibroid perfused portions is a possible indicator of relapse.8,9

Selection of patients that can be treated with MRI-guided EAU, includes the following parameters:10

- size (lesions up to 13 to 15cm can be treated); - location (fibroids which are mainly sub-

mucous are associated with a risk for possible post-treatment complication; pedunculated fibroids are considered as a relative contraindication for peduncles smaller than 2cm);

- signal intensity in T2- weighted images;- enhancement: post-contrast graphic behaviour

is essential to establish the indication. Fibroids with poor vascularity show poor response to treatment.

After treatment, in addition to the fibroid size, volume, (reduced) T2 intensity signal, location and enhancement must be considered.11

In some cases, after treatment with FUS or EAU, expulsion into the endometrial cavity can be observed.

1.2.5 Differential diagnosis The main differential diagnosis is between

adenomyosis and sarcomas:


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ADENOMYOSISAdenomyosis is frequently associated with

fibroids with rates ranging between 30 and 80%. MRI shows high sensitivity and specificity, with values of about 65 and 98%, respectively. Generally, adenomyosis appears as a lesion with undefined edges and with little mass effect.12

The basic criteria for the diagnosis of adenomyosis are the following.13,14

• Lesion characterised by blurred hypotensity, which is hard to define with cystic areas by T2- weighted images;

• Increased thickness of the endometrial line (>12 mm) with blurred margins;

• Sub-endometrial cystic formations well visible in T2- weighted images;

• Hypointense linear striae in T2- weighted images with involvement of radial myometrium arteries;

• Asymmetry of uterine walls;• Areas of hyperintensity in FS T1 images (a

highly specific but inconsistent sign related to the presence of stromal areas).

It should be pointed out that the aspects described may vary according to the patient’s hormonal status and, therefore, during treatment.

SARCOMASDifferential diagnosis can be complex. Recently,

a multi-parameter study with the development of a PRESS score (PRE-operative Sarcoma Score) with the combination of multiple parameters,

Imaging 2015;40(8):3182e90.7) Sato K, Yuasa N, Fujita M, Fukushima Y. Clinical application of diffusion-weighted imaging for preoperative differentiation between uterine leiomyoma and leiomyosarcoma. Am J Obstet Gynecol. 2014 Apr;210(4):3688) Ciolina F, Manganaro L, Scipione R, Napoli A. Alternatives to surgery for the treatment of myomas. Minerva Ginecol. 2016 Jun;68(3):364-79. Review9) Marigliano C, Panzironi G, Molisso L, Pizzuto A, Ciolina F, Napoli A, Ricci P. First experience of real-time elastography with transvaginal approach in assessing response to MRgFUS treatment of uterine fibroids. Radiol Med. 2016 Dec;121(12):926-934. 10) Kang SH, Lee SJ, Jeon GS, Yoon SW. Scaled Signal Intensity of Uterine Fibroids on T2-Weighted MR Imaging as a Predictor of the Potential Response to Uterine Fibroid Embolization. J Vasc Interv Radiol. 2017 Jun;28(6):844-849. 11) Harman M, Zeteroğlu S, Arslan H, Sengül M, Etlik O. Predictive value of magnetic resonance imaging signal and contrast-enhancement characteristics

including the evaluation of the T2 signal, DWI and post-contrastographic behaviour, has been recommended. However, multivariate analysis shows the inconsistency of such data.15

Generally, a leiomyosarcoma appears as a single mass with irregular edges with high to medium T2 signal. Extensive necrotic areas are observed after administration of the paramagnetic contrast agent. A haemorrhagic component can be identified in pre-contrast T1-weighted images.15,16,17

DWI shows a high signal for values of b 1000 with ADC maps with values between 0.791 and 1.17 10-3mm2/s 7.

Muscle tumours with uncertain malignancy (STUMP) show similar MRI aspects and their diagnosis is histological.

The identification of possible secondary signs (infiltration of surrounding structures, venous thrombosis, lymphadenopathy, ascites, peritoneal diffusion, hydroureteronephrosis) is essential in case of suspected sarcoma.

1) Sudderuddin S, Helbren E, Telesca M, Williamson R, Rockall A. MRI appearances of benign uterine disease. Clin Radiol. 2014 Nov;69(11):1095-104.2) Testa AC, Di Legge A, Bonatti M, Manfredi R, Scambia G. Imaging techniques for evaluation of uterine myomas. Best Pract Res Clin Obstet Gynaecol. 2016 Jul;34:37-53. 3) Fasih N, Prasad Shanbhogue AK, Macdonald DB. Leiomyomas beyond the uterus: unusual locations, rare manifestations. Radiographics 2008 Nov-Dec;28(7):1931e48.4) Bolan C, Caserta MP. MR imaging of atypical fibroids. Abdom Radiol (NY). 2016 Dec;41(12):2332-23495) Kim YJ, Kim KG, Lee SR, Lee SH, Kang BC.J Preoperative 3-dimensional Magnetic Resonance Imaging of Uterine Myoma and Endometrium Before Myomectomy. Minim Invasive Gynecol. 2017 Feb;24(2):309-314.6) Reiter MJ, Schwope RB, Lisanti CJ, et al. Can a T2 hyperintense rim sign differentiate uterine leiomyomas from other solid adnexal masses? Abdom



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on post-embolization volume reduction of uterine fibroids. Acta Radiol. 2006 May;47(4):427-35.12) Tamai K, Togashi K, Ito T, Morisawa N, Fujiwara T, Koyama T. MR imaging findings of adenomyosis: correlation with histopathologic features and diagnostic pitfalls. Radiographics. 2005 Jan-Feb;25(1):21-40. Review13) Tamai K, Koyama T, Umeoka S, Saga T, Fujii S, Togashi K. Spectrum of MR features in adenomyosis. Best Pract Res Clin Obstet Gynaecol. 2006 Aug;20(4):583-602. Review.14) Vinci V, Saldari M, Sergi ME, Bernardo S, Rizzo G, Porpora MG, Catalano C, Manganaro L. MRI, US or real-time virtual sonography in the evaluation of adenomyosis?. Radiol Med. 2017 May;122(5):361-368.15) Nagai T, Takai Y, Akahori T, Ishida H, Hanaoka T, Uotani T, Sato S, Matsunaga S, Baba K, Seki H. Highly

• Depth of myometrial invasion: evaluated by the study of the angle formed by the fibroid’s margin and the endometrium (the more acute is the angle, the less the extension of the fibroid inside the uterine wall and vice versa).

• Surface vascularity: on the surface of the fibroid, mainly thin sinusoidal vessels can be observed, the rupture of which can contribute to the bleeding frequently reported by the patients.

• Features of the surrounding endometrium.• Presence of any associated pathologies

(e.g.: polyps, endometrial hyperplasia, adenomyosis).

Many studies in the literature have evaluated the accuracy of hysteroscopy for the diagnosis of sub-mucous uterine fibroids.3-8 Most of these compared the diagnostic accuracy of hysteroscopy (HSC) versus trans-vaginal ultrasound (TVU), nuclear magnetic resonance (RMI) and sonohysterography.

In 1991, Fedele showed that HSC and TVU had substantially comparable diagnostic accuracy (100% sensitivity for both TVU and for HSC; specificity: 94% TVU vs 96 % HSC); he also concluded that the mapping of uterine fibroids was more accurate with transvaginal ultrasound.6

However in 2001, Dueholm pointed out that sonohysterography and MRI are the most precise methods of identification of submucous fibroids, and that MRI is better than other diagnostic techniques for the evaluation of the exact intramural portion of fibroids.3 Soares and his collaborators have also compared the accuracy of sonohysterography and trans-vaginal ultrasound

improved accuracy of the revised PREoperative sarcoma score (rPRESS) in the decision of performing surgery for patients presenting with a uterine mass. Springerplus. 2015 Sep 17;4:520. 16) Thomassin-Naggara I, Dechoux S, Bonneau C, et al. How to differentiate benign from malignant myometrial tumours using MR imaging. Eur Radiol 2013 23:2306–2314.17) Namimoto T, Yamashita Y, Awai K, et al. Combined use of T2-weighted and diffusion-weighted 3-T MR imaging for differentiating uterine sarcomas from benign leiomyomas. Eur Radiol 2009 19:2756–2764.18) Barral M, Placé V, Dautry R, Bendavid S, Cornelis F, Foucher R, Guerrache Y, Soyer P. Magnetic resonance imaging features of uterine sarcoma and mimickers. Abdom Radiol (NY). 2017 Jun;42(6):1762-1772. Review.

1.3 Hyseteroscopy1.3.1 What characteristics of uterine fibroids

can be better studied with hysteroscopy?It has been shown that ambulatory

hysteroscopy, in addition to ascertaining the presence of sub-mucous fibroids, also allows to evaluate important parameters used to assess whether hysteroscopic surgery is required or not:1-2

• Location: sub-mucous fibroids may affect the upper 1/3 region, the middle 1/3 region or the lower 1/3 region of the uterine cavity; sometimes they can also develop in the corneal regions and interfere with the lumen of the utero-tubal junction. It should be specified the fibroid location, with respect to the uterine walls, if there is a fundus, back or front or cervico-isthmic localisation.

• Size: the size can be assessed subjectively in relation to anatomical landmarks, such as interstitial distance, or in relation to the dimensions of miniaturized instruments (pincers, scissors, electrodes) introduced into the uterine cavity through the operative channel of modern surgical hysteroscopes. Experience shows that the size of the fibroid is not important as an absolute criterion for surgery, requiring, with expert hands, only extended surgical times.

• Texture: it is evaluated indirectly by exerting pressure on the formation with the distal end of the hysteroscope or with the tip of surgical instruments. Fibroids are usually hard, but in case of haemorrhagic infarction or ischemic necrosis, they may be soft, thus making differential diagnosis between fibroids characterised by degeneration (hyaline, colliquative or adipose) and leiomyosarcomas difficult.


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• Classification 1 (G1): fibroids with partial intramural development. Intracavitary component of the fibroid >50%.

• Classification 2 (G2): fibroid with prevalent intramural development. Intracavitary component of the fibroid <50%.

Lasmar et al. (2005)10 have proposed a new preoperative classification of submucous fibroids that considers not only the depth of myometrial invasion, but also additional parameters, such as the extension of the fibroid base with respect to the uterine wall, the size (cm) and the topography in the uterine cavity. A 0 to 2 score is attributed to each parameter and, based on the score, patients are classified into three groups:

• 0 to 4 score (Group I): low complexity hysteroscopic myomectomy;

• 5 to 6 score (Group II): High complexity hysteroscopic myomectomy (consider preparation with GnRH analogues or two surgical steps);

• 7 to 9 score (Group III): consider a non-hysteroscopic surgical alternative.

A recent multi-centre study by Lasmar et al. (2011)11 has shown that the above classification allows, with respect to the ESGE classification, a greater correlation with the possibility to remove fibroids, completely or not, by resectoscopic myomectomy.

for the diagnosis of uterine diseases, confirming that diagnostic hysteroscopy is the gold standard.8 Therefore, a clear superiority of one of the diagnostic techniques available in the diagnostic accuracy of submucous uterine fibroids was not demonstrated.

1.3.2 What is the role of ambulatory hysteroscopy in the pre-surgical assessment of fibroids?

Since the intramural extension of submucous fibroids can vary considerably, influencing the possibility of obtaining a complete resection, a preoperative hysteroscopic classification of submucosal fibroids has become indispensable since the dawn of resectoscopic surgery, in order to highlight the lomitation of a possible hysteroscopic surgery. The classification suggested by Wamsteker et al. (1993)9 and then adopted by the European Society for Gynaecological Endoscopy (ESGE), which takes into account only the depth of myometrial invasion of submucosal fibroids, is still the most widely used:

• Classification 0 (G0): fibroids entirely developed inside the uterine cavity, pedunculated or with limited implantation base.

6) Fedele L, Bianchi S., Dorta M., Brioschi D., Zanotti F., Vercellini P. Transvaginal ultrasonography versus hysteroscopy in the diagnosis of uterine submucous myomas. Obstet Gynecol 1991, May; 77 (5): 745-87) Cicinelli E, Romano F, Anastasio PS, Blasi N, Parisi C, Galantino P. Transabdominal sonohysterography, transvaginal sonography, and hy teroscopy in the evaluation of submucous myomas. Obstet Gynecol 1995;85:42–7. 8) Soares SR, Barbosa dos Reis MM, Camargos AF. Diagnostic accuracy of sonohysterography, transvaginal sonography, and hysterosalpingography in patients with uterine cavity diseases. Fertil Steril 2000;73: 406 –11 9) Wamsteker K, Emanuel MH, de Kruif JH. Transcervical hysteroscopic resection of submucous

1) Mazzon I, Sbiroli C. Manuale di chirurgia resettoscopica in ginecologia. Torino. UTET, 1997:91-2172) Di Spiezio Sardo A & Nappi C. Modern hysteroscopic approach for genital pathologies. Endopress TM 2014.3) Dueholm M, Lundorf E, Hansen E et al. Evaluation of the uterine cavity with magnetic resonance imaging, transvaginal sonography, hysterosonographic examination, and diagnostic hysteroscopy. Fertil Steril 20014) De Jong P, Doel F, Falconer A. Outpatient diagnostic hysteroscopy. Br J Obstet Gynaecol 1990;97:299–303. 5) Emanuel MH, Verdel MJ, Wamsteker K, Lammes FB. A prospective comparison of transvaginal ultrasonography and diagnostic hysteroscopy in the evaluation of patients with abnormal uterine bleeding: clinical implications. Am J Obstet Gynecol 1995;172:547–52.



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fibroids for abnormal uterine bleeding: results regarding the degree of intramural extension. Obstetrics and Gynecology 1993;82(5):736–40.10) Lasmar RB, Barrozo PR, Dias R, Oliveira MA. Submucous fibroids: a new presurgical classification to evaluate the viability of hysteroscopic surgical

for three months, and showed, in the three groups, the simultaneous decrease in the volume of the fibroids, but fewer adverse events associated with the use of mifepristone, at both the dose of 10 and 25 mg.6

Evidence is lacking on the possible relationship between administration and atypical endometrial hyperplasia.

2.1.2 Ulipristal acetateUlipristal acetate (UPA) has a mixed agonist-

antagonist action on Progesterone receptors with anti-proliferative effect on myomas.

Numerous recent studies identify UPA as the first medical choice for the treatment of fibroids.

In Phase III PEARL 1 and PEARL 2 studies, UPA has proved to be effective in both, bleed control and in reducing the size of fibroids before the surgical treatment. It also proved to be a medication with a good safety profile, even compared to previous reference medications, such as GnRh analogues.7-8

PEARL 1 study compared UPA with placebo in the pre-surgical treatment of symptomatic fibroids, showing a volumetric reduction of lesions after thirteen weeks of treatment at a dose of 5 mg, which is the currently marketed formulation, the reduction was of the 21% against the 3% of growth in the placebo group (P < 0.01). This effect remains for six months after the interruption of the therapy. The rate of amenorrhea at this dose is 73% and in most women, it occurs after 10 days of treatment.7

A second RTC showed a non-inferiority of UPA compared to leuprolide acetate in the control of menorrhagia related to uterine fibroids with symptom control in 90% of cases at a dose of 5 mg versus 89% of cases treated with the GnRH analogues, that however reported major vasomotor symptoms. With the SPRM under study, the average time to amenorrhea is 7 days versus 21 of Leuprolide acetate.8

Two RCTs showed the long-term efficacy of UPA. The first trial showed that the intermittent and repeated intake of UPA 10 mg is effective and safe in the control of bleeding and in the volumetric reduction of lesions in women with symptomatic uterine fibromatosis.9


treatment – preliminary report. The Journal of Minimally Invasive Gynecology 2005; 12: 308–11.11) Lasmar RB, Xinmei Z, Indman P, Keller R, Di Spiezio Sardo A. Feasibility of a new system classification of submucous mioma: a multicenter study. Fertility and Sterility 2011; 95(6): 2073–7

SECTION 2: MEDICAL TREATMENTThere are many pharmacological strategies

that can be used in the treatment of symptomatic uterine fibroids. Medical strategies have traditionally included medications that can control symptoms with specific action on the endometrium, such as estroprogestinic therapy and progesterone, or a dual action on the fibroids and on the endometrium, inducing a menopausal-like state, such as GnRH analogues. Ulipristal Acetate (UPA), a selective modulator of progesterone receptors (SPERMS), and the only drug with specific indication for the long-term treatment of symptomatic uterine fibroids was available in Europe in 2014.

In case of failure of medical therapies, the use of surgical techniques and alternative techniques may be indicated.

2.1 SPRMS (Selective Progesterone Receptor Modulators)

SPRMs are molecules able to bind progesterone receptors with agonist, antagonist or mixed effects on a responsive tissue.1

Many molecules belonging to this category have been studied, but randomized controlled trials (RCTs) are only available for two of them.

2.1.1 MifepristoneMifepristone (RU-486) has a pure antagonistic

action that, as evidenced by a meta-analysis of 11 RCTs of 2013, it induces a statistically significant volumetric decrease of both, the uterus and the lesion, in addition to a relief of fibromatosis associated symptoms.2

Mifepristone is effective in reducing bleeding, pain associated with fibroids, and their size.3 The dose and posology suggested by the authors is 2.5 mg per day for three to six months. The efficacy of mifepristone in the treatment of uterine fibroids has also been demonstrated with doses of 5 and 10 mg for treatment periods of 3, 6, and 12 months by other authors.4 One study showed that using 10 mg of mifepristone is equally effective as using 25 and 50 mg, with fewer side effects.5

A recent multicentre randomized controlled trial compared the efficacy of mifepristone at doses of 10 mg and 25 mg with Enantone 3.75 mg

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The second study evaluated efficacy and safety of the use of UPA at the dose of 5 mg and 10 mg with intermittent administration up to four cycles of three months each one. Both doses were effective in the control of bleeding (>80% for both groups) and in the volumetric reduction of lesions (reduction of 54% for 5 mg and 58% for 10 mg). In both groups, there was a reduction of pain and improvement in quality of life. Less than 5% of the treated patients discontinued treatment due to side effects.10

Already after 7 days, UPA normalizes bleeding with a more rapid action compared to GnRHa (about 30 days), and within the first 10 days, the 50% of patients with UPA 5 mg have amenorrhea.11

After three months of use, UPA allows, in 90% of cases, to control uterine bleeding and therefore to correct the consequent anaemia also in view of a subsequent surgery. The same study shows that the effect of UPA also has been going on for six months after its suspension, contrary with the use of analogues, which, on the other hand, determine a rapid regrowth after the end of the therapy (rebound effect).

In the vast majority of cases, fibroid shrinkage (≥25% in 80% of patients) and bleeding control (in> 90% of patients) made it possible to avoid surgery and restore haemoglobin level. This therapeutic scheme also showed a clinically significant reduction in fibroid volume from 62.3%, after the first cycle, to 78.1% of patients after 4 cycles, thus suggesting a greater benefit with repeated cycles.11-12

In case of a good patient response, the treatment can be interrupted after 4 cycles and patients re-evaluated.

Whether the symptoms should reoccur, medical therapy may be repeated. In this context, the goal is to reach menopause without surgery.13

Great attention was paid during phase III studies on the possible adverse effects of the medication and on the effect of this class of medications on the endometrium.

The treatment induces a spectrum of benign endometrial modifications called PAECs (PRM associated endometrial changes) found in about 30% of the treated women.14

As shown by PEARL studies, these changes are reduced to less than 30% after only one period and disappear 3 to 6 months after the suspension of the treatment.

The incidence of endometrial hyperplasia in phase III studies, both in the short and in the long term (excluding patients who took NETA to avoid bias), is 0.9%, 0.4% of which shows cellular atypia;

these percentages are lower than those found in the control group, confirming its safety profile.15

The safety of UPA (5mg/day) has been confirmed by several pharmacokinetic studies with higher doses.16-17 To date, the results of the studies demonstrate the efficacy of the treatment with 5 mg of UPA and confirm the safety of repeated administrations (4 sequential cycles of 3 months each) for symptomatic fibroids.13

The most frequently reported side effects, with the relative incidences of the first, second, third and fourth treatment cycles are: hot flashes in 5.7%, 3.7%, 1.7% and 2.8% of cases, respectively, breast tension or pain in 3.0%, 0.9%, 0% and 0.6% of cases, respectively, headache in 10.0%, 6.0%, 2.1% and 2.2% of cases, respectively. Headache incidence is higher during the first month of treatment. During the PEARL IV study, eight serious side effects were reported: five cases of menorrhagia, one bipolar disorder, one abdominal pain and one low back pain.

In all PEARL studies, blood estradiol levels remained higher than post-menopause, not altering bone mineral density, either at 5 or 10 mg (PEARL II).9

In the PEARL III study, the coagulation profile was analysed, which was unchanged after repeated cycles of UPA 10mg.9 During the PEARL IV study, no routine dosage was performed but no thromboembolic events occurred.10

Medical treatment with SPRMs may be very useful, since long-term intermittent therapy (repeated in the event of recurrence of symptoms during the interval) may help to avoid or at least delay surgery.

2.2 GnRH analoguesThis class of medications induces a state

of relative hypoestrogenism, and, therefore a temporary menopause with amenorrhea, which results in an improvement in haemoglobin levels in those patients with secondary anaemia and a reduction in the volume of fibroids.18

GnRH agonists are able to induce a volumetric reduction of fibroids above 50% after twelve weeks of treatment. The duration of the treatment with GnRH analogues is limited to three to six months, due to the hypoestrogenism caused by them, while volume reduction of lesions is only temporary (lesions grow back after only twelve weeks).

An add-back therapy can be added for the control of estrogenic deprivation symptoms.

A prospective randomized study on long-term use (> 6 months) of GnRH agonist medications



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associated with estrogen/progestin and progestin contraceptives showed that the addition of contraceptives can reduce the effect on the fibroid volumetric reduction and that with both regimens the loss of bone mass remains significant, approximately 3%.19-20

A recent systematic review shows that there is evidence of poor-moderate quality supporting the use of tibolone, raloxifene, estriol, and ipriflavone as an aid in preventing bone mass reduction during treatment with GnRH agonists. Medroxyprogesterone acetate (MPA) and tibolone showed good efficacy in reducing vasomotor symptoms.21

The use of GnRH agonists is useful for preoperative patient preparation because it reduces the volume of lesions and anaemia.22

Several studies show how preoperative use of GnRh-analogues can improve anaemia before surgery, reduce endometrial thickness and fibroid volume as well as its vascularity with reduction of intraoperative blood loss.23

2.3 GnRH antagonists GnRH antagonists induce a direct blocking

mechanism against the hormone receptor with the advantage of avoiding the initial “flare up” effect caused by agonists.24

In vitro studies show a possible role of this class of medications in controlling the growth of uterine fibroids but, at the moment, there is no evidence supporting their use. 25

2.4 Oral contraceptivesOral contraceptives (COCs) were used to

control fibroid bleeding. Their effectiveness in treating bleeding is limited and a reduction in the volume of fibroids has never been documented.26

There are no studies comparing the effectiveness of UPA with COCs. However, there is a small randomized trial comparing COCs with medroxyprogesterone acetate in women with excessive menstrual bleeding due to any etiology, and treatment with COC has been seen to reduce the bleeding by 88% with an average of 3 days.27

The use of COCs in the management of abnormal bleeding due to the presence of fibroids has been evaluated by very few studies. In a recent meta-analysis of cohort studies and case-control studies on this topic, COC treatment was associated with a 17% reduction in fibroid-associated symptoms.28

Another observational study compared the use of COCs with placebo and found a significant reduction in bleeding without any changes in the

fibroid volume.29

Low dose oral contraceptives can reduce menstrual bleeding in patients with uterine fibromatosis less than levonorgestrel-releasing intrauterine system or IUDs (see below).30

2.5 Oral progestins and levonorgestrel-releasing IUS

Progestin contraceptives, in addition to induction of endometrial atrophy, have a double biochemical effect on the growth of fibroids: a stimulating effect with the increase of the Epidermal Growth Factor (EGF), and an inhibitory effect with the negative modulation of insulin-like growth factor-1 and the down regulation of estrogen and progesterone receptors.31

A prospective study has shown that LNG-IUS (Levonorgestrel-releasing Intrauterine-Systems) significantly reduce blood loss and uterine volume in women with menorrhagia, associated with fibromatosis or not, while they have no effect on the size of the fibroids.32

One RCT showed superiority of LNG-IUD in the control of menorrhagia in patients with uterine fibroids compared to combined oral contraceptives.33

In a multi-centre randomized trial, the authors found a lower efficacy of Lynestrenol in the volumetric reduction of fibroids, when compared with the efficacy obtained with a GnRH analogue (Leuprorelin depot 3.75 mg).34

A systematic review of 2013 on the use of progestin contraceptives and LNG-IUDs concludes that Levonorgestrel-releasing IUDs are effective in the control of uterine bleeding associated with uterine fibromatosis and that oral administration of progestogen contraceptives does not reduce neither the volume of the lesions nor the symptoms associated with them.35

2.6 AndrogensThe most commonly used androgen for the

treatment of uterine fibromatosis is Danazol, which can cause a fibroid volume reduction of 20-25%36.

A subsequent systematic review did not confirm this action, as there were no randomized controlled trials supporting it.37

Because of the modest action and the side effects associated with its use, Danazol should not be used routinely for the management of symptomatic fibroids.38

2.7 Aromatase inhibitorsAromatase inhibitors, including Letrozole,


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inhibit the conversion of androgens to estrogens with growth inhibition of uterine fibroids. A systematic review of their use includes only one trial reporting a volumetric reduction of fibroids equal to 46% after twelve weeks compared to 32% obtained with GnRH agonists and minor vasomotor side effects (0/33 vs. 26/27, P < 0.05). Since the data on the volumetric reduction are not statistically significant, there is currently no evidence justifying their use.39

2.8 Estrogen receptor antagonists and SERMs (Selective Estrogen Receptor Modulators)

Estrogen receptor antagonists, including Fulvestrant, have shown, in a RCT, lower efficacy compared to GnRH agonists, in term of volumetric reduction and relief of bleeding due to fibroids.40

SERMs are selective modulators of estrogens receptors with non-steroidal composition characterised by a specific agonist or antagonist action. Raloxifene is the most used of these drugs for the treatment of uterine fibromatosis; despite this, there are still few studies on its use as a single-agent.41

What is the medical treatment for fertile women with symptomatic type 2 to 5 uterine fibroids?

1. Women who desire pregnancyIn the case of a type 2 fibroids, a therapy with

UPA can be proposed in order to reduce the size of the lesion before hysteroscopic myomectomy (that must be planned after the first menstrual bleeding) or even to obtain a volumetric reduction, so that the uterine cavity is no longer deformed and surgery is no longer required.9-10,42-46

In case of multiple fibroids or different types of fibroid (2 to 5), at least two treatment cycles for three months should be suggested, after which, based on the patient’s response, clinical options must be modulated.10,42-47 In case of an important volumetric reduction (> 50%) and absence of cavity distortion, patients can be advised to try to get pregnant naturally, or, if necessary, to contact a fertility centre. There are still little data in the literature regarding pregnancies after therapy with UPA, but they are encouraging, showing good pregnancy outcome even without surgery. If this clinical program is adopted, patients should be advised to try to get pregnant or initiate ovarian stimulation after the second menstruation occurred after the end of the treatment.48

In the case of a good volumetric reduction of the fibroid (≥25% but <50%), but not good enough to correct the cavity distortion or make the fibroid size clinically insignificant, surgery can be an option, at this point, it should be less invasive and with less complications.

If the patient does not respond to UPA, a pre-surgical treatment with GnRH analogues can be suggested, or myomectomy.49

2. Women not currently interested in having children

Prolonged and intermittent medical treatment with UPA (4 cycles of three months, possibly repeated in case of symptom recurrence) is a good option for fertile women suffering from fibromatosis not currently interested in having children, it reaches a good control of bleeding in more than 90% of patients and regression of lesions, ≥25% in 80% of patients.11

Given the high recurrence rate after myomectomy, equal to 60% in 4-5 years, medical therapy can help in symptom control and to avoid, or even postpone surgery until the patient wants to try to get pregnant.50



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What is the medical treatment for women in perimenopause with symptomatic type 2 to 5 uterine fibroids?

In this situation, medical treatment should aim to induce menopause without surgery.

The use of UPA at a dose of 5 mg for four cycles of three months shows a progressive increase of both effects the volumetric reduction and the bleeding decrease. Moreover, the medium PBAC score in the period between one cycle and the one other decrease if treatment cycles are repeated.

Patients should be re-evaluated after four cycles and therapy should be re-proposed in case of recurrence of symptoms. No cases of endometrial hyperplasia were recorded in women undergoing eight-month cycles of UPA 5 mg.10,13,14,48,51

What is the medical treatment for infertile women with symptomatic type 2 to 5 uterine fibroids?

In the case of patients with multiple fibroids, differently located, and who want to have children, medical therapy is now considered as the first-choice approach.

The efficacy of UPA, used according to an intermittent scheme which includes 2 cycles of treatment at a dose of 5 mg/day for three months alternating with two menstrual cycles has been demonstrated.10,13,46

In patients in wich there is a significant reduction in the volume of the fibroid (> 50%) with relief of symptoms, correction of anaemia and restoration of the endometrial cavity, surgery is not required and patients can try to get pregnant naturally. If the reduction in fibroid volume is > 25% but <50%, patients can still try to get pregnant naturally or opt for IVF.48,52

Medical therapy with one or two cycles of SPRMs could be an option even for patients with type 2 to 5 fibroids, with no symptoms, prior to start any in vitro fertilization or oocyte donation procedures already planned for any cause.53

Further clinical studies on the use of UPA in patients that are candidates for IVF are required.

However, in some cases, if the uterine cavity remains distorted or if the fibroid remains voluminous and the patient continues to be symptomatic, an indication for surgery remains.

In this case, a medical pre-treatment can allow surgery with a less invasive approach (laparoscopic myomectomy).

Despite the fact that several studies have suggested that intramural fibroids have a negative effect on fertility outcomes, it has been shown by different reviews that these results are not consistent.54-55

According to a meta-analysis and a review of 19 observational studies, reduced fertility is not only associated with submucous and intramural fibroids, distorting the uterine cavity, but also with the presence of fibroids that do not alter the uterine cavity.56

In case of symptomatic fibroids not responsive to medical therapy, myomectomy seems to be clearly indicated.

In terms of infertility, several uncontrolled studies have suggested that myomectomy produces a decrease in the rate of miscarriage in women with fibroids causing distortion of the uterine cavity.57-58

In a review of prospective and retrospective studies, Donnez and Jadoul reported a 49% pregnancy rate in patients who had undergone laparoscopic myomectomy.59

In another review, the postoperative pregnancy rate was 57%.60 These post-myomectomy pregnancy rates have been confirmed by other studies, but the lack of randomized trials represents a major drawback.61


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1) Chwalisz K, Perez MC, Demanno D, Winkel C, Schubert G, Elger W. Selective progesterone receptor modulator development and use in the treatment of leiomyomata and endometriosis. Endocr Rev 2005;26:423–438.2) Shen Q, Hua Y, Jiang W, Zhang W, Chen M, Zhu X. Effects of mifepristone on uterine leiomyoma in premenopausal women: a meta-analysis. Fertil Steril 2013;100:1722–1726.3) Steinauer J, Pritts EA, Jackson R, et al. Systematic review of mifepristone for the treatment of uterine leiomyomata. Obstet Gynecol 2004;103: 1331–6.4) Carbonell Esteve JL, Riveron AM, Cano M, et al. Mifepristone 2.5mg versus 5mg daily in the treatment of leiomyoma before surgery. Int J Womens Health 2012;4:75–84.5) Fiscella K, Eisinger SH, Meldrum S, et al. Effect of mifepristone for symptomatic leiomyomata on quality of life and uterine size: a randomized controlled trial. Obstet Gynecol 2006;108:1381.6) Liu C, Lu Q, Qu H, Geng L, Bian M, Huang M, Wang H, Zhang Y, Wen Z, Zheng S, Zhang Z. Different dosages of mifepristone versus enantone to treat uterine fibroids: A multicenter randomized controlled trial. Medicine (Baltimore). 2017 Feb;96(7):e6124.7) Donnez J, Tatarchuk TF, Bouchard P, Puscasiu L, Zakharenko NF, Ivanova T, Ugocsai G, Mara M, Jilla MP, Bestel E, et al. Ulipristal acetate versus placebo for fibroid treatment before surgery. N Engl j Med 2012a;366:409–420.8) Donnez J, Tomaszewski J, Vázquez F, Bouchard P, Lemieszczuk B, Baró F, Nouri K, Selvaggi L, Sodowski K, Bestel E, et al. Ulipristal acetate versus leuprolide acetate for uterine fibroids. N Engl J Med. 2012b;366:421–432.9) Donnez J, Vazquez F, Tomaszewski J, Nouri K, Bouchard P, Fauser B, et al. PEARL III and PEARL III Extension Study Group. Long-term treatment of uterine fibroids with ulipristal acetate*. Fertil Steril 2014;101(6):1565–1573.10) Donnez J, Hudecek R, Donnez O, Matule D, Arhendt HJ, Zatik J, Kasilovskiene Z, Dumitrascu MC, Fernandez H, Barlow DH, et al. Efficacy and Safety of repeated use of ulipristal acetate in uterine fibroids. Fertil Steril 2015a;103:519–527.11) Donnez J, Donnez O, Matule D, Ahrendt HJ, Hudecek R, Zatik J, Kasilovskiene Z, Dumitrascu MC, Fernandez H, Barlow DH, Bouchard P, Fauser BC, Bestel E, Loumaye E. Long-term medical management of uterine fibroids with ulipristal acetate. Fertil Steril. 2016 Jan;105(1):165-173.e4. 12) Donnez J, Donnez O, Matule D, Ahrendt HJ, Hudecek

R, Zatik J, Kasilovskiene Z, Dumitrascu MC, Fernandez H, Barlow DH, et al. Long–term medical management of uterine fibroids with ulipristal acetate. Fertil Steril 2016;105:165–173.13) Donnez J, Arriagada P, Donnez O, Dolmans MM. Current management of myomas: the place of medical therapy with the advent of selective progesterone receptor modulators. Curr Opin Obstet Gynecol 2015b;27:422–431.14) Donnez J, Donnez O, Matule D, Ahrendt HJ, Hudecek R, Zatik J, Kasilovskiene Z, Dumitrascu MC, Fernandez H, Barlow DH, Bouchard P, Fauser BC, Bestel E, Loumaye E. Long-term medical management of uterine fibroids with ulipristal acetate. Fertil Steril. 2016 Jan;105(1):165-173.e4.15) Deng L, Wu T, Chen XY, Xie L, Yang J. Selective estrogen receptor modulators(SERMs) for uterine leiomyomas. Cochrane Database Syst Rev. 2012 Oct 17;10:CD005287.16) Pohl O, Zobrist RH, Gotteland JP. The clinical pharmacology and pharmacokinetics of ulipristal acetate for the treatment of uterine fibroids. Reprod Sci. 2015 Apr;22(4):476-83.17) Pohl O, Osterloh I, Gotteland JP. Ulipristal acetate - safety and pharmacokinetics following multiple doses of 10-50 mg per day. J Clin Pharm Ther. 2013 Aug;38(4):314-20.18) Donnez J, Schrurs B, Gillerot S, Sandow J, Clerckx F. Treatment of uterine fibroids with implants of gonadotropin-releasing hormone agonist: assessment by hysterography. Fertil Steril 1989;51:947–950.19) Carr BR, Marshburn PB, Weatherall PT, Bradshaw KD, Breslau NA, Byrd W, et al. An evaluation of the effect of gonadotropin-releasing hormone analogs and medroxyprogesterone acetate on uterine leiomyomata volume by magnetic resonance imaging: a prospective, randomized, double blind, placebo-controlled, crossover trial. J Clin Endocrinol Metab 1993;76:1217–122320) Friedman AJ, Daly M, Juneau-Norcross M, Rein MS, Fine C, Gleason R, et al. A prospective, randomized trial of gonadotropin-releasing hormone agonist plus estrogen-progestin or progestin “add-back” regimens for women with leiomyomata uteri. J Clin Endocrinol Metab 1993;76:1439–1445.21) Moroni RM, Martins WP, Ferriani RA, Vieira CS, Nastri CO, Candido Dos Reis FJ, Brito LG. Add-back therapy with GnRH analogues for uterine fibroids. Cochrane Database Syst Rev. 2015 Mar 20;(3):CD010854.22) Friedman AJ, Hoffman DI, Comite F, Browneller



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RW, Miller JD. Treatment of leiomyomata uteri with leuprolide acetate depot: a double-blind, placebo-controlled, multicenter study. The Leuprolide Study Group. Obstet Gynecol 1991;77:720–725.23) Reissmann T, Diedrich K, Comaru-Schally AM, Schally AV. Introduction of LHRH-antagonists into the treatment of gynaecological disorders. Human Reprod 1994;9:767–769.24) Britten JL, Malik M, Levy G, Mendoza M, Catherino WH. Gonadotropin-releasing hormone (GnRH) agonist leuprolide acetate and GnRH antagonist cetrorelix acetate directly inhibit leiomyoma extracellular matrix production. Fertil Steril. 2012 Nov;98(5):1299-307.25) Britten JL, Malik M, Levy G, Mendoza M, Catherino WH. Gonadotropin-releasing hormone (GnRH) agonist leuprolide acetate and GnRH antagonist cetrorelix acetate directly inhibit leiomyoma extracellular matrix production. Fertil Steril 2012;98:1299–1307.26) De Leo V, Morgante G, La Marca A, Musacchio MC, Sorace M, Cavicchioli C, et al. A benefit-risk assessment of medical treatment for uterine leiomyomas. Drug Saf 2002;25(11):759e79.27) Munro MG, Mainor N, Basu R, Brisinger M, Barreda L. Oralmedroxyprogesterone acetate and combination oral contraceptives for acute uterine bleeding: A randomized controlled trial. Obstet Gynecol 2006;108(4):924e9.28) Qin J, Yang T, Kong F, Zhou Q. Oral contraceptive use and uterine leiomyoma risk: A meta-analysis based on cohort and case-control studies. Arch Gynecol Obstet 2013;288(1):139e48.29) Orsini G, Laricchia L, Fanelli M. Low-dose combination oral contraceptives use in women with uterine leiomyomas. Minerva Ginecol 2002;54(3):253e61.30) Sayed GH, Zakherah MS, El-Nashar SA, Shaaban MM. A randomized clinical trial of a levonorgestrel-releasing intrauterine system and a low-dose combined oral contraceptive for fibroid-related menorrhagia. Int J Gynaecol Obstet 2011;112:126–130.31) Maruo T, Ohara N, Yoshida S, Nakabayashi K, Sasaki H, Xu Q, et al. Translational research with progesterone receptor modulator motivated by the use of levonorgestrel-releasing intrauterine system. Contraception 2010;82:435-441.32) Magalhães J, Aldrighi JM, de Lima GR. Uterine volume and menstrual patterns in users of the levonorgestrel-releasing intrauterine system with idiopathic menorrhagia or menorrhagia due to leiomyomas. Contraception 2007;75:193–198.33) Sayed GH, Zakherah MS, El-Nashar SA, Shaaban MM. A randomized clinical trial of a levonorgestrel-releasing intrauterine system and a low-dose combined oral contraceptive for fibroid-related menorrhagia. Int J Gynaecol Obstet 2011;112:126–130.34) Verspyck E, Marpeau L, Lucas C. Leuprorelin depot 3.75 mg versus lynestrenol in the preoperative treatment of symptomatic uterine myomas: a multicentre randomised trial. Eur J Obstet Gynecol Reprod Biol 2000;89:7–13.35) Sangkomkamhang US, Lumbiganon P, Laopaiboon M, Mol BW. Progestogens or progestogen-releasing

intrauterine systems for uterine fibroids. Cochrane Database Syst Rev 2013;2:CD008994.36) ACOG Committee on Practice Bulletins-Gynecology. ACOG practice bulletin: surgical alternatives to hysterectomy in the management of leiomyomas. Int J Gynaecol Obstet 2001;73:285–294.37) Ke LQ, Yang K, Li J, Li CM. Danazol for uterine fibroids. Cochrane Database Syst Rev 2009;3:CD007692.38) NICE guideline Heavy menstrual bleeding: assessment and management 2016.39) Song H, Lu D, Navaratnam K, Shi G. Aromatase inhibitors for uterine fibroids. Cochrane Database Syst Rev 2013;10:CD009505.40) Donnez J, Hervais Vivancos B, Kudela M, Audebert A, Jadoul P. A randomized, placebo-controlled, dose-ranging trial comparing fulvestrant with goserelin in premenopausal patients with uterine fibroids awaiting hysterectomy. Fertil Steril 2003;79:1380–1389.41) Deng L, Wu T, Chen XY, Xie L, Yang J. Selective estrogen receptor modulators (SERMs) for uterine leiomyomas. Cochrane Database Syst Rev 2012;10:CD005287.42) M.S. Kim, Y.K. Uhm, J.Y. Kim, B.C. Jee, Y.B. Kim. Obstetric outcomes after uterine myomectomy: laparoscopic versus laparotomic approach. Obstet Gynecol Sci, 56 (2014), pp. 375–381.43) Richards T, Musallam KM, Nassif J, Ghazeeri G, Seoud M, Gurusamy KS, Jamali FR. Impact of preoperative anaemia and blood transfusion on postoperative outcomes in gynaecological surgery. PLoS One 2015;6:10.44) Lethaby A, Vollenhoven B, Sowter M. Pre-operative GnRH analogue therapy before hysterectomy or myomectomy for uterine fibroids. Cochrane Database Syst Rev. 2001;(2):CD000547. Review. PubMed PMID: 11405968.45) Donnez J, Donnez O, Dolmans MM. Safety of treatment of uterine fibroids with the selective progesterone receptor modulator, ulipristal acetate. Expert Opin Drug Saf. 2016 Dec;15(12):1679-1686. PubMed PMID: 27740868.46) Donnez J, Donnez O, Dolmans MM. With the advent of selective progesterone receptor modulators, what is the place of myoma surgery in current practice. Fertil Steril 2014a;102:640–648.47) Lethaby A, Vollenhoven B, Sowter M. Pre-operative GnRH analogue therapy before hysterectomy or myomectomy for uterine fibroids. Cochrane Database Syst Rev. 2001;(2):CD000547.48) Luyckx M, Squifflet JL, Jadoul P, Votino R, Dolmans MM, Donnez J. First series of 18 pregnancies after ulipristal acetate treatment for uterine fibroids. Fertil Steril 2014;102:1404–1409.49) Friedman AJ, Hoffman DI, Comite F, Browneller RW, Miller JD. Treatment of leiomyomata uteri with leuprolide acetate depot: a double-blind, placebo-controlled, multicenter study. The Leuprolide Study Group. Obstet Gynecol 1991;77:720–725.50) Malone LJ. Myomectomy: recurence after removal of solitary and multiple myomas. Obstet Gynecol 1969;34:200–209.


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51) Fauser BC, Donnez J, Bouchard P, Barlow DH, Vázquez F, Arriagada P, Skouby SO, Palacios S, Tomaszewski J, Lemieszczuk B, William AR. Safety after extended repeated use of ulipristal acetate for uterine fibroids. PLoS One. 2017 Mar 7;12(3):e0173523.52) Monleón J, Martínez-Varea A, Galliano D, Pellicer A. Successful pregnancy after treatment with ulipristal acetate for uterine fibroids. Case Rep Obstet Gynecol 2014;2014:314587.53) Yan L MD, Ding L, Li C, Wang YD PH, Tang R, Chen ZJ. Effect of fibroids not distorting the endometrial cavity on the outcome of in vitro fertilization treatment: a retrospective cohort study. Fertil Steril 2014;101:716–721.54) Metwally M, Farquhar CM, Li TC. Is another meta-analysis on the effects of intramural fibroids on reproductive outcomes needed? Reprod Biomed Online 2011;23:2–14.55) Segars JH, Parrott EC, Nagel JD, Guo XC, Gao X, Birnbaum LS, Pinn VW, Dixon D. Proceedings from the Third National Institutes of Health International Congress on Advances in Uterine Leiomyoma Research: comprehensive review, conference summary and future recommendations. Hum Reprod Update.

(G0) or mostly (G1) intracavitary, can be easily removed in a single procedure with fibroid size representing the main limiting factor (generally no more than 5 cm). “Resectoscopic slicing” still represents the “gold standard” technique for the treatment of such fibroids, even if several other effective techniques including morcellation, and office myomectomy have been proposed, mostly for small myomas.

On the other hand, the resection of fibroids with prevalent intramural extension (G2) is advisable only for expert surgeons as it is technically hard and has a higher risk of complications respect to other hysteroscopic procedures. Currently there is still not a single technique proven to be unequivocally superior for the treatment of such fibroids. Most techniques aim to transform an intramural fibroid to a totally intracavitary lesion, thus avoiding a deep cut into the myometrium. At present, the “cold loop” technique developed by Dr. Ivan Mazzon seems to represent the best option as it allows a safe and complete removal of such fibroids in just one surgical procedure, while respecting the surrounding healthy myometrium. Hysteroscopic myomectomy is the ideal approach for the treatment of submucous fibroids, both for those entirely located within the uterine cavity (G0) and for those with more than 50% of their

SECTION 3: SURGICAL TREATMENTS3.1 Hysteroscopy Surgery3.1.1 When hysteroscopic myomectomy is

the “gold standard” for the treatment of uterine fibroids?

Currently, conservative and less invasive techniques, such as hysteroscopy, are valid surgical alternatives to traditional techniques such as hysterectomy and myomectomy (laparotomy), for the treatment of symptomatic submucous fibroids.

Hysteroscopic myomectomy is the best therapeutic option for the treatment of submucous fibroids since it allows to improve the clinical conditions and to preserve the integrity of the uterine wall.

Moreover, hysteroscopic resection, compared to traditional techniques, is associated with shorter operative times, less blood loss and a lower risk of infections and adhesions. Other advantages of this technique include the reduction of surgery costs and, more importantly, a reduction in the duration of recovery and the relevant costs. Patients, in witch only myomectomy is necessary, will have a less traumatic postoperative course also in a psychological point of view.

The choice of the technique mostly depends on the intramural extension of the fibroid, as well as on personal experience and available equipment. It is well established that fibroids, completely

2014 May-Jun;20(3):309-33.56) Sunkara SK, Khairy M, El-Toukhy T, Khalaf Y, Coomarasamy A. The effect of intramural fibroids without uterine cavity involvement on the outcome of IVF treatment: a systematic review and meta-analysis. Hum Reprod 2010;25: 418–29.57) Saravelos SH, Yan J, Rehmani H, Li TC. The prevalence and impact of fibroids and their treatment on the outcome of pregnancy in women with recurrent miscarriage. Hum Reprod. 2011 Dec;26(12):3274-9.58) Parazzini F, Tozzi L, Bianchi S. Pregnancy outcome and uterine fibroids. Best Pract Res Clin Obstet Gynaecol. 2016 Jul;34:74-84.59) Donnez J, Jadoul P. What are the implications of myomas on fertility? A need for a debate? Hum Reprod. 2002 Jun;17(6):1424-30.60) Somigliana E, Vercellini P, Daguati R, Pasin R, De Giorgi O, Crosignani PG. Fibroids and female reproduction: a critical analysis of the evidence. Hum Reprod Update. 2007 Sep-Oct;13(5):465-76. Epub 2007 Jun 21.61) Galliano D. Ulipristal acetate in uterine fibroids. Fertil Steril. 2015 Feb;103(2):359-60.



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volume in the uterine cavity (G1). Fibroids with an intracavitary component of less than 50% (G2) are harder to treat by hysteroscopy and may require long operative times. Moreover, although fibroids larger than 5 cm and with a more remarkable intramural component can be treated hysteroscopically, usually hysteroscopic myomectomy is recommended only for fibroids smaller than 5 cm in diameter.

3.1.2 What are the indications for and the limits of hysteroscopic myomectomy in an outpatient setting?

In recent years, many uncontrolled clinical trials have been published, demonstrating the feasibility, tolerability and safety of office hysteroscopy. Already in 2002, Bettocchi assessed the efficacy, safety and acceptability of operative hysteroscopy in an outpatient setting without analgesia or anaesthesia for the treatment of benign intracavitary diseases with 5Fr bipolar electrodes.26

The literature available from 1990 to 2002 has clearly demonstrated that this technique allows to treat small fibroids safely, without dilatation of the cervical canal and without anaesthesia.

Fibroid treatment depends mainly on location, size and number of fibroids. Currently, it is (or should be) widely accepted that a 0.5 cm lesion affecting the uterine cavity can cause more serious damage than a 3cm lesion that develops in the serosa.

Small fibroids, whether completely (G0) or partially (G1) intracavitary, symptomatic or asymptomatic, with a size ranging from 1.5 to 2 cm, can be effectively and safely removed by

ambulatory surgery using the technique described by Bettocchi.26 It is very important to carefully evaluate the size of the lesion; since fibroids usually have a roundish shape, the linear growth in the diameter of a fibroid corresponds to the quadratic growth in its surface and to the cubed growth of its volume.

Data provided by the international literature concerning the need to treat small submucous fibroids, confirm that, for fertile women with small submucous fibroids, waiting is no longer acceptable, even if such lesions are asymptomatic, especially if they can be easily and safely removed by ambulatory surgery, with minimal patient discomfort.26-32

3.1.3 Does hysteroscopic myomectomy result in an improvement in reproductive outcomes in infertile women?

Although epidemiological data show that most of women with fibroids are fertile, much evidence suggests that fibroids may interfere with fertility; in particular, submucous fibroids seem to exert the majority of the negative effects on reproductive outcomes. Although this association is not supported by a clear biological rationale, several hypotheses have been proposed in order to explain how submucous fibroids can cause prolonged sterility or repeated miscarriages. Fibroids may interfere with sperm migration, oocyte transport or embryo implantation. All of these effects could be mediated or altered by the contour of the uterine cavity, with a consequent increase in mechanical pressure, or by the occurrence of abnormalities in uterine contractility. Currently, however, none of these hypotheses seems to be supported by certain clinical data. Fibroids have also been associated with implant failure or premature termination of pregnancy due to focal vascular disorders of the endometrium, endometrial inflammation, secretion of vasoactive substances or a local increase in androgens.

The presence of submucous fibroids may also be associated with an increased risk of obstetric


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complications (miscarriage, preterm birth, abnormal fetal presentation, placenta previa, abruptio placentae). In 2008, Klatsky reported an increase in the risk of miscarriage and preterm birth of 16% and an abnormal fetal presentation rate of 13% (about 2.5 times higher than the general population) in women with uterine fibroids compared to women with no fibroids.32 In the same study, Klatsky also reported a twice-higher risk of placenta previa and 3% abruptio placentae in women with intramural submucous fibroids, compared to the control group.33

Similarly, Pritts, in his meta-analysis, confirmed the results of previous studies, including women undergoing assisted reproduction techniques.

The different studies provided by the literature are characterised by a real discrepancy in the estimated risk of adverse obstetric events in women with submucous fibroids, even if most of them show a risk twice more high respect to the general population.33-47

Many authors have evaluated the effects of hysteroscopic myomectomy on reproductive outcomes in infertile women. The post-operative pregnancy rate ranges from 16.7% to 76.9% with an average of 45%. This great variability can be due to the hard control of multiple concomitant factors potentially determining the condition of infertility, such as differences in the sample size, duration of follow-up, different characteristics of the patients enrolled (age, primary or secondary infertility) and to the different characteristics of the treated fibroid (number, size, intramural extension and concomitant presence of intramural fibroids). A recent cohort study showed that, in women with recurrent miscarriage and intracavitary uterine fibroids, hysteroscopic myomectomy – by restoring the normal uterine morphology – significantly improves reproductive outcomes, doubling the rate of live births. Dietterich and colleagues, on the other hand, have shown that small fibroids, which do not modify the morphology of the uterine cavity, do not seem to influence fertility, even in older women. One RCT (Boostel et al 2010) compared hysteroscopic myomectomy with the decision to not perform the surgery in 94 patients with primary infertility and the results were not statistically significant.

In general, uncontrolled studies have suggested a decrease in the rate of miscarriage after myomectomy, compared to the miscarriage rate before surgery. In a study that included women with recurrent miscarriage and/or uterine cavity distortion, who underwent myomectomy, a decrease in miscarriage rates from 21.7% to 0%

in the second trimester in subsequent pregnancies was demonstrated. Other studies have also shown a remarkable decrease in the rate of miscarriage (from 61.6% to 26.3%) after hysteroscopic treatment of uterine fibroids.

Published data suggest that pregnancy, live births and miscarriage rates will normalize after myomectomy for submucous fibroids, compared to infertile women without fibroids.

In 2012, Metwallt published a review of randomized trials, about the effect of surgical treatment of fibroids on fertility, in this review he identified a study, which showed no evidence of a significant effect on the rate of miscarriage. This study also showed an increase in the spontaneous pregnancy rate after surgical treatment of submucous fibroids, while the pregnancy rate after the removal of intramural or subserosal fibroids was not increased compared to the control group (patients who had not yet undergone surgery).48-54

There are no randomized trials published after 2012 on this subject.

In conclusion, clinical experience and observational studies suggest that treatment of uterine fibroids could improve reproductive outcomes. However, due to the lack of large randomized clinical trials and the collection of limited and inconclusive data, it is not possible to draw conclusions on the actual effect of hysteroscopic myomectomy on fertility.

Surgical treatment of uterine fibroids is also associated with complications, including intrauterine adhesion. So, the potential benefit that could result from surgical treatment can be reversed by the negative effects of surgery on uterine integrity.

We can say, therefore, that fertility problems remain a sensitive and controversial topic, for which every treatment option must be widely discussed with the couple.

However, in women with unexplained infertility, or with a history of recurrent miscarriage or early loss of pregnancy, the removal of these lesions should always be recommended. The treatment of subserosal fibroids, on the other hand, is not recommended.



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3.1.4 Can the removal of asymptomatic fibroids be indicated in cases of uterine cavity distortion or in ART candidate patients, in the absence of other causes of infertility?

The development of ART (Assisted Reproductive Technology), and in particular in vitro fertilization (IVF) have helped to clarify the relationship between uterine fibroids and embryo reproductive outcomes. However, there is no consensus on the hypothesis that the presence of fibroids negatively affects post-ART reproductive outcomes and therefore on the fact that they must always be removed before ART. The position and size of the fibroid are considered key factors of post-ART reproductive outcomes.

The effect of hysteroscopic myomectomy on post-IVF reproductive outcome has not been well investigated in the literature. Among the few studies available, four meta-analyses evaluated the impact of fibroids on IVF cycles. Pritts reported significantly lower pregnancy rates and implantation rates in patients with submucous fibroids and abnormal uterine cavities, compared to the control group of infertile women without fibroids, while not showing an increase in the pregnancy rate in infertile patients undergoing surgery for intramural fibroids.

The results provided by Donnez and Jadoul confirmed that only submucous fibroids have a negative impact on embryo implantation.55 Somigliana carried out an updated meta-analysis

2001: a comprehensive review. Acta Obstet Gynecol Scand. 2001 Sep;80(9):773-838) Murakami T, Tamura M, Ozawa Y et al. Safe techniques in surgery for hysteroscopic myomectomy. J Obstet Gynaecol Res. 2005 Jun;31(3):216-239) Neurwirth RS, Amin HK. Excission of submucous fibroids with hysteroscopic control. Am J Obstet Gynecol 1976;126:95-9910) Mazzon I. Nuova tecnica per la miomectomia isteroscopica: enucleazione con ansa fredda. In: Cittadini E, Perino A, Angiolillo M, Minelli L (eds). Testo-Atlante di Chirurgia Endoscopica Ginecologica. Palermo: COFESE Ed, 1995, cap. XXXIIIb11) Litta P, Vasile C, Merlin F et al. A new technique of hysteroscopic myomectomy with enucleation in toto. J Am Assoc Gynecol Laparosc 2003;10:263-27012) Loffer FD. Removal of large symptomatic intrauterine growths by the hysteroscopic resectoscope. Obstet Gynecol 1990; 76:836-84013) Hamou J. Electroresection of fibroids. In: Sutton C, Diamond MP (eds). Endoscopic Surgery for Gynecologists. London: WB Saunders, 1993:327-33014) Hallez JP. Single-stage total hysteroscopic

and reported significantly lower pregnancy rates for patients with submucosal and intramural fibroids.55 Of the three studies assessing the impact of prior myomectomy on IVF cycles, only two included patients who underwent surgery for submucosal fibroids. A meta-analysis of these two studies shows that hysteroscopic myomectomy seems to positively affect the probability of post-IVF pregnancy. However, this positive effect could be challenged, since this meta-analysis is based on only two retrospective studies, both characterized by low sample size.55-60

In the international literature, there are not prospective studies comparing the removal of submucous fibroids in women undergoing ART, with a diameter of less than 1.5 cm, with no surgery (waiting behaviour).

However, even considering the potential risk of failure, we believe that patients with unexplained infertility or with a history of recurrent miscarriage should undergo surgical treatments to improve the morphology and function of the uterine cavity before undergoing any fertility treatment cycle.

1) Wamsteker K, Emanuel MH, de Kruif JH. Transcervical hysteroscopic resection of submucous fibroids for abnormal uterine bleeding: results regarding the degree of intramural extension. Obstetrics and Gynecology 1993;82(5):736–40.2) Lasmar RB, Barrozo PR, Dias R, Oliveira MA. Submucous fibroids: a new presurgical classification to evaluate the viability of hysteroscopic surgical treatment – preliminary report. The Journal of Minimally Invasive Gynecology 2005; 12: 308–11.3) Lasmar RB, Xinmei Z, Indman P, Keller R, Di Spiezio Sardo A. Feasibility of a new system classification of submucous mioma: a multicenter study. Fertility and Sterility 2011; 95(6): 2073–7.4) Mazzon I, Sbiroli C. Manuale di chirurgia resettoscopica in ginecologia. Torino. UTET, 1997:91-2175) Indman PD. Hysteroscopic treatment of submucous fibroids. Clin Obstet Gynecol 2006; 49:811-8206) Emanuel MH, Wamsteker K. The Intra Uterine Morcellator: a new hysteroscopic operating technique to remove intrauterine polyps and fibroid. J Minim Invasive Gynecol 2005; 12:62-837) Wieser F, Tempfer C, Kurz C et al. Hysteroscopy in


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myomectomies: indications, techniques, and results. Fertil Steril 1995;63:703-70815) Lin B, Akiba Y, Iwata Y. One-step hysteroscopic removal of sinking submucous fibroid in two infertile patients. Fertil Steril 2002;74:1035-103816) Haney AF Clinical decision making regarding leiomyomata: what we need in the next millenium. Environ Health Perspect 2000; 108, Suppl 5, 835-839.17) Munoz JL, Jimenez JS, Hernandez C, Vaquero G, Perez Sagaseta C, Noguero R, et al. Hysteroscopic myomectomy: our experience and review. JSLS 2003; 7: 39-48. 18) Berkeley AS, DeCherney AH, Polan ML. Abdominal myomectomy and subsequent fertility. Surg Gynecol Obstet 1983; 156: 319-322.19) Buttram VC Jr and Reiter RC. Uterine leiomyomata: etiology, symptomatology, and management. Fertil Steril 1981;36:433-445.20) Walker CL, Stewart EA Uterine fibroids: the elephant in the room. Science 2005; 308: 1589-1592. 21) Bradley LD. Abnormal uterine bleeding. Nurse Pract 2005;30:38-42.22) Takeda A, Manabe S, Hosono S, Nakamura H. Preoperative evaluation of submucosal myoma by virtual hysteroscopy. J Am Assoc Gynecol Laparosc 2004; 11, 404-409.23) Vercellini P, Zaina B, Yaylayan L et al. Hysteroscopic myomectomy: long-term effects on menstrual pattern and fertility. Obstet Gynecol 1999;94:341–34724) Camanni M, Bonino L, Delpiano EM, Ferrero B, Migliaretti G, Deltetto F. Hysteroscopic management of large symptomatic submucous uterine myomas. J Minim Invasive Gynecol 2010;17:59–65.25) Mazzon I, Favilli A, Grasso M, Horvath S, Di Renzo GC, Gerli S. Is Cold Loop Hysteroscopic Myomectomy a Safe and Effective Technique for the Treatment of Submucous Myomas With Intramural Development? A Series of 1434 Surgical Procedures. J Minim Invasive Gynecol. 2015 Jul-Aug;22(5):792-8.26) Di Spiezio Sardo A, Bettocchi S, Spinelli M, Guida M, Nappi L, Angioni S, Sosa Fernandez LM, Nappi C. Review of New Office-Based Hysteroscopic Procedures 2003–2009. Journal of Minimally Invasive Gynecology 2010; 17: 436–448. 27) Di Spiezio Sardo A, Bramante S, Mazzon I, Bettocchi S, Bifulco G, Guida M, et al. Hysteroscopic myomectomy: a comprehensive review of surgical techniques. Hum Reprod Update 2008 Mar-Apr;14(2):101-1928) Bettocchi S, Nappi L, Ceci O, Selvaggi L. What does ‘‘diagnostic hysteroscopy’’ mean today? The role of the new techniques. Curr Opin Obstet Gynecol 2003;15:303–829) Bettocchi S. New Era of Office Hysteroscopy. J Am Assoc Gynecol Laparosc. 1996; 3(4, Supplement):S4. 30) Bettocchi S, Ceci O, Di Venere R, Pansini MV, Pellegrino A, Marello F, Nappi L. Advanced operative office hysteroscopy without anaesthesia: analysis of 501 cases treated with a 5 Fr. bipolar electrode. Hum Reprod. 2002;17(9):2435-8. 31) Paschopoulos M, Paraskevaidis E, Stefanidis K, Kofinas G, Lolis D. Vaginoscopic approach to

outpatient hysteroscopy. J Am Assoc Gynecol Laparosc 1997; 4:465-7.32) Bettocchi S, Ceci O, Nappi L, Di Venere R, Masciopinto V, Pansini V, et al. Operative office hysteroscopy without anesthesia: analysis of 4863 cases performed with mechanical instruments. J Am Assoc Gynecol Laparosc. 2004;11(1):59-61. 33) Klatsky PC, Tran ND, Caughey AB, et al. Fibroids and reproductive outcomes: a systematic literature review from conception to delivery. Am J Obstet Gynecol 2008;198:357e66.34) Garcia CR, Tureck RW Submucosal leiomyomas and infertility. Fertil Steril 1984; 42: 16-19. 35) Smith DC, Uhlir JK Myomectomy as a reproductive procedure. Am J Obstet Gynecol 1990; 162: 1476-1479 36) Verkauf BS. Myomectomy for fertility enhancement and preservation. Fertil Steril 1992; 58: 1-15. 37) Sudik R, Husch K, Steller J, Daume E. Fertility and pregnancy outcome after myomectomy in sterility patients. Eur J Obstet Gynecol Reprod Biol 1996; 65:209-214. 38) Ubaldi F, Tournaye H, Camus M, Van der Pas H, Gepts E, Devroey P. Fertility after hysteroscopic myomectomy. Hum Reprod Update 1995;1: 81-90.39) Stout MJ, Odibo AO, Graseck AS, et al. Leiomyomas at routine second-trimester ultrasound examination and adverse obstetric outcomes. Obstet Gynecol 2010;116:1056e63.40) Pritts EA, Parker WH, Olive DL. Fibroids and infertility: an updated systematic review of the evidence. Fertil Steril 2009;91:1215e23.41) Shavell VI, Thakur M, Sawant A, et al. Adverse obstetric outcomes associated with sonographically identified large uterine fibroids. Fertil Steril 2012;97:107e10.42) Stout MJ, Odibo AO, Shanks AL, et al. Fibroid tumors are not a risk factor for adverse outcomes in twin pregnancies. Am J Obstet Gynecol 2013;208(68):e61e65.43) Navid S, Arshad S, Qurat ul A, et al. Impact of leiomyoma in pregnancy. J Ayub Med Coll Abbottabad 2012;24:90e2.44) Ciavattini A, Clemente N, Delli Carpini G, et al. Number and size of uterine fibroids and obstetric outcomes. J Matern Fetal Neonatal Med 2015;28:484e8.45) Chen YH, Lin HC, Chen SF, et al. Increased risk of preterm births among women with uterine leiomyoma: a nationwide population-based study. Hum Reprod 2009;24:3049e56.46) Coronado GD, Marshall LM, Schwartz SM. Complications in pregnancy, labor, and delivery with uterine leiomyomas: a population-based study. Obstet Gynecol 2000;95:764e9.47) Conti N, Tosti C, Pinzauti S, et al. Uterine fibroids affect pregnancy outcome in women over 30 years old: role of other risk factors. J Matern Fetal Neonatal Med 2013;26:584e7.48) Metwally M, Farquhar CM, Li TC. Is another meta-analysis on the effects of intramural fibroids on reproductive outcomes needed? Reprod Biomed Online 2011;23:2e14.49) Brady PC, Stanic AK, Styer AK. Uterine fibroids and subfertility: an update on the role of myomectomy.



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Curr Opin Obstet Gynecol 2013;25:255e9.50) Metwally M, Cheong YC, Horne AW. Surgical treatment of fibroids for subfertility. Cochrane Database Syst Rev 2012;11: CD003857. 51) Borja de Mozota D, Kadhel P, Janky E. Fertility, pregnancy outcomes and deliveries following myomectomy: experience of a French Caribbean University Hospital. Arch Gynecol Obstet 2014;289:681e6.52) Zhang Y, Hua KQ. Patients’ age, myoma size, myoma location, and interval between myomectomy and pregnancy may influence the pregnancy rate and live birth rate after myomectomy. J Laparoendosc Adv Surg Tech A 2014;24:95e9.53) Saravelos SH, Yan J, Rehmani H, et al. The prevalence and impact of fibroids and their treatment on the outcome of pregnancy in women with recurrent miscarriage. Hum Reprod 2011;26:3274e9.54) Shokeir TA. Hysteroscopic management in submucous fibroids to improve fertility. Arch Gynecol Obstet 2005;273:50e4.55) Donnez J, Jadoul P. What are the implications of fibroids on fertility? A need for a debate? Human Reproduction 2002; 17: 1424–1430.

the final histological examination, and the use of morcellators, in this case, significantly compromises the prognosis, this is why the FDA, in 2014, has discouraged the use of these devices. 8 Therefore, the use of morcellators is not recommended in case of suspected malignancy. Endobag morcellation, on the other hand, is an innovative technique not associated with oncological risks. To perform this technique, the removed mass must be placed inside a laparoscopic endobag, whose edges are pulled out by one of the surgical incisions to allow a safe manual or automatic morcellation and to avoid nebulization of cells in the peritoneal cavity. This is a technique similar to that used routinely to extract adnexal masses to avoid spillage, which would change the stage of disease in case of malignancy.9

Today new endobags are available on the market, which allow the insertion of trocars inside them to facilitate the procedure of morcellation.10-11

Generally, the use of GnRH analogues is not recommended as it does not reduce operative times and may alter the anatomical limits of the fibroid, and seems to be associated with a higher rate of reoccurrence, but has proved useful in patients with low levels of preoperative hemoglobin.12

A 2016 retrospective study shows that a pre-treatment with UPA three months before performing a laparoscopic myomectomy

56) Somigliana E, Vercellini P, Daguati R, Pasin R, De Giorgi O, Crosignani PG. Fibroids and female reproduction: a critical analysis of the evidence. Human Reproduction Update 2007; 13: 465–476.57) Tian YC, Long TF, Dai YM. Pregnancy outcomes following different surgical approaches of myomectomy. J Obstet Gynaecol Res 2015;41:350e7.58) Sunkara SK, Khairy M, El-Toukhy T, Khalaf Y, Coomarasamy A. The effect of intramural fibroids without uterine cavity involvement on the outcome of IVF treatment: a systematic review and meta-analysis. Human Reprod 2010;25:418–29.59) Bozdag G, Esinler I, Boynukalin K, Aksu T, Gunalp S, Gurgan T. Single intramural leiomyoma with normal hysteroscopic findings does not affect ICSI-embryo transfer outcome. Reproductive Biomedicine Online 2009;19:276–80.60) Marret H., Fritel X., Ouldamer L., Bendifallah S., Jean-Luc Brun, De Jesus I., Derrien J., Giraudet G., Kahn V., Koskas M., Legendre G., Lucot JP., Niro J., Panel P., Pelage J.P.,Fernandez H., Therapeutic management of uterine fibroid tumors: updated French guidelines. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2012; 156-164.

3.2 Laparascopy3.2.1 Laparoscopic myomectomyThe size and location of the fibroid are the

main criteria for the choice of laparoscopic myomectomy.

Laparoscopic myomectomy, compared to laparotomy, offers many advantages, such as a reduction in intraoperative and post-operative morbidity, a faster recovery and good overlapping results in terms of fertility.1-3 This procedure, however, is associated with objective difficulties, especially those related to the hysterotomic suture.

The presence of an intramural fibroid larger than 10 cm, or the presence of multiple fibroids located in different areas of the uterus, that would require numerous incisions, are generic contraindications, depending mostly on the experience of the surgeon and on the surgical technique.4-5 Whether very long operative times are expected due to the size, location or number of fibroids, laparotomy is a more appropriate choice.

The risk of uterine rupture during pregnancy after laparoscopic myomectomy does not appear to be greater than laparotomy, in large series it was less than 1% if the hysterotomy has been adequately repaired.6 Moderate use of electrosurgery and multilayer suture can reduce the risk of dehiscence in pregnancy.7

The use of morcellators is often required for laparoscopic myomectomy. It seems that 1 fibroid out of 400 is a leiomyosarcoma, as confirmed by


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is strongly recommended for patients with voluminous uterine fibroids, since operative times are reduced, as well as intraoperative blood loss, and, consequently post-operative blood transfusions.13

laparoscopic myomectomy? J Minim Invasive Gynecol. 2008 May-Jun;15(3):292-300.6) Dubuisson J.B., Chapron C., Chavet X., Gregorakis, S.S. Fertility after laparoscopic myomectomy of large intramural myomas: preliminary results. Hum Reprod. 1996; 11: 518–522.7) Parker WH, Einarsson J, Istre O, Dubuisson JB. Risk factors for uterine rupture after laparoscopic myomectomy. J Minim Invasive Gynecol. 2010 Sep-Oct;17(5):551-4. doi: 10.1016/j.jmig.2010.04.015. Epub 2010 Jun 29. Review. Erratum in: J Minim Invasive Gynecol. 2010 Nov-Dec;17(6):809.8) Food and Drug Administration. Quantitative assessment of the prevalence of unsuspected uterine sarcoma in women undergoing treatment of uterine fibroids: summary and key findings. Silver Spring, MD: FDA; 2014. Available at http://www.fda.gov/downloads/ MedicalDevices/Safety/AlertsandNotices/UCM393589.pdf. Accesssed on November 11, 2014.9) Anapolski M, Panayotopoulos D, Alkatout I, Soltesz S, Mettler L, Schiermeier S, Hatzmann W, Noé G. Power morcellation inside a secure endobag: a pilot study. Minim Invasive Ther Allied Technol. 2016 Aug;25(4):203.10) Kujansuu S, Salari BW, Galloway M, Findley A, Yaklic JL, Massengill JC, Lindheim SR. Contained morcellation using the GelPOINT advance access platforms and 3M Steri-Drape endobag. Fertil Steril. 2015 May;103(5):e36.11) Anapolski M, Panayotopoulos D, Alkatout I, Soltesz S, Schiermeier S, Noé G. Preclinical safety testing for morcellation and extraction for an endobag with sealable ports: in vitro pilot study. Surg Endosc. 2017 Jan;31(1):494-500.12) Chen I, Motan T, Kiddoo D. Gonadotropin-releasing hormone agonist in laparoscopic myomectomy: systematic review and meta-analysis of randomized controlled trials. J Minim Invasive Gynecol. 2011 May-Jun;18(3):303-9.13)Ferrero S, Alessandri F, Vellone VG, et al. Three-month treatment with ulipristal acetate prior to laparoscopic myomectomy of large uterine myomas: a retrospective study. Eur J Obstet Gynecol Reprod Biol 2016; 205: 43-47.

3.3 Hysterectomy Hysterectomy has long been considered as the

first-choice treatment for patients with large fibroids resistant to medical treatment and symptomatic fibroids in women who are not trying to get pregnant or are near to menopause.In recent years, laparoscopy has become the most used technique, compared to laparotomy, even if, according to recent data provided by Cochrane, the vaginal approach is still recommended under certain conditions.1-2

Contraindications for laparoscopic hysterectomy

1) Alessandri F, Lijoi D, Mistrangelo E, Ferrero S, Ragni N. Randomized study of laparoscopic versus minilaparotomic myomectomy for uterine myomas. J Minim Invasive Gynecol. 2006 Mar-Apr;13(2):92-7.2) Shen Q, Chen M, Wang Y, Zhou Q, Tao X, Zhang W, Zhu X. Effects of laparoscopic versus minilaparotomic myomectomy on uterine leiomyoma: a meta-analysis. J Minim Invasive Gynecol. 2015 Feb;22(2):177-84.3) Palomba S, Zupi E, Falbo A, Russo T, Marconi D, Tolino A, Manguso F, Mattei A, Zullo F. A multicenter randomized, controlled study comparing laparoscopic versus minilaparotomic myomectomy: reproductive outcomes. Fertil Steril. 2007 Oct;88(4):933-41.4) Parazzini F, Tozzi L, Bianchi S. Pregnancy outcome and uterine fibroids. Best Pract Res Clin Obstet Gynaecol 2015;S1521–6934:00231–0023.5) Sinha R, Hegde A, Mahajan C, Dubey N, Sundaram M. Laparoscopic myomectomy: do size, number, and location of the myomas form limiting factors for


include a uterine volume equal to pregnancy at 13-14 weeks.


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1) Donnez O, Jadoul P, Squifflet J, Donnez J. A series of 3190 laparoscopic hysterectomies for benign disease from 1990 to 2006: evaluation of complications compared with vaginal and abdominal procedures. BJOG 2009;116:492–500.

2) Aarts JW, Nieboer TE, Johnson N, Tavender E, Garry R, Mol BW, Kluivers KB. Surgical approach to hysterectomy for benign gynaecological disease. Cochrane Database Syst Rev 2015; 8:CD003677.

3.4 LaparotomyThe traditional laparotomy surgical technique

is still the most used in our country today. The number of fibroids (>3), their size (> 7 cm), as well as their location, often associated with higher risks (intramural fibroids near the ostia or some intraligamentary fibroids that come in contact with big vessels and/or the ureters) are the main criteria for the choice of the traditional technique. Laparotomy is the most invasive surgery for patients, with a higher rate of postoperative complications than minimally invasive techniques and with longer hospitalization and recovery times.1

3.4.1 What are the advantages of minilaparotomy?

Minilaparotomy (transverse suprapubic skin

uterine leiomyomas treated by myomectomy through conventional laparotomy or ultraminilaparotomy. Fertil Steril. 2008 Dec;90(6):2361-6.5) Tan J, Sun Y, Zhong B, Dai H, Wang D. A randomized, controlled study comparing minilaparotomy versus isobaric gasless laparoscopic assisted minilaparotomy myomectomy for removal of large uterine myomas: short-term outcomes. Eur J Obstet Gynecol Reprod Biol. 2009 Jul;145(1):104-8.6) Maneschi F, Ceccacci I, Vestri A, Pane C, Simeone A, Perugini A. Minilaparotomic myomectomy for large symptomatic uterine myomas: a prospective study. Minerva Ginecol. 2011 Jun;63(3):219-25.7) Parker WH. Uterine myomas: management. Fertil Steril. 2007 Aug;88(2):255-71.

incision < 9 cm) is a valid alternative to laparoscopic myomectomy, especially for those operators who are not familiar with laparoscopic sutures.2 According to a randomized clinical trial and a non-randomized trial, it offers better aesthetic results, compared to a classical laparotomy, with reduced postoperative pain, less blood loss and faster postoperative recovery times.3-4

Laparoscopically assisted minilaparotomy is a technique often used to avoid morcellation, and has been proven to be better than classical minilaparotomy in terms of intraoperative and postoperative outcomes in a randomized clinical trial conducted in China.5

The limits of minilaparotomy reported in the literature include the position of the fibroid in the isthmic and posterior region, fibroid size (> 12cm), patients’ obesity (BMI> 27), intralegamentary fibroids and to concomitant adnexal pathologies not previously diagnosed.6-7

1) Jin C, Hu Y, Chen XC, Zheng FY, Lin F, Zhou K, Chen FD, Gu HZ. Laparoscopic versus open myomectomy--a meta-analysis of randomized controlled trials. Eur J Obstet Gynecol Reprod Biol. 2009 Jul;145(1):14-21.2) Glasser MH. Minilaparotomy myomectomy: a minimally invasive alternative for the large fibroid uterus. J Minim Invasive Gynecol. 2005 May-Jun;12(3):275-83. 3) Cagnacci A, Pirillo D, Malmusi S, Arangino S, Alessandrini C, Volpe A. Early outcome of myomectomy by laparotomy, minilaparotomy and laparoscopically assisted minilaparotomy. A randomized prospective study. Hum Reprod 2003;18:2590–4. 4) Wen KC, Sung PL, Chao KC, Lee WL, Liu WM, Wang PH. A prospective short-term evaluation of


Does preoperative pharmacological treatment improve the surgical prognosis?

The main purpose of preoperative medical treatment of uterine fibroids is to obtain a reduction of intraoperative blood loss, as well as a reduction in the volume of the fibroids. However, many studies have shown greater difficulties in the removal of fibroids after medical therapy due

to the frequent colliquation of the fibroid tissue, mainly linked to the use of GnRH analogues.

GnRH analogues and, recently, also SPRMs are the most frequently used medications.

1) Baranowski W. Ulipristal acetate before high complexity endoscopic (hysteroscopic, laparoscopic) myomectomy - a mini-review. Prz

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Menopauzalny. 2016.2) Ferrero S et al. Three-month treatment with ulipristal acetate prior to laparoscopic myomectomy of large uterine myomas: a retrospective study. Eur J Obstet Gynecol Reprod Biol. 2016.3) Chang WC e al. Comparison of Laparoscopic Myomectomy in Large Myomas With and Without Leuprolide Acetate. J Minim Invasive Gynecol. 2015.4) Lethaby A et al. Pre-operative GnRH analogue therapy before hysterectomy or myomectomy for uterine fibroids. Cochrane Database Syst Rev. 2001.5) Ferrero S et al. Ulipristal Acetate Before High Complexity Hysteroscopic Myomectomy: A Retrospective Comparative Study. J Minim Invasive Gynecol. 2016.

Is prevention of post-surgical adhesions a

valid reason for choosing laparoscopic myomectomy?The development of adhesions in gynecological

surgeries is particularly relevant, because of its

the literature does not guarantee a successful pregnancy outcome.4

A meta-analysis of 2013 showed that the complication rate after UAE is lower than surgical procedures, but the risk of a second surgery is higher.5

4.2 Thermal ablation Magnetic resonance-guided focused

ultrasound (MRgFUS) surgery is a type of thermal ablation that uses MRI to visualize fibroids and to define their edges. Focused ultrasound treatments exploit the direct energy of acoustic waves at a specific point within the fibroid to induce a temperature increase with thermal coagulation and necrosis of the leiomyomatous tissue.

Damage to the surrounding tissue should be minimal, but, the impact on adjacent critical structures cannot be ruled out.6 Case-series showed in the literature demonstrate an adequate short-term efficacy and a complication rate of about 7%, but these are mostly minor complications, such as small skin burns and post-procedure pain, while intestinal perforations have been rarely reported.7-9

A recent randomized placebo-control study


potential impact on the reproductive function. For women who want to get pregnant, laparoscopy, if performed by expert hands and qualified operators, should be preferred, also because it is associated with a reduced risk to develop adhesions compared to laparotomy.

1) Asgari Z et al. Intrauterine synechiae after myomectomy; laparotomy versus laparoscopy: Non-randomized interventional trial. Iran J Reprod Med. 2015.2) Gambadauro P et al. Intrauterine Adhesions following Conservative Treatment of Uterine Fibroids. Obstet Gynecol Int. 2012.3) Campo S et al. Reproductive outcome before and after laparoscopic or abdominal myomectomy for subserous or intramural myomas. Eur J Obstet Gynecol Reprod Biol. 2003.4) Metwally M et al. Surgical treatment of fibroids for subfertility. Cochrane Database Syst Rev. 2012.5) Gutt CN et al. Fewer adhesions induced by laparoscopic surgery? Surg Endosc. 2004.

SECTION 4: ALTERNATIVE TREATMENTSUterine Artery Embolization (UAE), thermal

ablation and uterine artery occlusion are all alternative procedures.

4.1 Uterine Artery EmbolizationUAE is practiced by interventional radiologists

injecting an embolization agent into the uterine arteries with the aim of reducing symptoms associated with fibroids. Although UAE is highly effective in the treatment of symptoms (reduction of bleeding and decrease in the size of the fibroid), the risk of a second surgery is high: 15 to 20% after successful embolization, and greater than 50% in cases of incomplete embolization. The impact of UAE on the ovarian reserve and reproductive outcomes are an unresolved theme.1 A systematic review of 15 randomized trials and prospective cohort studies showed that loss of ovarian function occurred mainly in women older than 45 years.2 A randomized clinical trial that compared this procedure to myomectomy showed a lower rate of pregnancies and a higher incidence of miscarriages in patients treated with UAE.3

Results and complications of UAE were assessed in a very recent review, which pointed out that the desire of a future pregnancy remains a relative contraindication, as the lack of data in


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range compared to cryotherapy (about 6cm) in a 30-minute session, but is not compatible with magnetic resonance, and is performed using double laparoscopic and ultrasound or CT guidance. The reduction in the volume of fibroids is associated with an improvement in symptoms.18-20

4.3 Uterine artery occlusionUterine artery occlusions are performed with

the laparoscopic, laparotomic or vaginal approach with locking devices that remains in place for 6 hours, determining the fibroid ischemia, interfering with the blood supply of the uterus.21 However, this technique is not recommended for women who want to get pregnant in the future.

showed that in women who undergo this treatment there may be a placebo effect to explain the improvement in symptoms.10

The results in terms of pregnancies in some of these cases are limited but encouraging.11

The main limitations to the use of this technique are the selection of patients that may undergo this procedure, long sessions, the possibility to treat only a single fibroid per session and the relevant costs, which are still very high.12

Other fibroid thermal ablation systems include laser, cryotherapy and radiofrequency ablation.

Fibroid laser ablation uses MRI-guided endoscopic or percutaneous methods. A low-power laser (wavelength: 1,064nm) is used, which penetrates deeply into the tissue inducing a laser-photocoagulation of the fibroid cells. A substantial shrinkage of the fibroid (50-70%) can be achieved, but there is still no strong evidence in the literature.13-15

Cryotherapy uses argon gas to quickly freeze and unfreeze the fibroid. It can be performed by endoscopy or, since 2000, as an MRI-guided technique.16-17

Radiofrequency ablation has a broader

8) Bouwsma EV, Hesley GK, Woodrum DA, Weaver AL, Leppert PC, Peterson LG, et al. Comparing focused ultrasound and uterine artery embolization for uterine fibroids-rationale and design of the Fibroid Interventions: Reducing Symptoms Today and Tomorrow (FIRSTT) trial. Fertil Steril 2011;96:704–10. 9) Bouwsma EV, Gorny KR, Hesley GK, Jensen JR, Peterson LG, Stewart EA. Magnetic resonance-guided focused ultrasound surgery for leiomyoma-associated infertility. Fertil Steril 2011;96:e9–e12.10) Jacoby VL, Kohi MP, Poder L, Jacoby A, Lager J, Schembri M, Rieke V, Grady D, Vittinghoff E, Coakley FV. PROMISe trial: a pilot, randomized, placebo-controlled trial of magnetic resonance guided focused ultrasound for uterine fibroids. Fertil Steril. 2016 Mar;105(3):773-80.11) Clark NA, Mumford SL, Segars JH. Reproductive impact of MRI-guided focused ultrasound surgery for fibroids: a systematic review of the evidence. Curr Opin Obstet Gynecol. 2014 Jun;26(3):151-61.12) Zupi E, Centini G, Sabbioni L, Lazzeri L, Argay IM, Petraglia F. Nonsurgical alternatives for uterine fibroids. Best Pract Res Clin Obstet Gynaecol 2015;S1521– 6934:00227–00228.13) Law P, Gedroyc WM, Regan L. Magnetic-resonance-guided percutaneous laser ablation of uterine fibroids. Lancet. 1999;354(9195):2049–2050.14) Law P, Regan L. Interstitial thermo-ablation under

1) Gupta JK, Sinha A, Lumsden MA, Hickey M. Uterine artery embolization for symptomatic uterine fibroids. Cochrane Database Syst Rev. 2014;12:CD00507.2) Kaump GR, Spies JB. The impact of uterine artery embolization on ovarian function. J Vasc Interv Radiol 2013;24:459–467.3) Mara M, Kubinova K. Embolization of uterine fibroids from the point of view of the gynecologist: pros and cons. Int J Womens Health 2014;6:623–9.4) Zupi E, Centini G, Sabbioni L, Lazzeri L, Argay IM, Petraglia F. Nonsurgical alternatives for uterine fibroids. Best Pract Res Clin Obstet Gynaecol 2015;S1521– 6934:00227–00228.5) Martin J, Bhanot K, Athreya S. Complications and reinterventions in uterine artery embolization for symptomatic uterine fibroids: a literature review and meta-analysis. Cardiovasc Intervent Radiol 2013;36:395–402.6) Clark NA, Mumford SL, Segars JH. Reproductive impact of MRI-guided focused ultrasound surgery for fibroids: a systematic review of the evidence. Curr Opin Obstet Gynecol 2014;26:151–161.7) Gorny KR, Woodrum DA, Brown DL, Henrichsen TL, Weaver AL, Amrami KK, Hangiandreou NJ, Edmonson HA, Bouwsma EV, Stewart EA, Gostout BS, Ehman DA, Hesley GK. Magnetic resonance-guided focused ultrasound of uterine leiomyomas: review of a 12-month outcome of 130 clinical patients. J Vasc Interv Radiol. 2011 Jun;22(6):857-64.


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MRI guidance for the treatment of fibroids. Curr Opin Obstet Gynecol. 2000;12(4):277–282. 15) Donnez J, Squifflet J, Polet R, Nisolle M. Laparoscopic myolysis. Hum Reprod Update. 2000;6(6):609–613.16) Sakuhara Y, Shimizu T, Kodama Y, et al. Magnetic resonance-guided percutaneous cryoablation of uterine fibroids: clinical experiences. Cardiovasc Intervent Radiol. 2006;29(4):552–558. 17) Cowan BD. Myomectomy and MRI-directed cryotherapy. Semin Reprod Med. 2004;22(2):143–148.18) Milic A, Asch MR, Hawrylyshyn PA, et al. Laparoscopic ultrasound-guided radiofrequency ablation of uterine fibroids. Cardiovasc Intervent Radiol. 2006;29(4):694–698.

19) Kim HS, Tsai J, Jacobs MA, Kamel IR. Percutaneous image-guided radiofrequency thermal ablation for large symptomatic uterine leiomyomata after uterine artery embolization: a feasibility and safety study. J Vasc Interv Radiol. 2007;18(1 Pt 1):41–48.20) Recaldini C, Carrafiello G, Laganà D, et al. Percutaneous sonographically guided radiofrequency ablation of medium-sized fibroids: feasibility study. AJR Am J Roentgenol. 2007;189(6):1303–1306.21) Hald K, Langebrekke A, Klow NE, Noreng HJ, Berge AB, Istre O. Laparoscopic occlusion of uterine vessels for the treatment of symptomatic fibroids: Initial experience and comparison to uterine artery embolization. YMOB 2004;190:37–43.


1. DENOMINAZIONE DEL MEDICINALE. MECLON “20% + 4% crema vaginale” MECLON “200 mg/10 ml + 1 g/130 ml soluzione vaginale”. 2. COMPOSIZIONE QUALITATIVA E QUANTITATIVA. Crema vaginale. 100 g contengono: Principi attivi: Metronidazolo 20 g; Clotrimazolo 4 g. Eccipienti: contiene sodio metil p-idrossibenzoato e sodio propil p-idros-sibenzoato. Per l’elenco completo degli eccipienti, vedere paragrafo 6.1. Soluzione vaginale.Flacone da 10 ml. 10 ml contengono: Principio attivo: Clotrimazolo 200 mg. Flacone da 130 ml. 130 ml contengono: Principio attivo: Metronidazolo 1 g. Eccipienti: contiene sodio metil p-idrossibenzoato e sodio propil p-idrossibenzoato. Per l’elenco completo degli eccipien-ti, vedere paragrafo 6.1. 3. FORMA FARMACEUTICA. Crema vaginale. Soluzione vaginale. 4. INFORMAZIONI CLINICHE. 4.1 Indicazioni terapeutiche. Crema vaginale. Cervico-vagi-niti e vulvo-vaginiti causate da Trichomonas vaginalis anche se associato a Candida albicans, Gardnerella vaginalis ed altra � ora batterica sensibile. MECLON crema vaginale può essere impiegato anche nel partner a scopo pro� lattico. Soluzione vaginale. Coadiuvante nella tera-pia di cervico-vaginiti, vulvo-vaginiti causate da Trichomonas vaginalis anche se associato a Candida albicans, Gardnerella vaginalis ed altra � ora batterica sensibile. MECLON soluzione vaginale può essere impiegato anche dopo altra terapia topica od orale, allo scopo di ridurre il rischio di recidive. 4.2 Posologia e modo di somministrazione. Crema vaginale. Som-ministrare profondamente in vagina il contenuto di un applicatore una volta al giorno per almeno sei giorni consecutivi, preferibilmente alla sera prima di coricarsi, oppure secondo prescrizione medica. Nelle trichomoniasi, maggior sicurezza di risultato terapeutico si veri� ca con il contemporaneo uso di Metronidazolo per via orale sia nella donna non gestante che nel partner maschile. Per un’ottimale somministrazione si consiglia una posizione supina, con le gambe leggermente piegate ad angolo. Per ottenere una migliore sterilizzazione è preferibile spalmare un po’ di MECLON crema vaginale anche esternamente, a livello perivulvare e pe-rianale. Se il medico prescrive il trattamento del partner a scopo pro� lattico, la crema deve essere applicata sul glande e sul prepuzio per almeno sei giorni. Istruzioni per l’uso: Dopo aver riempito di crema un applicatore, somministrare la crema in vagina mediante pressione sul pistone, � no a completo svuotamento. Soluzione vaginale. Somministrare la soluzione vaginale pronta una volta al giorno, preferibilmente al mattino, oppure secondo prescrizione medica.Nella fase di attacco l’uso della soluzione vaginale deve essere associato ad adeguata terapia topica e/o orale. L’irrigazione va eseguita preferibilmente in posizione supina. Un lento svuota-mento del � acone favorirà una più prolungata permanenza in vagina dei principi attivi e quindi una più ef� cace azione antimicrobica e detergente. Istruzioni per l’uso: Dopo aver versato il contenuto del � aconcino nel � acone, inserire la cannula vaginale sul collo del � acone stesso.Introdurre la cannula in vagina e somministrare l’intero contenuto. 4.3 Controindicazioni. Ipersensibilità verso i principi attivi od uno qualsiasi degli eccipienti. 4.4 Avvertenze speciali e opportune precauzioni d’impiego. Informi il paziente di evitare il contatto con gli occhi. L’impiego contemporaneo di Metronidazolo per via orale è soggetto alle controindicazioni, effetti collaterali ed avvertenze descritte per il prodotto summenzionato. Evitare il trattamen-to con Meclon durante il periodo mestruale. Con medicinali contenenti Metronidazolo per uso sistemico sono stati segnalati casi di epatotossicità severa/insuf� cienza epatica acuta, comprendenti casi con esito fatale, con esordio molto rapido dopo l’inizio del trattamento in pazienti affetti da sindrome di Cockayne. Pertanto, in questa popolazione Metronidazolo deve essere utilizzato dopo un’attenta valutazione del rapporto rischio-bene� cio e solo in man-canza di trattamenti alternativi. Le analisi della funzionalità epatica devono essere effettuate appena prima dell’inizio della terapia, durante e dopo la � ne del trattamento, � no a quando i parametri della funzionalità epatica non saranno rientrati nella norma o non saranno rag-giunti i valori al basale. Se i valori delle analisi della funzionalità epatica dovessero aumentare notevolmente durante il trattamento, il farmaco deve essere interrotto. I pazienti affetti da sindrome di Cockayne devono essere avvisati della necessità di segnalare immediatamente al medico qualsiasi sintomo di potenziali lesioni epatiche e di interrompere il trattamento con Metronidazolo. 4.5 Interazioni con altri medicinali e altre forme di interazione. Nessuna.4.6 Gravidanza e allattamento. In gravidanza il prodotto deve essere impiegato solo in caso di effettiva necessità e sotto il diretto controllo del medico. 4.7 Effetti sulla capacità di guidare veicoli e sull’uso di macchinari. MECLON non altera la capacità di guidare veicoli o di usare macchinari. 4.8 Effetti indesiderati. Dato lo scarso assorbimento per applicazione locale dei principi attivi Metronidazolo e Clotrimazolo, le reazioni avverse riscontrate con le formulazioni topiche sono limitate a: Disturbi del sistema immunitario: Non nota (la frequenza non può essere de� nita sulla base dei dati disponibili): reazioni di ipersensibilità. Patologie

della cute e del tessuto sottocutaneo: Molto rari (frequenza <1/10.000): fenomeni irritativi locali quale prurito, dermatite allergica da contatto, eruzioni cutanee. L’eventuale manifestarsi di effetti indesiderati comporta l’interruzione del trattamento. 4.9 Sovradosaggio. Non sono stati descritti sintomi di sovradosaggio. 5. PROPRIETÀ FARMACOLOGICHE. 5.1 Proprietà farmacodinamiche. Categoria farmacoterapeutica: Antinfettivi ed antisettici ginecologici/Associazioni di derivati imidazolici - Codice ATC: G01AF20. Meccanismo d’azione/effetti farmacodinamici: Il MECLON è una associazione tra Metronidazolo (M) e Clotrimazolo (C). Il (M) è un derivato nitroimidazolico ad ampio spettro di azione antiprotozoaria e antimicrobica.Ha effetto trichomonicida diretto ed è attivo su cocchi Gram-positivi anaerobi, bacilli sporigeni, anaerobi Gram-negativi. Presenta attività spiccata sulla Gardnerella vaginalis. Non è attivo sulla � ora acido� la vaginale. Il (C) è un imidazolico con spettro antifungino molto ampio (Can-dida, etc.). È attivo anche su Trichomonas vaginalis, cocchi Gram-positivi, Toxoplasmi, etc. È stato documentato che l’associazione Clotrimazolo-Metronidazolo dà luogo ad effetti di tipo additivo, pertanto essa è in grado di conseguire tre vantaggi terapeutici principali: 1) Amplia-mento dello spettro d’azione antimicrobica, per sommazione degli effetti dei due principi attivi;2) Potenziamento dell’attività antimicotica, antiprotozoaria ed antibatterica; 3) Abolizione o ritardo della comparsa dei fenomeni di resistenza. Studi microbiologici in vitro hanno dimo-strato che l’attività trichomonicida e antimicotica risulta potenziata quando il (M) e il (C) sono associati nelle stesse proporzioni che sono presenti nel MECLON. Anche l’attività antibatterica esaminata su diversi ceppi di microorganismi è risultata elevata ed è emerso un potenzia-mento di essa quando i due principi attivi del MECLON vengono associati. 5.2 Proprietà farmacocinetiche. Dalle indagini farmacocinetiche sui conigli, cani e ratti risulta che dopo ripetute applicazioni topiche di MECLON non si rilevano concentrazioni apprezzabili di Clo-trimazolo e Metronidazolo nel sangue. Per applicazione vaginale nella donna il (M) e il (C) vengono assorbiti in una percentuale che varia tra il 10% e il 20% circa. 5.3 Dati preclinici di sicurezza. La tossicità acuta del MECLON nel topo e nel ratto (os) è risultata molto bassa, con una mortalità di appena il 20% dopo 7 giorni, a dosi molto elevate (600 mg/Kg di (C) e 3.000 mg/Kg di (M), sia da soli che associati). Nelle prove di tossicità subacuta (30 giorni) il MECLON, somministrato per via locale (genitale) nel cane e nel coniglio, non ha determinato alcun tipo di lesione nè locale nè sistemica anche per dosi molte volte superiori a quelle comunemente impiegate in terapia umana (3-10 Dtd nel cane e 100-200 Dtd nel coniglio; 1 Dtd = dose terapeutica/die per l’uomo = ca. 3,33 mg/Kg di (C) e ca. 16,66 mg/Kg di (M)). Il MECLON somministrato durante il periodo di gravidanza per via topica vaginale nel coniglio e nel ratto non ha fatto evidenziare alcun segno di sofferenza fetale per dosi die di 100 Dtd, nè in� ussi negativi sullo stato gestazionale. 6. INFORMAZIONI FARMACEUTICHE. 6.1 Elenco degli eccipienti: Crema vaginale. Eccipienti: Stearato di glicole e polietilenglico-le; Paraf� na liquida; Sodio metile p-idrossibenzoato; Sodio propile p-idrossibenzoato; Acqua depurata. Soluzione vaginale. Flacone da 10 ml. Eccipienti: Alcool ricinoleilico; Etanolo; Ac-qua depurata. Flacone da 130 ml. Eccipienti: Sodio metile p-idrossibenzoato; Sodio propile p-idrossibenzoato; Acqua depurata. 6.2 Incompatibilità. Non sono note incompatibilità con altri farmaci. 6.3 Periodo di validità. Crema vaginale: 3 anni. Soluzione vaginale: 3 anni. 6.4 Precauzioni particolari per la conservazione. Questo medicinale non richiede alcu-na particolare condizione per la conservazione. 6.5 Natura e contenuto del contenitore. MECLON crema vaginale. Tubo in alluminio verniciato internamente con resine epossidiche e fenoliche. Gli applicatori monouso sono di polietilene. Tubo da 30 g + 6 applicatori monousoMECLON soluzione vaginale. Flaconi di polietilene a bassa densità; � aconcini di polietilene; cannule vaginali di polietilene. 5 � aconi da 10 ml + 5 � aconi da 130 ml + 5 cannule vaginali monouso. 6.6 Precauzioni particolari per lo smaltimento e la manipolazione. Nessuna istruzione particolare. 7. TITOLARE DELL’AUTORIZZAZIONE ALL’IMMISSIONE IN COM-MERCIO. Alfasigma S.p.A. - Viale Sarca, n. 223 - 20126 Milano (MI). 8. NUMERI DELL’AU-TORIZZAZIONE ALL’IMMISSIONE IN COMMERCIO. MECLON crema vaginale: A.I.C. n. 023703046. MECLON soluzione vaginale: A.I.C. n. 023703059. 9. DATA DELLA PRIMA AUTORIZZAZIONE/RINNOVO DELL’AUTORIZZAZIONE. 16.01.1979 / 01.06.2010.10. DATA DI REVISIONE DEL TESTO. Agosto 2017.

Medicinale non soggetto a prescrizione medica (SOP) . CLASSE C.

Riassunto delle Caratteristiche del Prodotto

1. DENOMINAZIONE DEL MEDICINALE. MECLON “20% + 4% crema vaginale” MECLON “200 mg/10 ml + 1 g/130 ml soluzione vaginale”. 2. COMPOSIZIONE QUALITATIVA E QUANTITATIVA. Crema vaginale. 100 g contengono: Principi attivi: Metronidazolo 20 g; Clotrimazolo 4 g. Eccipienti: contiene sodio metil p-idrossibenzoato e sodio propil p-idros-sibenzoato. Per l’elenco completo degli eccipienti, vedere paragrafo 6.1. Soluzione vaginale.Flacone da 10 ml. 10 ml contengono: Principio attivo: Clotrimazolo 200 mg. Flacone da 130 ml. 130 ml contengono: Principio attivo: Metronidazolo 1 g. Eccipienti: contiene sodio metil p-idrossibenzoato e sodio propil p-idrossibenzoato. Per l’elenco completo degli eccipien-ti, vedere paragrafo 6.1. 3. FORMA FARMACEUTICA. Crema vaginale. Soluzione vaginale. 4. INFORMAZIONI CLINICHE. 4.1 Indicazioni terapeutiche. Crema vaginale. Cervico-vagi-niti e vulvo-vaginiti causate da Trichomonas vaginalis anche se associato a Candida albicans, Gardnerella vaginalis ed altra � ora batterica sensibile. MECLON crema vaginale può essere impiegato anche nel partner a scopo pro� lattico. Soluzione vaginale. Coadiuvante nella tera-pia di cervico-vaginiti, vulvo-vaginiti causate da Trichomonas vaginalis anche se associato a Candida albicans, Gardnerella vaginalis ed altra � ora batterica sensibile. MECLON soluzione vaginale può essere impiegato anche dopo altra terapia topica od orale, allo scopo di ridurre il rischio di recidive. 4.2 Posologia e modo di somministrazione. Crema vaginale. Som-ministrare profondamente in vagina il contenuto di un applicatore una volta al giorno per almeno sei giorni consecutivi, preferibilmente alla sera prima di coricarsi, oppure secondo prescrizione medica. Nelle trichomoniasi, maggior sicurezza di risultato terapeutico si veri� ca con il contemporaneo uso di Metronidazolo per via orale sia nella donna non gestante che nel partner maschile. Per un’ottimale somministrazione si consiglia una posizione supina, con le gambe leggermente piegate ad angolo. Per ottenere una migliore sterilizzazione è preferibile spalmare un po’ di MECLON crema vaginale anche esternamente, a livello perivulvare e pe-rianale. Se il medico prescrive il trattamento del partner a scopo pro� lattico, la crema deve essere applicata sul glande e sul prepuzio per almeno sei giorni. Istruzioni per l’uso: Dopo aver riempito di crema un applicatore, somministrare la crema in vagina mediante pressione sul pistone, � no a completo svuotamento. Soluzione vaginale. Somministrare la soluzione vaginale pronta una volta al giorno, preferibilmente al mattino, oppure secondo prescrizione medica.Nella fase di attacco l’uso della soluzione vaginale deve essere associato ad adeguata terapia topica e/o orale. L’irrigazione va eseguita preferibilmente in posizione supina. Un lento svuota-mento del � acone favorirà una più prolungata permanenza in vagina dei principi attivi e quindi una più ef� cace azione antimicrobica e detergente. Istruzioni per l’uso: Dopo aver versato il contenuto del � aconcino nel � acone, inserire la cannula vaginale sul collo del � acone stesso.Introdurre la cannula in vagina e somministrare l’intero contenuto. 4.3 Controindicazioni. Ipersensibilità verso i principi attivi od uno qualsiasi degli eccipienti. 4.4 Avvertenze speciali e opportune precauzioni d’impiego. Informi il paziente di evitare il contatto con gli occhi. L’impiego contemporaneo di Metronidazolo per via orale è soggetto alle controindicazioni, effetti collaterali ed avvertenze descritte per il prodotto summenzionato. Evitare il trattamen-to con Meclon durante il periodo mestruale. Con medicinali contenenti Metronidazolo per uso sistemico sono stati segnalati casi di epatotossicità severa/insuf� cienza epatica acuta, comprendenti casi con esito fatale, con esordio molto rapido dopo l’inizio del trattamento in pazienti affetti da sindrome di Cockayne. Pertanto, in questa popolazione Metronidazolo deve essere utilizzato dopo un’attenta valutazione del rapporto rischio-bene� cio e solo in man-canza di trattamenti alternativi. Le analisi della funzionalità epatica devono essere effettuate appena prima dell’inizio della terapia, durante e dopo la � ne del trattamento, � no a quando i parametri della funzionalità epatica non saranno rientrati nella norma o non saranno rag-giunti i valori al basale. Se i valori delle analisi della funzionalità epatica dovessero aumentare notevolmente durante il trattamento, il farmaco deve essere interrotto. I pazienti affetti da sindrome di Cockayne devono essere avvisati della necessità di segnalare immediatamente al medico qualsiasi sintomo di potenziali lesioni epatiche e di interrompere il trattamento con Metronidazolo. 4.5 Interazioni con altri medicinali e altre forme di interazione. Nessuna.4.6 Gravidanza e allattamento. In gravidanza il prodotto deve essere impiegato solo in caso di effettiva necessità e sotto il diretto controllo del medico. 4.7 Effetti sulla capacità di guidare veicoli e sull’uso di macchinari. MECLON non altera la capacità di guidare veicoli o di usare macchinari. 4.8 Effetti indesiderati. Dato lo scarso assorbimento per applicazione locale dei principi attivi Metronidazolo e Clotrimazolo, le reazioni avverse riscontrate con le formulazioni topiche sono limitate a: Disturbi del sistema immunitario: Non nota (la frequenza non può essere de� nita sulla base dei dati disponibili): reazioni di ipersensibilità. Patologie

della cute e del tessuto sottocutaneo: Molto rari (frequenza <1/10.000): fenomeni irritativi locali quale prurito, dermatite allergica da contatto, eruzioni cutanee. L’eventuale manifestarsi di effetti indesiderati comporta l’interruzione del trattamento. 4.9 Sovradosaggio. Non sono stati descritti sintomi di sovradosaggio. 5. PROPRIETÀ FARMACOLOGICHE. 5.1 Proprietà farmacodinamiche. Categoria farmacoterapeutica: Antinfettivi ed antisettici ginecologici/Associazioni di derivati imidazolici - Codice ATC: G01AF20. Meccanismo d’azione/effetti farmacodinamici: Il MECLON è una associazione tra Metronidazolo (M) e Clotrimazolo (C). Il (M) è un derivato nitroimidazolico ad ampio spettro di azione antiprotozoaria e antimicrobica.Ha effetto trichomonicida diretto ed è attivo su cocchi Gram-positivi anaerobi, bacilli sporigeni, anaerobi Gram-negativi. Presenta attività spiccata sulla Gardnerella vaginalis. Non è attivo sulla � ora acido� la vaginale. Il (C) è un imidazolico con spettro antifungino molto ampio (Can-dida, etc.). È attivo anche su Trichomonas vaginalis, cocchi Gram-positivi, Toxoplasmi, etc. È stato documentato che l’associazione Clotrimazolo-Metronidazolo dà luogo ad effetti di tipo additivo, pertanto essa è in grado di conseguire tre vantaggi terapeutici principali: 1) Amplia-mento dello spettro d’azione antimicrobica, per sommazione degli effetti dei due principi attivi;2) Potenziamento dell’attività antimicotica, antiprotozoaria ed antibatterica; 3) Abolizione o ritardo della comparsa dei fenomeni di resistenza. Studi microbiologici in vitro hanno dimo-strato che l’attività trichomonicida e antimicotica risulta potenziata quando il (M) e il (C) sono associati nelle stesse proporzioni che sono presenti nel MECLON. Anche l’attività antibatterica esaminata su diversi ceppi di microorganismi è risultata elevata ed è emerso un potenzia-mento di essa quando i due principi attivi del MECLON vengono associati. 5.2 Proprietà farmacocinetiche. Dalle indagini farmacocinetiche sui conigli, cani e ratti risulta che dopo ripetute applicazioni topiche di MECLON non si rilevano concentrazioni apprezzabili di Clo-trimazolo e Metronidazolo nel sangue. Per applicazione vaginale nella donna il (M) e il (C) vengono assorbiti in una percentuale che varia tra il 10% e il 20% circa. 5.3 Dati preclinici di sicurezza. La tossicità acuta del MECLON nel topo e nel ratto (os) è risultata molto bassa, con una mortalità di appena il 20% dopo 7 giorni, a dosi molto elevate (600 mg/Kg di (C) e 3.000 mg/Kg di (M), sia da soli che associati). Nelle prove di tossicità subacuta (30 giorni) il MECLON, somministrato per via locale (genitale) nel cane e nel coniglio, non ha determinato alcun tipo di lesione nè locale nè sistemica anche per dosi molte volte superiori a quelle comunemente impiegate in terapia umana (3-10 Dtd nel cane e 100-200 Dtd nel coniglio; 1 Dtd = dose terapeutica/die per l’uomo = ca. 3,33 mg/Kg di (C) e ca. 16,66 mg/Kg di (M)). Il MECLON somministrato durante il periodo di gravidanza per via topica vaginale nel coniglio e nel ratto non ha fatto evidenziare alcun segno di sofferenza fetale per dosi die di 100 Dtd, nè in� ussi negativi sullo stato gestazionale. 6. INFORMAZIONI FARMACEUTICHE. 6.1 Elenco degli eccipienti: Crema vaginale. Eccipienti: Stearato di glicole e polietilenglico-le; Paraf� na liquida; Sodio metile p-idrossibenzoato; Sodio propile p-idrossibenzoato; Acqua depurata. Soluzione vaginale. Flacone da 10 ml. Eccipienti: Alcool ricinoleilico; Etanolo; Ac-qua depurata. Flacone da 130 ml. Eccipienti: Sodio metile p-idrossibenzoato; Sodio propile p-idrossibenzoato; Acqua depurata. 6.2 Incompatibilità. Non sono note incompatibilità con altri farmaci. 6.3 Periodo di validità. Crema vaginale: 3 anni. Soluzione vaginale: 3 anni. 6.4 Precauzioni particolari per la conservazione. Questo medicinale non richiede alcu-na particolare condizione per la conservazione. 6.5 Natura e contenuto del contenitore. MECLON crema vaginale. Tubo in alluminio verniciato internamente con resine epossidiche e fenoliche. Gli applicatori monouso sono di polietilene. Tubo da 30 g + 6 applicatori monousoMECLON soluzione vaginale. Flaconi di polietilene a bassa densità; � aconcini di polietilene; cannule vaginali di polietilene. 5 � aconi da 10 ml + 5 � aconi da 130 ml + 5 cannule vaginali monouso. 6.6 Precauzioni particolari per lo smaltimento e la manipolazione. Nessuna istruzione particolare. 7. TITOLARE DELL’AUTORIZZAZIONE ALL’IMMISSIONE IN COM-MERCIO. Alfasigma S.p.A. - Viale Sarca, n. 223 - 20126 Milano (MI). 8. NUMERI DELL’AU-TORIZZAZIONE ALL’IMMISSIONE IN COMMERCIO. MECLON crema vaginale: A.I.C. n. 023703046. MECLON soluzione vaginale: A.I.C. n. 023703059. 9. DATA DELLA PRIMA AUTORIZZAZIONE/RINNOVO DELL’AUTORIZZAZIONE. 16.01.1979 / 01.06.2010.10. DATA DI REVISIONE DEL TESTO. Agosto 2017.



1. DENOMINAZIONE DEL MEDICINALE. MECLON “100 mg + 500 mg ovuli”. 2. COMPOSIZIONE QUALITATIVA E QUANTITATIVA. Un ovulo da 2,4 g contiene: Principi attivi: Metronidazolo 500 mg; Clotrimazolo 100 mg. Per l’elenco completo degli eccipienti, vedere paragrafo 6.1. 3. FORMA FARMACEUTICA. Ovuli. 4. INFORMAZIONI CLINICHE. 4.1 Indicazioni terapeutiche. Cerviciti, cervico-vaginiti, vaginiti e vulvo-vaginiti da Trichomonas vaginalis anche se associato a Candida o con componente batterica. 4.2 Posologia e modo di somministrazione. Lo schema terapeutico ottimale risulta il seguente: 1 ovulo di MECLON in vagina, 1 volta al dì. 4.3 Controindicazioni. Ipersensibilità verso i principi attivi od uno qualsiasi degli eccipienti. 4.4 Avvertenze speciali e opportu-ne precauzioni d’impiego. Informi il paziente di evitare il contatto con gli occhi. L’impiego contemporaneo di Metronidazolo per via orale è soggetto alle controindicazioni, effetti col-laterali ed avvertenze descritte per il prodotto summenzionato. Evitare il trattamento con Meclon durante il periodo mestruale. MECLON ovuli va impiegato nella prima infanzia sotto il diretto controllo del medico e solo nei casi di effettiva necessità. Con medicinali contenen-ti Metronidazolo per uso sistemico sono stati segnalati casi di epatotossicità severa/insuf� -cienza epatica acuta, comprendenti casi con esito fatale, con esordio molto rapido dopo l’inizio del trattamento in pazienti affetti da sindrome di Cockayne. Pertanto, in questa po-polazione metronidazolo deve essere utilizzato dopo un’attenta valutazione del rapporto ri-schio-bene� cio e solo in mancanza di trattamenti alternativi. Le analisi della funzionalità epatica devono essere effettuate appena prima dell’inizio della terapia, durante e dopo la � ne del trattamento, � no a quando i parametri della funzionalità epatica non saranno rien-trati nella norma o non saranno raggiunti i valori al basale. Se i valori delle analisi della funzionalità epatica dovessero aumentare notevolmente durante il trattamento, il farmaco deve essere interrotto. I pazienti affetti da sindrome di Cockayne devono essere avvisati della necessità di segnalare immediatamente al medico qualsiasi sintomo di potenziali lesio-ni epatiche e di interrompere il trattamento con metronidazolo. 4.5 Interazioni con altri medicinali e altre forme di interazione. Nessuna. 4.6 Gravidanza e allattamento. In gravidanza il prodotto deve essere impiegato solo in caso di effettiva necessità e sotto il diretto controllo del medico. 4.7 Effetti sulla capacità di guidare veicoli e sull’uso di macchinari. Meclon non altera la capacità di guidare veicoli o di usare macchinari. 4.8 Effetti indesiderati. Dato lo scarso assorbimento per applicazione locale dei principi attivi Metronidazolo e Clotrimazolo, le reazioni avverse riscontrate con le formulazioni topi-che sono limitate a: Disturbi del sistema immunitario: Non nota (la frequenza non può essere de� nita sulla base dei dati disponibili):reazioni di ipersensibilità. Patologie della cute e del tessuto sottocutaneo: Molto rari (frequenza <1/10.000): fenomeni irritativi locali quale pru-rito, dermatite allergica da contatto, eruzioni cutanee. L’eventuale manifestarsi di effetti in-desiderati comporta l’interruzione del trattamento. 4.9 Sovradosaggio. Non sono stati de-scritti sintomi di sovradosaggio. 5. PROPRIETÀ FARMACOLOGICHE. 5.1 Proprietà farma-codinamiche. Categoria farmacoterapeutica: Antinfettivi ed antisettici ginecologici/Associazioni di derivati imidazolici - Codice ATC: G01AF20. Meccanismo d’azione/effetti farmacodinamici: Il MECLON è una associazione tra Metronidazolo (M) e Clotrimazolo (C). Il (M) è un derivato nitroimidazolico ad ampio spettro di azione antiprotozoaria e antimicrobica.

Ha effetto trichomonicida diretto ed è attivo su cocchi Gram-positivi anaerobi, bacilli spori-geni, anaerobi Gram-negativi. Presenta attività spiccata sulla Gardnerella vaginalis. Non è attivo sulla � ora acido� la vaginale. Il (C) è un imidazolico con spettro antifungino molto am-pio (Candida, etc.). È attivo anche su Trichomonas vaginalis, cocchi Gram-positivi, Toxoplasmi, etc. È stato documentato che l’associazione Clotrimazolo-Metronidazolo dà luogo ad effetti di tipo additivo, pertanto essa è in grado di conseguire tre vantaggi terapeu-tici principali: 1) Ampliamento dello spettro d’azione antimicrobica, per sommazione degli effetti dei due principi attivi; 2) Potenziamento dell’attività antimicotica, antiprotozoaria ed antibatterica; 3) Abolizione o ritardo della comparsa dei fenomeni di resistenza. Studi micro-biologici in vitro hanno dimostrato che l’attività trichomonicida e antimicotica risulta poten-ziata quando il (M) e il (C) sono associati nelle stesse proporzioni che sono presenti nel MECLON. Anche l’attività antibatterica esaminata su diversi ceppi di microorganismi è risul-tata elevata ed è emerso un potenziamento di essa quando i due principi attivi del MECLON vengono associati. 5.2 Proprietà farmacocinetiche. Dalle indagini farmacocinetiche sui conigli, cani e ratti risulta che dopo ripetute applicazioni topiche di MECLON non si rilevano concentrazioni apprezzabili di Clotrimazolo e Metronidazolo nel sangue. Per applicazione vaginale nella donna il (M) e il (C) vengono assorbiti in una percentuale che varia tra il 10% e il 20% circa. 5.3 Dati preclinici di sicurezza. La tossicità acuta del MECLON nel topo e nel ratto (os) è risultata molto bassa, con una mortalità di appena il 20% dopo 7 giorni, a dosi molto elevate (600 mg/Kg di (C) e 3.000 mg/Kg di (M), sia da soli che associati). Nelle prove di tossicità subacuta (30 giorni) il MECLON, somministrato per via locale (genitale) nel cane e nel coniglio, non ha determinato alcun tipo di lesione nè locale nè sistemica anche per dosi molte volte superiori a quelle comunemente impiegate in terapia umana (3-10 Dtd nel cane e 100-200 Dtd nel coniglio; 1 Dtd = dose terapeutica/die per l’uomo = ca. 3,33 mg/Kg di (C) e ca. 16,66 mg/Kg di (M)). Il MECLON somministrato durante il periodo di gravidanza per via topica vaginale nel coniglio e nel ratto non ha fatto evidenziare alcun segno di sofferenza fetale per dosi die di 100 Dtd, nè in� ussi negativi sullo stato gestazio-nale. 6. INFORMAZIONI FARMACEUTICHE. 6.1 Elenco degli eccipienti. Eccipienti: Miscela idro� la di mono, di, tri-gliceridi di acidi grassi saturi. 6.2 Incompatibilità. Non sono note incompatibilità con altri farmaci. 6.3 Periodo di validità. 3 anni. 6.4 Precauzioni particolari per la conservazione. Questo medicinale non richiede alcuna particolare con-dizione per la conservazione. 6.5 Natura e contenuto del contenitore. 10 ovuli in valve in PVC, racchiusi in scatola di cartone. 6.6 Precauzioni particolari per lo smaltimento e la manipolazione. Nessuna istruzione particolare. 7. TITOLARE DELL’AUTORIZZAZIONE ALL’IMMISSIONE IN COMMERCIO. Alfasigma S.p.A.- Viale Sarca, n. 223 - 20126 Milano (MI). 8. NUMERO DELL’AUTORIZZAZIONE ALL’IMMISSIONE IN COMMERCIO. A.I.C. n. 023703010. 9. DATA DELLA PRIMA AUTORIZZAZIONE/RINNOVO DELL’AUTORIZZAZIONE.16.01.1979 / 01.06.2010. 10. DATA DI REVISIONE DEL TESTO. Agosto 2017.



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