Reproductive BioMedicine Online (2015) 30, 462–481

w w w. s c i e n c e d i r e c t . c o m w w w. r b m o n l i n e . c o m

REVIEW

Safety and efficacy of the minilaparotomy for myomectomy: a systematic review and metaanalysis of randomized and non-randomized controlled trials Stefano Palomba a,*, Eleonora Fornaciari a, Angela Falbo a, Giovanni Battista La Sala a,b a

Obstetrics and Gynecology Unit, IRCCS – ASMN of Reggio Emilia, Italy; b University of Modena and Reggio Emilia, Italy

* Corresponding author.

E-mail addresses: [email protected]; [email protected] (S Palomba). Professor Stefano Palomba obtained his medical degree and specialization in obstetrics and gynecology at the Federico II University of Naples. In 2009, he won the Award of the European Society of Gynecology as best researcher under 40. He has worked as Associate Professor of Obstetrics and Gynecology at the University ‘Magna Graecia’ of Catanzaro and is currently Full Professor of Obstetrics and Gynecology and Head of Training and Scientific Research at the IRCCS – ASMN of Reggio Emilia, Italy. He has authored more than 200 peer-reviewed papers and is Editor-in-Chief of Current Drug Therapy, Co-Editor-in-Chief of Journal of Ovarian Research and Associate Editor of Human Reproduction.

Myomectomy is the most frequent reproductive surgery to preserve, improve fertility, or both. The present study was designed to assess the safety and efficacy of minilaparotomy for myomectomy through a systematic review of randomized and nonrandomized controlled trials with a meta-analysis. All available studies comparing minilaparotomy myomectomy with laparotomy, other minimally invasive surgeries, or both, were included. Available surgical and reproductive data were extrapolated, and a qualitative and quantitative analysis was carried out. Fourteen studies were included in the final analysis for an overall sample of 2151 patients. A total of 1139 patients were treated with minilaparotomy, whereas 239 and 773 patients were treated, respectively, with the laparotomy or laparoscopy. Only two studies comparing minilaparotomy with laparoscopy assessed the reproductive outcomes, and their data synthesis did not demonstrate significant difference between the two surgical techniques. Specific surgical endpoints differed significantly between minilaparotomy and laparotomy or laparoscopy, even if those differences were not clinically relevant. In conclusion, current data do not permit a definite conclusion to be drawn. Further studies are needed to clarify the risk– benefit ratio of the minilaparotomy compared with the other minimally invasive surgical procedures for myomectomy to provide clinical recommendations with strong scientific evidence. Abstract

© 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

http://dx.doi.org/10.1016/j.rbmo.2015.01.013 1472-6483/© 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

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KEYWORDS: fibroid, meta-analysis, minilaparotomy, myomectomy, surgery, systematic review

Introduction Uterine leiomyomas are the most common pelvic tumours in women, and are associated with significant morbidity and high economic burden (Marshall, 1997). Although several therapeutic options are available for patients with uterine fibroids, myomectomy is still the gold standard treatment and is carried out at a rate of 1.3 and 9.2 per 10,000 women per year for white and black women, respectively (Wechter et al., 2011). Although the effects of leiomyomas on human reproduction are still unclear (Metwally et al., 2011; Vimercati et al., 2007), myomectomy is the only approach to treat these tumours among reproductive-aged women desiring to conceive and to preserve their childbearing potential, and for patients who require uterine preservation (Falcone and Parker, 2013). Because of social and cultural changes that lead to a delay in pregnancy onset, a growing number of women wishing to retain their uterus for future childbearing has been observed during the past decades, and the rate of myomectomies is expected to increase by 30% by 2050 (Wechter et al., 2011). Therefore, more conservative and minimally invasive surgical techniques for the treatment of uterine myomas are, and will be, investigated. Although the myomectomy by laparotomy still has an important role in clinical practice (Falcone and Parker, 2013), it is well known that laparoscopic myomectomies have many remarkable advantages (Bhave Chittawar et al., 2014; Luciano, 2009). A recent systematic review with meta-analysis (Bhave Chittawar et al., 2014) confirmed that laparoscopic myomectomy is associated to lower postoperative pain, lower postoperative fever rates and a shorted hospitalization time after the intervention. Nevertheless open techniques are characterized by shorter time of execution (Bhave Chittawar et al., 2014). However, laparoscopic myomectomy is a more challenging and complex surgical technique with a long learning curve, a longer operating time, a notable numbers of conversions to open surgery (owing to the difficulties in suturing hysterotomies) and higher incidence of myoma recurrence resulting from intraoperative difficulty in recognizing small intramural tumours (Luciano, 2009; Mattei et al., 2011). In recent years, a compromise between the advantages of the classical laparotomy (i.e. a shorter learning curve and operating time) and those of the minimal access techniques (i.e. short hospitalization, little postoperative pain and rapid return to normal activities) seems to have been reached by minilaparotomy. This technique has been proposed as an alternative procedure to reduce the rate of traditional laparotomies in the treatment of several diseases, including large uterine fibroids (Glasser, 2005). To date, no clear recommendation or consensus has been reached about the surgical approach to myomectomy, and no evidence-based data are available for minilaparotomy. On the other hand, on April 17, 2014, the Food and Drug Administration published on the web a safety communication about the use of laparoscopic uterine power morcellation in hysterectomy and myomectomy (www.fda.gov/medicaldevices/ safety/alertsandnotices/ucm393576.htm). This bulletin underlines the risk of spreading unsuspected cancerous tissue, especially for sarcoma, within the abdomen and the pelvis

with the use of laparoscopic uterine power morcellators, and discourages their use in case of uterine leiomyomas. In addition, many alterative surgical treatments for managing uterine leiomyomas, including minilaparotomy, are proposed and recommended to healthcare providers, suggesting that, in the next years, more and more laparoscopic myomectomies will be completed, removing the leiomyomas through minilaparotomy (or colpotomy). On the basis of these considerations, the aim of the present study was to test, through a systematic review with a metaanalysis, the safety and efficacy of minilaparotomy using as comparator arm laparotomy, which is still considered the goldstandard intervention for myomectomy, or other minimally invasive approaches to myomectomy.

Materials and methods The protocol design followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines for reporting systematic reviews and meta-analyses (Moher et al., 2009).

Study selection Inclusion and exclusion criteria for the studies were established before conducting the literature search. Specifically, all included studies were characterized by symmetric interventions for intramural and subserous fibroids between two surgical treatments for myomectomy. All studies that did not have a study arm using the minilaparotomy approach were excluded from the final analysis. Although minilaparotomy for myomectomy was initially defined as an abdominal access obtained with a 3- to 6-cm suprapubic skin incision (Glasser, 2005), for the current study, all studies reporting data on myomectomies conducted using skin incisions no longer than 7 cm were arbitrarily included. No criteria were established for the comparator arm (laparotomy, other minimally invasive surgical techniques, or both, were included). Additionally, no exclusion criteria were applied for either the definition of minilaparotomy (e.g. longitudinal or transverse skin incisions, dimensions of the skin incisions less than or equal to 7 cm and the use or non-use of laparoscopy assistance), or type of laparotomy (e.g. longitudinal or transverse skin incisions, dimensions of the skin incisions larger than 7 cm), mini-invasive surgical techniques, or both. For laparoscopic techniques, both traditional gas laparoscopy, gasless laparoscopy, or both, were considered. Hysteroscopic techniques were not included in the search, and all papers addressing the efficacy and the safety of hysteroscopic myomectomy, surgical treatment of submucous fibroids, or both, were excluded from final analysis. Studies were also excluded if any data on surgical techniques, indication to intervention or at least one outcome measure were either not available, not extractable, not documented, or if the authors did not respond; if the data were inconsistent or

464 suspected duplicates (the corresponding authors were contacted by email and asked for clarification, and, if no clarification was obtained, data sets were considered overlapping and only the largest was included). Initially the systematic review included only randomized controlled trials (RCTs). Subsequently, the search was also extended to prospective nonrandomized and retrospective studies. When data were unavailable for quantitative analysis, the studies were included and detailed only in the qualitative analysis.

Search strategy The bibliographic search for identification of articles, abstracts, and study protocols was conducted every month up to July 2014. No language restriction was applied. A combination of the following medical subject headings or keywords were included: ‘clinical trial’, ‘fibroid’, ‘gasless laparoscopy’, ‘isobaric laparoscopy’, ‘laparoscopy’, ‘laparoscopic-assisted minilaparotomy’, ‘LAM’, ‘laparoendoscopic single-site’, ‘LESS’, ‘leiomyoma’, ‘leiomyomata’, ‘microlaparoscopy’, ‘minilaparoscopy’, ‘minilaparotomy’, ‘laparotomy’, ‘meta-analysis’, ‘myomas’, ‘myomectomy’, ‘natural orifices transluminal endoscopic surgery’, ‘NOTES’, ‘roboticassisted laparoscopy’, ‘RAL’, ‘single-incision laparoscopy’, ‘single-port laparoscopy’, ‘single-site laparoscopy’, ‘surgery’, ‘treatment’, ‘ultraminilaparotomy’, ‘vaginal myomectomy’. MEDLINE through PubMed (1966 to July 2014), EMBASE (1966 to July 2014), CINAHL (1981 to July 2014), Cochrane Library (1970 to July 2014), Clinical Evidence, UpToDate, and DARE were electronically searched for relevant studies. The Institute for Scientific Information (ISI), Web of Science (WoS), Scopus, Google Scholar, and the websites for the registration of controlled trials were also consulted for relevant clinical trials up to July 2014. In addition, bibliographies of retrieved articles, books and expert opinion review articles were manually searched and reviewed. A systematic attempt to search the grey literature was also made through Open Grey (www.opengrey.eu). Titles and abstracts were screened, and potentially relevant articles were identified and reviewed for inclusion and exclusion criteria. Then, the protocols and results of the studies were examined according to specific inclusion criteria. Finally, only studies that met the inclusion and exclusion criteria were considered for the final analysis. Two independent reviewers (EF and AF), not blinded at any point to the authors or sources of publication, simultaneously reviewed the full manuscripts of all citations that potentially matched the predefined selection criteria. Final exclusion or inclusion decisions were made on examination of the full manuscripts. Disagreements between the reviewers on inclusion were discussed and solved by consensus or arbitration (SP).

Data extraction After data selection, two reviewers (EF and AF) again independently extracted the data using the same preformed extraction tables. Extracted data consisted of the general characteristics of the included studies and their surgical and

S Palomba et al. reproductive findings. All methodological and procedural characteristics of each study and the variables reported (including the demographic and clinical characteristics, indications to the intervention of myomectomy and definition of the treatment received) were noted and analysed. Surgical data consisted of operative time, intraoperative blood loss and haemoglobin level change, need for transfusion, postoperative ileus duration, postoperative pain, hospitalization, intraand postoperative complications, and conversions to laparotomy. Reproductive data included the rates of pregnancies, abortions and live births. Obstetric data included the rates of vaginal and caesarean deliveries and preterm deliveries. Recurrence of leiomyomas and costs of the surgical procedures were also evaluated. All extracted data were tabulated by two other authors (SP and GBLS) who, in case of disagreement among extraction tables, revised the original papers and, after discussion, reached a consensus.

Qualitative data analysis Two other reviewers (SP and GBLS) independently assessed the quality of available RCTs using the Cochrane Collaboration’s tool for assessing the risk of bias (Higgins and Green, 2011). All available data of interest were then summarized and presented in a comparing, contrasting fashion, or both.

Quantitative data analysis and synthesis Quantitative data analysis was conducted for all end-points extracted and tabulated. In the case of more than one study, data synthesis for each outcome was carried out. Statistical analyses were carried out according to the statistical guidelines for review authors developed by The Cochrane Collaboration and published in the Cochrane Handbook for Systematic Reviews of Interventions. All of the statistical analyses were carried out using Review Manager Version 5.3, provided by the Cochrane Menstrual Disorders and Subfertility Group (www.ims.cochrane.org/revman). The analysis of the treatment effect was carried out according to the intention-to-treat (ITT). The odds ratio (OR), with 95% confidence intervals (CI), was used to describe the intervention effect for each dichotomous outcome using the Mantel–Haenszel method (Mantel and Haenszel, 1959). Continuous outcome differences between the two groups were presented as the mean difference with 95% CI. A fixedeffect model was initially used in the analysis, unless a significant heterogeneity occurred; in which case a randomeffects model analysis was used to account for the extra uncertainty caused by heterogeneity. Potential heterogeneity of the treatment effects of each trial was examined by testing inconsistency (I2) (Higgins et al., 2003). In case of incomplete data (no standard deviation), the mathematic formula described by Hozo et al. (2005) was applied according to the sample size. P < 0.05 or 95% CI that did not contain unity were considered statistically significant. A statistical trend was arbitrarily established for P-values that ranged between 0.05 and 0.09.

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465

Records identified through database searching (n = 2247)

Records screened (n = 2247)

Full-text articles assessed for eligibility (n = 26)

Records excluded (n = 2221)

Full-text articles excluded (n = 12), -No laparotomy/minimally invasive techniques as control group (n = 11) -Results of one trial reported in double item (n = 1)

Studies included in qualitative synthesis (n = 14)

Studies included in quantitative synthesis (meta-analysis) (n = 14)

Figure 1

Study selection (Moher et al., 2009).

Results Search data Figure 1 shows the flow diagram of the study selection according to the PRISMA statement (Moher et al., 2009). Only published data were included because no un-published study or in-progress study protocol was identified. Fourteen studies were included in the final analysis (Alessandri et al., 2006; Benassi et al., 2005; Cagnacci et al., 2003; Ciavattini et al., 2010; Cicinelli et al., 2009; Fanfani et al., 2005; Kalogiannidis et al., 2010; Malzoni et al., 2010; Palomba et al., 2007a, 2007b; Prapas et al., 2009; Sesti et al., 2008; Tan et al., 2008; Wen et al., 2008, 2010) for an overall population of 2151 patients. Seven studies (Alessandri et al., 2006; Benassi et al., 2005; Cagnacci et al., 2003; Cicinelli et al., 2009; Palomba et al., 2007a, 2007b; Sesti et al., 2008; Tan et al., 2008) were RCTs, whereas other five were prospective non-randomized (Fanfani et al., 2005; Kalogiannidis et al., 2010; Prapas et al., 2009; Wen et al., 2008, 2010) and two retrospective (Ciavattini et al., 2010; Malzoni et al., 2010). The quality of the RCTs included in the analysis is detailed in Table 1 (Higgins and Green, 2011). In the non-randomized studies (Ciavattini et al., 2010; Fanfani et al., 2005; Kalogiannidis et al., 2010; Malzoni et al.,

2010; Prapas et al., 2009; Wen et al., 2008, 2010), the decision to use a specific technique was taken by surgeons according to patient and leiomyoma(s) characteristics (Fanfani et al., 2005; Malzoni et al., 2010) or by patients (Kalogiannidis et al., 2010; Prapas et al., 2009; Wen et al., 2008, 2010), whereas in one study (Ciavattini et al., 2010) it was not reported. A total of 1139 patients were treated with minilaparotomy (Alessandri et al., 2006; Benassi et al., 2005; Cagnacci et al., 2003; Ciavattini et al., 2010; Cicinelli et al., 2009; Fanfani et al., 2005; Kalogiannidis et al., 2010; Malzoni et al., 2010; Palomba et al., 2007a, 2007b; Prapas et al., 2009; Sesti et al., 2008; Tan et al., 2008; Wen et al., 2008, 2010), whereas 239 and 773 patients received, respectively, a laparotomy (Benassi et al., 2005; Cagnacci et al., 2003; Kalogiannidis et al., 2010; Wen et al., 2008, 2010) or other minimally invasive surgical techniques (Alessandri et al., 2006; Ciavattini et al., 2010; Cicinelli et al., 2009; Fanfani et al., 2005; Malzoni et al., 2010; Palomba et al., 2007a, 2007b; Prapas et al., 2009; Sesti et al., 2008; Tan et al., 2008). Specifically, the minimally invasive surgeries used as comparative procedures consisted of either traditional gas laparoscopy (Alessandri et al., 2006; Ciavattini et al., 2010; Cicinelli et al., 2009; Fanfani et al., 2005; Malzoni et al., 2010; Palomba et al., 2007a, 2007b; Prapas et al., 2009) or isobaric gasless laparoscopy (Sesti et al., 2008; Tan et al.,

466 Table 1

S Palomba et al. Quality of the randomized controlled trials included in the final analysis (Higgins and Green, 2011).

Author

Cagnacci et al., 2003 Benassi et al., 2005 Alessandri et al., 2006 Palomba et al., 2007a Sesti et al., 2008 Tan et al., 2008 Cicinelli et al., 2009

Adequate sequence generation

Allocation concealment

Blinding

Incomplete data outcome

Free of selective reporting

Free of other bias

Yes Yes Yes Yes Unclear Yes Yes

Unclear Unclear Yes Yes Yes No No

Yes No No Yes Unclear Unclear Yes

Yes Yes No No No Yes Yes

No No Yes No No No No

No No No No No No No

2008). No studies comparing minilaparotomy with either micro- or mini-laparoscopy, single-port laparoscopy, natural orifices transluminal endoscopic surgery, robot-assisted laparoscopy or vaginal myomectomy were identified. In one RCT (Alessandri et al., 2006), two randomized patients treated with traditional laparoscopy were erroneously excluded from the final analysis of the postoperative outcomes because of intraoperative complications (i.e. one conversion to laparotomy for difficult haemostasis and one case of secondary laparotomy for acute diffuse peritonitis caused by ileal perforation during laparoscopy.

Qualitative data analysis The main characteristics of the populations studied are reported in Table 2. All of the patients were affected by intramural or subserous leiomyomas (Alessandri et al., 2006; Benassi et al., 2005; Cagnacci et al., 2003; Ciavattini et al., 2010; Cicinelli et al., 2009; Fanfani et al., 2005; Kalogiannidis et al., 2010; Malzoni et al., 2010; Palomba et al., 2007a, 2007b; Prapas et al., 2009; Sesti et al., 2008; Tan et al., 2008; Wen et al., 2008, 2010). In one study (Ciavattini et al., 2010) also patients with intramural-submucosal leyomyomas were included. Submucosal leiomyomas were formally excluded in six studies (Alessandri et al., 2006; Fanfani et al., 2005; Malzoni et al., 2010; Palomba et al., 2007a, 2007b; Prapas et al., 2009; Tan et al., 2008). The presumed presence of peduncolated leiomyomas was a further exclusion criterion in eight studies (Cagnacci et al., 2003; Ciavattini et al., 2010; Fanfani et al., 2005; Prapas et al., 2009; Sesti et al., 2008; Tan et al., 2008; Wen et al., 2008, 2010). The patients underwent the surgical intervention for leiomyoma-related symptoms (Ciavattini et al., 2010; Fanfani et al., 2005; Kalogiannidis et al., 2010; Malzoni et al., 2010; Palomba et al., 2007a, 2007b; Prapas et al., 2009; Wen et al., 2008, 2010), recurrent abortion (Alessandri et al., 2006; Malzoni et al., 2010) or for leiomyoma-associated or unexplained infertility (Alessandri et al., 2006; Cagnacci et al., 2003; Ciavattini et al., 2010; Fanfani et al., 2005; Kalogiannidis et al., 2010; Malzoni et al., 2010; Palomba et al., 2007a, 2007b; Prapas et al., 2009; Sesti et al., 2008; Tan et al., 2008; Wen et al., 2008, 2010). Another indication for the surgical procedure was the presence of a rapidly growing leiomyoma (Alessandri et al., 2006; Kalogiannidis et al., 2010; Sesti et al., 2008). Four studies generically referred to symptomatic leiomyomas as a criterion of inclusion in the trial, but the

symptoms were not detailed (Benassi et al., 2005; Cagnacci et al., 2003; Cicinelli et al., 2009; Tan et al., 2008). In four studies (Malzoni et al., 2010; Palomba et al., 2007a, 2007b; Wen et al., 2008, 2010) other causes for infertility were formally excluded. In one study (Fanfani et al., 2005), a previous suprapubic longitudinal laparotomy was an exclusion criterion. Similarly, in another (Wen et al., 2008), the absence of previous abdominal or pelvic surgery was required for the study inclusion. The medical treatment for ovarian suppression before surgery (i.e. gonadotrophin releasing hormone analogs, was not reported in any study. In four studies, it was formally clarified that no patient received pre-surgical treatment or hormonal drugs (Alessandri et al., 2006; Kalogiannidis et al., 2010; Palomba et al., 2007a, 2007b; Sesti et al., 2008).

Surgical techniques The surgical procedures differed widely among the studies. In one study (Prapas et al., 2009), all surgical procedures were performed between the days 7 and 17 of the menstrual cycle but no explanation was given regarding this. Minilaparotomy Although in all studies (Alessandri et al., 2006; Benassi et al., 2005; Cagnacci et al., 2003; Ciavattini et al., 2010; Cicinelli et al., 2009; Fanfani et al., 2005; Kalogiannidis et al., 2010; Malzoni et al., 2010; Palomba et al., 2007a, 2007b; Prapas et al., 2009; Sesti et al., 2008; Tan et al., 2008; Wen et al., 2008, 2010) a transverse skin incision was carried out for minilaparotomy, the length and height varied among the studies. In three studies, the skin incisions were of 5 cm (Cagnacci et al., 2003; Cicinelli et al., 2009) or 6 cm (Benassi et al., 2005) in length. In the others, they varied from 2–4 cm (Wen et al., 2008, 2010), from 3–4 cm (Kalogiannidis et al., 2010; Prapas et al., 2009), from 4–6 cm (Alessandri et al., 2006; Malzoni et al., 2010), and from 4–7 cm (Fanfani et al., 2005; Palomba et al., 2007a, 2007b; Sesti et al., 2008; Tan et al., 2008) according to the number, size, and position of the leiomyomas (Alessandri et al., 2006; Palomba et al., 2007a, 2007b; Sesti et al., 2008; Tan et al., 2008) or according to the size of the largest one (Kalogiannidis et al., 2010; Prapas et al., 2009). In one study (Ciavattini et al., 2010), the length of the skin incisions were not formally reported. In only one study (Alessandri et al., 2006), the presence of central obesity was

Characteristics of the population studied. Design

Comparison

Sample size

Cagnacci et al., 2003

RCT

Benassi et al., 2005

RCT

Not assisted minilaparotomy versus laparoscopically assisted minilaparotomy versus traditional laparotomy Not assisted minilaparotomy versus traditional laparotomy

Fanfani et al., 2005

Prospective nonrandomized trial RCT

17 versus Presence of either 17 versus leiomyoma-related 17 symptoms or leiomyomaassociated infertility. 55 versus Diagnosis of symptomatic 44 leiomyoma(s); presence of intramural or subserous leiomyomas. 120 Presence of either versus 93 symptomatic or infertility-associated leiomyomas. 74 versus Presence of symptomatic 74 subserous or intramural leiomyoma; size of the largest ranging from 3–7 cm. 68 versus Presence of leiomyoma68 related symptoms or unexplained infertility.

Author and year of publication

Alessandri et al., 2006

Palomba et al., 2007a, 2007b

RCT

Not assisted minilaparotomy versus traditional gas laparoscopy Not assisted minilaparotomy versus traditional gas laparoscopy

Not assisted minilaparotomy versus traditional gas laparoscopy

Inclusion criteria

Exclusion criteria

Presence of five or more intramural or subserous leiomyomas (without peduncle) with a total diameter between 5 and 15 cm.

Minilaparotomy for myomectomy

Table 2

Total sonographic volume of leiomyomas over 1000 cc; previous uterine surgery (including cesarean section); hormone treatments given in the three months before surgery. Presence of 5 or more intramural or subserous leiomyomas with a maximum diameter of 10 cm; presumed presence of submucosal, pedunculated leiomyomas, or both; previous suprapubic longitudinal laparotomy; age of 45 or more years. Presence of submucosal leiomyomas; presence of 5 or more leiomyomas; association with ovarian or uterine lesions; age more than 45 years; BMI more than 29; contraindications for general anaesthesia; systemic infections; psychiatric disorders precluding consent. Major medical conditions; endocrine disease (including basal FSH >10 UI/L); psychiatric disorders; current or past history of acute or chronic physical illness. Premenstrual syndrome, according to the DSM-IV; current or past (a washout period of at least 6 months was considered appropriate before enrollment) use of hormonal drugs or drugs influencing cognition, vigilance or mood; inability to complete the daily diary; a history of alcohol abuse; no desire to conceive; presence of more than three uterine leiomyomas and of leiomyomas with a main diameter less than 3 cm or more than 10 cm; hypoechoic or calcified leiomyomas diagnosed at ultrasound; presence of submucosal leiomyomas or alterations of the uterine cavity screened by hysteroscopy; other uterine or adnexal abnormalities at ultrasound; pattern of hyperplasia with cytological atypia in the endometrial biopsy performed for abnormal bleeding under hysteroscopy on suspected areas; abnormal Papanicolaou smear; positive urine pregnancy test; symptomatic women who did not have a previous conception resulting in a live baby or with a tubal or male factor subfertility. (continued on next page)

467

468

Table 2

(continued)

Author and year of publication

Design

Sesti et al., RCT 2008

Comparison

Sample size

Inclusion criteria

Exclusion criteria

Not assisted minilaparotomy versus isobaric gasless laparoscopy

Presence of more than five leiomyomas with a diameter less than three or more than 10 cm; presence of subserous pedunculated myomas; BMI of 30 kg/m2 or more. Previous uterine surgery. Suspicion of malignant gynecologic disease. Presence of more than 5 leiomyomas with a diameter less than 3 or more than 10 cm. Presence of subserous pedunculated myomas; major medical conditions; psychiatric disorders; current or past history of acute or chronic physical illness; premenstrual syndrome, according to the DSM-IV; current or past (a washout period of at least 6 months was considered appropriate before enrollment) use of hormonal drugs or drugs influencing cognition, vigilance or mood; inability to complete the daily diary; a history of alcohol abuse; no desire to conceive; hypoechoic or calcified leiomyomas diagnosed at ultrasound scanning; presence of submucosal leiomyomas or alterations of the uterine cavity screened by hysteroscopy; other uterine or adnexal abnormalities at ultrasound scanning; pattern of hyperplasia with cytologic atypia in the endometrial biopsy performed for abnormal bleeding under hysteroscopy on suspected areas; abnormal Papanicolaou smear; positive urine pregnancy test; symptomatic women who did not have a previous conception resulting in a live baby or with a tubal or male factor subfertility. 41 versus Presence of symptomatic Presence of more than five leiomyomas. Presence of subserous pedunculated myomas; prominent or significant pelvic 72 leiomyomas; wish to adhesion on clinical evaluation; previous abdominal or pelvic surgery. receive myomectomy; wish to retain one’s own uterus; intramural or subserous leiomyomas; maximum diameter of no more than 8 cm. (continued on next page)

50 versus Presence of symptomatic 50 intramural or subserous leiomyomas associated with either infertility or fast growth. Laparoscopically assisted 26 versus Presence of symptomatic minilaparotomy versus isobaric 26 intramural or subserous gasless laparoscopy leiomyomas associated with either infertility or fast growth.

Tan et al., 2008

RCT

Wen et al., 2008

Prospective Ultraminilaparotomy versus nontraditional laparotomy randomized trial

S Palomba et al.

(continued)

Author and year of publication

Design

Comparison

Sample size

Inclusion criteria

Not assisted minilaparotomy 40 versus Presence of no more versus traditional gas 40 than three symptomatic laparoscopy subserous or intramural leiomyomas no larger than 7 cm. Laparoscopically assisted 76 versus Premenopausal patients Prapas Prospective minilaparotomy versus 40 not older than 42 years et al., nontraditional gas laparoscopy with symptomatic 2009 randomized intramural and subserous trial leiomyomas. Ciavattini Retrospective Ultraminilaparotomy versus 32 versus Presence of one to five et al., case-control traditional gas laparoscopy 32 symptomatic or 2010 study infertility-associated subserous (without peduncle), intramural, intramural-submucosal leiomyomas; diameter equal or higher than 5 cm. Laparoscopically assisted 48 versus Presence of intramural Kalogiannidis Prospective minilaparotomy versus 27 or subserous et al., nontraditional laparotomy leiomyomas. 2010 randomized trial Malzoni Retrospective Not assisted minilaparotomy 330 Symptomatic subserous et al., case-control versus traditional gas versus or intramural 2010 study laparoscopy 350 leiomyomas. Cicinelli et al., 2009

Wen et al., 2010

RCT

Prospective nonrandomized trial

Ultraminilaparotomy vs. laparoscopically assisted ultraminilaparotomy vs. traditional laparotomy

71 versus Intramural or subserous 74 versus leiomyomas. 79

Exclusion criteria

Cardiopulmonary disease contraindicating the laparoscopy approach; preoperative haemoglobin level less than 9 g/dL.

Minilaparotomy for myomectomy

Table 2

Submucosal and pedunculated leiomyomas; presence of more than three leiomyomas with a diameter less than 3 cm or higher than 9 cm. Ovarian disease; contraindication to general anaesthesia; previous medical treatment for ovarian suppression; pregnancy; abnormal Papanicolaou test smear; hyperplasia (with or without atypia) in case of endometrial biopsy. Leiomyoma size equal or higher than 15 cm; presence of more than six leiomyomas; pattern of endometrial hyperplasia with cytologic atypia; abnormal Papanicolaou smear; positive plasma pregnancy test.

Leiomyoma size higher than 9 cm; other pathology of the genital tract, such as dubious uncertain or abnormal Papanicolaou smear, adnexal masses, endometrial hyperplasia with or without atypia. Submucosal leiomyomas; presence of more than five leiomyomas with a diameter less than 2 cm or higher than 10 cm; contraindications to general anaesthesia; systemic infections; more than five uterine leiomyomas or of leiomyomas with main diameter more than 10 cm; adnexal abnormalities at ultrasound; abnormal Papanicolaou smear; positive plasma pregnancy test. Presence of more than five leiomyomas with a diameter higher than 8 cm; presence of subserous pedunculated myomas; previous abdominal or pelvic surgery; prominent or significant pelvic adhesion on clinical evaluation; preoperative or postoperative adjuvant therapy; other pelvic pathologies except fibroids.

BMI = body mass index; RTC = randomised controlled trial.

469

470 a factor influencing the incision size. In one study (Ciavattini et al., 2010) the incision was equal or less than 4 cm. The distance of the incision from the pubic symphysis also varied according to leiomyoma dimension (Palomba et al., 2007a, 2007b) and localization (Cicinelli et al., 2009; Palomba et al., 2007a, 2007b) from 1–3 cm (Cicinelli et al., 2009), 3 cm (Kalogiannidis et al., 2010; Malzoni et al., 2010), or 2–4 cm (Ciavattini et al., 2010; Fanfani et al., 2005). In other studies, it was 1–2 cm below the pubic hairline (Benassi et al., 2005; Cagnacci et al., 2003; Fanfani et al., 2005; Wen et al., 2008). To avoid accidental extension of the minilaparotomy (Ciavattini et al., 2010; Fanfani et al., 2005; Kalogiannidis et al., 2010; Palomba et al., 2007a, 2007b; Prapas et al., 2009), two sutures were made at the ends of the skin incision. The subcutaneous fat and the abdominal fascia were transversely (Alessandri et al., 2006; Cagnacci et al., 2003; Ciavattini et al., 2010; Malzoni et al., 2010; Sesti et al., 2008; Tan et al., 2008; Wen et al., 2008) with a 5–6 cm incision (Wen et al., 2010), or longitudinally (Cagnacci et al., 2003; Cicinelli et al., 2009; Fanfani et al., 2005; Kalogiannidis et al., 2010; Palomba et al., 2007a, 2007b; Prapas et al., 2009) opened 2 cm (Sesti et al., 2008; Tan et al., 2008) or 2–3 cm (Benassi et al., 2005; Ciavattini et al., 2010; Fanfani et al., 2005; Wen et al., 2008) above the skin incision. Only few studies (Benassi et al., 2005; Ciavattini et al., 2010; Fanfani et al., 2005; Wen et al., 2008, 2010) reported the incision length of the fascia (i.e. 10–12 cm) (Benassi et al., 2005; Fanfani et al., 2005), 5–6 cm (Wen et al., 2008), 6–8 cm (Ciavattini et al., 2010). The abdominal muscle and the parietal peritoneum were longitudinally opened on the medline in many studies (Alessandri et al., 2006; Benassi et al., 2005; Ciavattini et al., 2010; Cicinelli et al., 2009; Fanfani et al., 2005; Kalogiannidis et al., 2010; Malzoni et al., 2010; Palomba et al., 2007a, 2007b; Prapas et al., 2009; Sesti et al., 2008; Tan et al., 2008). In two studies, it was clarified that no intestinal gauzes were inserted into the abdomen (Benassi et al., 2005; Palomba et al., 2007a, 2007b), whereas in others (Fanfani et al., 2005; Wen et al., 2008) they (warm and wet) were used when required. The uterine manipulator was used in two cases (Cagnacci et al., 2003; Palomba et al., 2007a, 2007b) to elevate the uterus toward the incision. In three studies (Palomba et al., 2007a, 2007b; Wen et al., 2008, 2010), a vasoconstrictor solution (bupivacaine chloridrate plus epinephrine or diluted vasopressin) was injected in the serosa of the myometrium overlying the leiomyoma (Palomba et al., 2007a, 2007b) and into the leiomyoma (Wen et al., 2008, 2010) before the uterine incision. In four other studies (Cagnacci et al., 2003; Cicinelli et al., 2009; Fanfani et al., 2005; Kalogiannidis et al., 2010) no vasoconstriction was used. In two studies (Cagnacci et al., 2003; Kalogiannidis et al., 2010) it was also clarified that no mechanical vascular occlusion technique was used before uterine incision. Hysterotomy was transversally (Ciavattini et al., 2010; Sesti et al., 2008; Tan et al., 2008) or longitudinally (Palomba et al., 2007a, 2007b) carried out using a monopolar knife (Cicinelli et al., 2009; Palomba et al., 2007a, 2007b; Sesti et al., 2008; Tan et al., 2008) with a cutting current of 70 W (Palomba et al., 2007a, 2007b; Tan et al., 2008), or with a cold knife (Kalogiannidis et al., 2010; Prapas et al., 2009). These data were not reported in the other studies (Alessandri et al., 2006; Benassi et al., 2005; Cagnacci et al., 2003; Fanfani et al., 2005; Wen et al., 2008).

S Palomba et al. The uterine defects were closed in a single or multiple layer, according to the depth of the uterine defect (Cagnacci et al., 2003; Ciavattini et al., 2010; Malzoni et al., 2010; Palomba et al., 2007a, 2007b; Sesti et al., 2008), with interrupted (Alessandri et al., 2006; Cagnacci et al., 2003; Ciavattini et al., 2010; Cicinelli et al., 2009; Malzoni et al., 2010) sutures. In two studies (Kalogiannidis et al., 2010; Prapas et al., 2009), the defect was repaired with a single layer continuous suture. In two other studies (Cagnacci et al., 2003; Wen et al., 2008), the serosa was re-approximated separately. In eight studies (Ciavattini et al., 2010; Fanfani et al., 2005; Kalogiannidis et al., 2010; Malzoni et al., 2010; Palomba et al., 2007a, 2007b; Prapas et al., 2009; Wen et al., 2008, 2010), a morcellament technique with the use of a cold knife to remove leiomyoma(s) from the abdomen in case of a tumour size greater than the skin incision was reported, whereas no specific data were given in the other studies (Alessandri et al., 2006; Benassi et al., 2005; Cagnacci et al., 2003; Cicinelli et al., 2009; Sesti et al., 2008; Tan et al., 2008). Adhesion barriers or saline dextrane macromolecular solutions were never used in two studies (Palomba et al., 2007a, 2007b; Tan et al., 2008), whereas in others six studies (Benassi et al., 2005; Cagnacci et al., 2003; Ciavattini et al., 2010; Kalogiannidis et al., 2010; Prapas et al., 2009; Wen et al., 2008) various anti-adhesion agents, procedures were used, or both (i.e. peritoneal irrigation with a 1:10000 dilution of heparincontaining normal saline solution, or with Ringer’s lactate solution that was also left intra-abdominally, placement of oxidized regenerated cellulose). In five studies (Cagnacci et al., 2003; Kalogiannidis et al., 2010; Prapas et al., 2009; Tan et al., 2008; Wen et al., 2010), the minilaparotomy was laparoscopy-assisted. A trocar with the laparoscope was inserted through an infraumbilical incision of 10 mm, and an ancillary incision of 5 mm to the left of the umbilicus was used to insert operative instruments and the suction-irrigation cannula (Cagnacci et al., 2003; Kalogiannidis et al., 2010; Prapas et al., 2009; Sesti et al., 2008). In one study (Wen et al., 2010), three ancillary trocars were inserted into the abdomen to introduce operative instruments and the suction-irrigation cannula. After the identification of the leiomyoma by video-laparoscopy, a 5-mm suprapubic midline trocar was inserted close to the location of the uterine leiomyoma (Kalogiannidis et al., 2010; Prapas et al., 2009) and a tenaculus through this port was used to arrest the myoma. After closure of the peritoneum, haemostasis was controlled under videolaparoscopy and the pelvic cavity was washed with saline solution via a suctionirrigator (Cagnacci et al., 2003; Sesti et al., 2008). Laparotomy In five studies (Benassi et al., 2005; Cagnacci et al., 2003; Kalogiannidis et al., 2010; Wen et al., 2008, 2010), a traditional laparotomy was carried out in the comparator arm. No data were formally provided in one study (Benassi et al., 2005) about the laparotomy procedure. In one study (Cagnacci et al., 2003), the laparotomy was carried out with a 10–12 cm transverse suprapubic incision; the subcutaneous fat and the abdominal fascia (Cagnacci et al., 2003) were always opened transversally. In two studies (Wen et al., 2008, 2010), a 8–12 cm supra-pubic Pfannenstiel incision was made 2–4 cm above the pubic symphysis (Wen et al., 2010). The subcutaneous fat and the abdominal fascia were opened with a

Minilaparotomy for myomectomy transversal incision (Wen et al., 2008, 2010) of 10–16 cm (Wen et al., 2010), 2–3 cm above the skin incision (Wen et al., 2008, 2010). In one study (Kalogiannidis et al., 2010) the suprapubic Pfannenstiel incision was made 3 cm above the pubic symphysis, and the subcutaneous fat and abdominal fascia were open transversally. The muscle and parietal peritoneum were open longitudinally (Cagnacci et al., 2003; Kalogiannidis et al., 2010; Wen et al., 2008). A maximum effort was given by the surgeons to omit the use of self retractor (Kalogiannidis et al., 2010; Wen et al., 2008) and surgical gauzes or pads (Kalogiannidis et al., 2010) in peritoneal cavity to avoid tissue, intestinal trauma, or both. On the other hand, intestinal gauzes or pads were always used in three studies (Cagnacci et al., 2003; Wen et al., 2008, 2010) and a self retaining retractor in one study (Wen et al., 2010). In two studies (Wen et al., 2008, 2010), a vasoconstrictor solution (diluted vasopressin) was injected in the serosa of the myometrium overlying and into the leiomyoma before the uterine incision. Neither vasoconstriction was used nor mechanical vascular occlusion technique was used before uterine incision in one study (Cagnacci et al., 2003). The uterine incision was made on the anterior wall or the fundus in an attempt to reduce postoperative adhesions (Cagnacci et al., 2003). In one trial (Kalogiannidis et al., 2010), the uterine incision was made longitudinally using a cold knife, as close to midline as possible. Double layer continuous sutures were used to repair the uterine defect (Kalogiannidis et al., 2010). Leiomyomas were removed from the abdomen always intact (Wen et al., 2008), and uterine defects were reconstructed outside the abdomen (Wen et al., 2008). Uterine defects were closed in single or double layer interrupted sutures (Cagnacci et al., 2003), or in double layer interrupted sutures (Wen et al., 2010). The serosa was also re-approximated separately (Cagnacci et al., 2003; Wen et al., 2008). To prevent adhesions, the pelvis was irrigated either with 1:10000 dilution of heparin-containing normal saline solution (Wen et al., 2008) or with a Ringer’s lactate solution (Cagnacci et al., 2003), or oxidized regenerated cellulose was placed on uterine sutures (Cagnacci et al., 2003; Kalogiannidis et al., 2010). Laparoscopy In nine studies (Alessandri et al., 2006; Ciavattini et al., 2010; Cicinelli et al., 2009; Fanfani et al., 2005; Malzoni et al., 2010; Palomba et al., 2007a, 2007b; Prapas et al., 2009; Sesti et al., 2008; Tan et al., 2008), the comparator arm for minilaparotomy was the laparoscopy. In seven studies (Alessandri et al., 2006; Ciavattini et al., 2010; Cicinelli et al., 2009; Fanfani et al., 2005; Malzoni et al., 2010; Palomba et al., 2007a, 2007b; Prapas et al., 2009), it consisted of traditional gas laparoscopy and was isobaric gasless laparoscopy in two other studies (Sesti et al., 2008; Tan et al., 2008). Traditional gas laparoscopy In seven studies (Alessandri et al., 2006; Ciavattini et al., 2010; Cicinelli et al., 2009; Fanfani et al., 2005; Malzoni et al., 2010; Palomba et al., 2007a, 2007b; Prapas et al., 2009), the technique was conducted by positioning the laparoscope through one infraumbilical 10-mm entry, and using two or three 5–10 mm ancillary trocars; the uterine manipulator was frequently used to permit uterine movements and organ exposure. In four studies (Cicinelli et al., 2009; Malzoni et al., 2010;

471 Palomba et al., 2007a, 2007b; Prapas et al., 2009), a closed technique was conducted using the Veress needle, whereas, in the other study (Alessandri et al., 2006), an open approach was preferred. A vasoconstrictor solution was injected in the serosa of the myometrium overlying the leiomyoma before the uterine incision in one study (Palomba et al., 2007a, 2007b), whereas no vasoconstrictor agent was used in another (Cicinelli et al., 2009). The uterus was incised longitudinally in two studies (Palomba et al., 2007a, 2007b; Prapas et al., 2009). The incision was made with a monopolar needle in four studies (Ciavattini et al., 2010; Cicinelli et al., 2009; Malzoni et al., 2010; Palomba et al., 2007a, 2007b), whereas in another (Prapas et al., 2009) with the use of bipolar scissors. The uterine defects were closed in a single or double layer, according to the depth of the uterine defect (Ciavattini et al., 2010; Malzoni et al., 2010; Palomba et al., 2007a, 2007b), with interrupted sutures (Alessandri et al., 2006; Cicinelli et al., 2009; Malzoni et al., 2010; Palomba et al., 2007a, 2007b; Prapas et al., 2009) using intracorporeal (Alessandri et al., 2006; Ciavattini et al., 2010; Palomba et al., 2007a, 2007b) or extracorporeal knots (Malzoni et al., 2010). In another study (Cicinelli et al., 2009), the investigators always sutured in two layers using extracorporeal knots. In one study (Palomba et al., 2007a, 2007b), no adhesion barriers, saline dextrane macromolecular solutions, or both, were used. In two studies (Ciavattini et al., 2010; Prapas et al., 2009), adhesion agents, specific procedures, or both, were used (i.e. Ringer’s lactate solution that was also left intrabdominally or oxidized regenerated cellulose) to prevent pelvic adhesions. In all studies (Alessandri et al., 2006; Ciavattini et al., 2010; Cicinelli et al., 2009; Fanfani et al., 2005; Malzoni et al., 2010; Palomba et al., 2007a, 2007b; Prapas et al., 2009), the leiomyomas were extracted from abdomen with the use of laparoscopic electrosurgical morcellator. Gasless isobaric laparoscopy Gasless laparoscopy was carried out using a Laparotenser in one study (Sesti et al., 2008), whereas, in the other (Tan et al., 2008), the abdominal wall lifting was carried out with the introduction of a Kirschner’s needle. Laparotenser (Lucini surgical concept, Milan, Italy) is an abdominal-wall-lifting device with two curved ‘pluriplan’ needles with blunt tips that are subcutaneously introduced through two very small (2 mm) skin incisions in the pubis; they were suspended from a mechanical arm attached to a rigid pillar, and then elevated as far as necessary to obtain the exposure (Sesti et al., 2008). Alternatively, in the other study (Tan et al., 2008), the abdominal wall lifting was obtained with the introduction of a Kirschner’s needle (diameter of 2 mm) vertically through the subcutaneous tissue 10 cm below the laparoscope. They subsequently suspended both ends of the steel needle at the cross arm of a lifting–pulling device via a saddle chain (Tan et al., 2008). Finally, the cross arm was connected with a vertical arm, fixed at one side of the operating table (Tan et al., 2008). In one study (Sesti et al., 2008), the surgical technique for myomectomy was specific for Laparotenser and consisted of two 15 mm lower skin incisions on the right side and 10 mm on the left side. The myomectomy was carreid out using long laparotomy instruments (Sesti et al., 2008). The uterine defect

472 was repaired with a long needle-holder in two continuous layers (Sesti et al., 2008). At the level of the right apex, extracorporeal knot tying was used to secure the suture ends with the aid of the index finger introduced through the ancillary right access (Sesti et al., 2008). The leiomyomas were extracted from the abdomen using a morcellament technique with the use of a cold knife or scissors (Sesti et al., 2008). In the other study (Tan et al., 2008), a solution of oxytocin or pituitrin was used before a hysterotomy that was carried out using a monopolar needle with a cutting current of 70 W, and repaired using continuous ‘layer-by-layer’ sutures. Adhesion barrier, saline dextrane macromolecular solutions, or both, were not formally used in one study (Tan et al., 2008).

Outcome measures Nine of the included studies (Alessandri et al., 2006; Benassi et al., 2005; Cagnacci et al., 2003; Fanfani et al., 2005; Palomba et al., 2007a, 2007b; Sesti et al., 2008; Tan et al., 2008; Wen et al., 2008, 2010), reported postoperative pain assessments, but different methods of evaluation were used (i.e. Visual Analogic Scales [VAS] at 6, 24 and 48 h after surgery, the number of vials of analgesics used, the number of patients requesting analgesics, and others). Five studies (Ciavattini et al., 2010; Cicinelli et al., 2009; Kalogiannidis et al., 2010; Malzoni et al., 2010; Prapas et al., 2009) conducted no evaluation of postoperative pain. In four studies comparing minilaparotomy and laparotomy (Benassi et al., 2005; Cagnacci et al., 2003; Wen et al., 2008, 2010), postoperative pain was assessed using a VAS after 24 h, 48 h, and 7 days, and distinguished between suprapubic and abdominal pain in one study (Cagnacci et al., 2003) or without reporting specific timing and anatomic site in the others (Benassi et al., 2005; Wen et al., 2008, 2010). Two studies (Wen et al., 2008, 2010) reported also the use of analgesics, specifically the number of patients that received continuous pain-control anesthesia, those that needed meperidine hydrochloride and the accumulation dose of meperidine. An evaluation of post-operative pain was carried out in five studies (Alessandri et al., 2006; Fanfani et al., 2005; Palomba et al., 2007a, 2007b; Sesti et al., 2008; Tan et al., 2008) comparing minilaparotomy and laparoscopy; in three studies (Alessandri et al., 2006; Sesti et al., 2008; Tan et al., 2008), the values of the VAS scores after 24 h from surgery were reported, whereas two studies reported the analgesic request (Alessandri et al., 2006; Palomba et al., 2007a, 2007b). In one study (Fanfani et al., 2005) it was simply stated that no significant differences in postoperative analgesic administration had been detected. Only two studies (Malzoni et al., 2010; Sesti et al., 2008) reported the definition of postoperative ileus. The length of postoperative ileus was evaluated by asking the patient when they recovered the ability to pass stool or gas (Sesti et al., 2008), or simply gas (Malzoni et al., 2010). Few intra-operative complications were reported in 10 trials (Alessandri et al., 2006; Ciavattini et al., 2010; Cicinelli et al., 2009; Fanfani et al., 2005; Kalogiannidis et al., 2010; Palomba et al., 2007a, 2007b; Prapas et al., 2009; Sesti et al., 2008; Tan et al., 2008; Wen et al., 2008), whereas they were not mentioned in four trials (Benassi et al., 2005; Cagnacci et al., 2003; Malzoni et al., 2010; Wen et al., 2010). The most common intraoperative

S Palomba et al. complication was the conversion to laparotomy for the position or dimension of the leiomyomas (Alessandri et al., 2006; Ciavattini et al., 2010; Cicinelli et al., 2009; Palomba et al., 2007a, 2007b), for difficulty with the haemostasis (Alessandri et al., 2006) or the reconstruction of the uterine wall (Cicinelli et al., 2009). An ileal perforation (Alessandri et al., 2006) and a bladder injury were reported during laparoscopy. In one study (Wen et al., 2008), the enlargement of the skin incision during minilaparotomy was also considered as a complication. In one trial (Kalogiannidis et al., 2010), the number of the complications was recorded, describing them generally as intestinal, urologic and vascular injuries, without specifying in which arm they occurred. The other trials stated that no complication occurred during interventions (Sesti et al., 2008; Tan et al., 2008). Postoperative complications were reported by 11 studies (Cagnacci et al., 2003; Ciavattini et al., 2010; Cicinelli et al., 2009; Fanfani et al., 2005; Kalogiannidis et al., 2010; Malzoni et al., 2010; Palomba et al., 2007a; Prapas et al., 2009; Sesti et al., 2008; Wen et al., 2008, 2010). The most common postoperative complication was fever (Cagnacci et al., 2003; Ciavattini et al., 2010; Cicinelli et al., 2009; Fanfani et al., 2005; Kalogiannidis et al., 2010; Malzoni et al., 2010; Palomba et al., 2007a, 2007b; Prapas et al., 2009; Sesti et al., 2008; Wen et al., 2010), but urinary tract infections (Palomba et al., 2007a, 2007b), wound infections (Palomba et al., 2007a, 2007b), wound dehiscence (Palomba et al., 2007a, 2007b) and postoperative anaemia (Kalogiannidis et al., 2010; Prapas et al., 2009) were also detected. Two studies (Wen et al., 2008, 2010) reported paralytic ileus as a complication, without specifying the duration. One study (Malzoni et al., 2010) reported a postoperative uterine haematoma that needed to be drained with laparoscopic intervention. Of note, in one study (Cagnacci et al., 2003), an elevation of body temperature higher than 37°C was observed in all patients and four of the 17 patients (23.5%) in each of the groups had a fever higher than 38°C. Two studies (Malzoni et al., 2010; Palomba et al., 2007a, 2007b), both comparing not assisted minilaparotomy to traditional gas laparoscopy, assessed the reproductive outcomes during the follow-up, which was of 12 months in one study (Palomba et al., 2007a, 2007b), and ranged from 4–63 months in the other (Malzoni et al., 2010). Leiomyoma recurrence at 6 months was assessed in three studies (Alessandri et al., 2006; Cicinelli et al., 2009; Malzoni et al., 2010), in which laparoscopy was the comparator arm (Alessandri et al., 2006; Cicinelli et al., 2009; Malzoni et al., 2010), and recurrence was not registered in any patient. In one study (Wen et al., 2008), the recurrence was assessed after 1 year of follow-up, and showed no recurrence in the two treatment groups. Only one trial (Wen et al., 2010) assessed the recurrence rate for a follow-up period longer that 1 year showing that laparoscopically assisted minilaparotomy was the technique associated to the longer period without recurrence compared with minilaparotomy and traditional laparotomy, and that minilaparotomy had an increasing trend toward recurrent leiomyomas of the posterior and lateral uterine wall. In only three studies (Alessandri et al., 2006; Benassi et al., 2005; Wen et al., 2008), the economic costs of the surgical procedures were assessed. Minilaparotomy was found to be cheaper than laparotomy (about 3512 euro versus about

Minilaparotomy for myomectomy 4132 euro for minilaparotomy and laparotomy, respectively) (Benassi et al., 2005), (about 53561 NT$ versus about 56693 NT$ for minilaparotomy and laparotomy, respectively) (Wen et al., 2008) and laparoscopy (about 1975 euro and about 2330 euro for minilaparotomy and laparoscopy, respectively, including a conversion to laparotomy) (Alessandri et al., 2006).

Quantitative data analysis and synthesis The data synthesis for the main outcome measures is presented in Table 3. Quantitative data analysis was carried out for all 14 studies (Alessandri et al., 2006; Benassi et al., 2005; Cagnacci et al., 2003; Ciavattini et al., 2010; Cicinelli et al., 2009; Fanfani et al., 2005; Kalogiannidis et al., 2010; Malzoni et al., 2010; Palomba et al., 2007a, 2007b; Prapas et al., 2009; Sesti et al., 2008; Tan et al., 2008; Wen et al., 2008, 2010). Because the mean, standard deviation, or both, of many outcomes was not reported in four papers (Benassi et al., 2005; Cagnacci et al., 2003; Ciavattini et al., 2010; Fanfani et al., 2005), a request for data information was made to the authors for meta-analytic purposes. Because the authors did not respond, a mathematic formula (Hozo et al., 2005) was applied according to the sample size when possible (Cagnacci et al., 2003; Fanfani et al., 2005), whereas in other cases (Benassi et al., 2005; Ciavattini et al., 2010), the outcomes were excluded from the analysis for lack of information.

Operative time No difference between the minilaparotomy and traditional laparotomy techniques, with significant heterogeneity across the studies (Benassi et al., 2005; Cagnacci et al., 2003; Kalogiannidis et al., 2010; Wen et al., 2008, 2010), was observed in operative time, with a shorter duration of minilaparotomy compared with laparotomy (Figure 2a). This result was confirmed when not assisted minilaparotomy alone (Benassi et al., 2005; Cagnacci et al., 2003; Wen et al., 2008, 2010) or laparoscopically assisted minilaparotomy alone (Cagnacci et al., 2003; Kalogiannidis et al., 2010; Wen et al., 2010) were compared with traditional laparotomy with significant heterogeneity across the studies (Table 3). The operative time was significantly different between the minilaparotomy and laparoscopy techniques (Alessandri et al., 2006; Cicinelli et al., 2009; Fanfani et al., 2005; Malzoni et al., 2010; Palomba et al., 2007a, 2007b; Prapas et al., 2009; Sesti et al., 2008; Tan et al., 2008), with significant heterogeneity across the studies, and showed a shorter duration for minilaparotomy (Figure 2b). Both not assisted minilaparotomy (Alessandri et al., 2006; Cicinelli et al., 2009; Fanfani et al., 2005; Malzoni et al., 2010; Palomba et al., 2007a, 2007b) and laparoscopically assisted minilaparotomy (Prapas et al., 2009; Tan et al., 2008) were faster than laparoscopy. A significant heterogeneity across the studies was detected only in the first case (Table 3).

Blood loss, haemoglobin drop and need for transfusion Intraoperative estimated blood loss was significantly lower in minilaparotomy compared with traditional laparotomy

473 (Kalogiannidis et al., 2010; Wen et al., 2008, 2010), without significant heterogeneity across the studies. Those data were confirmed when not assisted minilaparotomy alone (Wen et al., 2008, 2010) and laparoscopically assisted minilaparotomy alone (Wen et al., 2010) were compared with traditional laparotomy (Kalogiannidis et al., 2010; Wen et al., 2008, 2010) (Table 3). Haemoglobin drops were not significantly different after minilaparotomy compared with traditional laparotomy, with significant heterogeneity across the studies (Benassi et al., 2005; Cagnacci et al., 2003; Kalogiannidis et al., 2010) (Figure 3a). Those data were confirmed when laparoscopically assisted minilaparotomy was compared with traditional laparotomy (Benassi et al., 2005; Cagnacci et al., 2003), with significant heterogeneity across the studies. When not assisted minilaparotomy was compared with traditional laparotomy (Cagnacci et al., 2003; Kalogiannidis et al., 2010), haemoglobin drop was significantly lower after not assisted minilaparotomy (Table 3). The rate of blood transfusions during or after the intervention was not significantly different when minilaparotomy was compared with traditional laparotomy (Kalogiannidis et al., 2010; Wen et al., 2008, 2010), without significant heterogeneity across the studies. That data were confirmed for both not assisted minilaparotomy (Wen et al., 2008, 2010) and laparoscopically assisted minilaparotomy (Kalogiannidis et al., 2010; Wen et al., 2010). Intraoperative blood loss (Cicinelli et al., 2009; Fanfani et al., 2005; Malzoni et al., 2010; Palomba et al., 2007a, 2007b; Prapas et al., 2009; Sesti et al., 2008; Tan et al., 2008) and haemoglobin drop (Alessandri et al., 2006; Cicinelli et al., 2009; Malzoni et al., 2010; Palomba et al., 2007a, 2007b; Prapas et al., 2009; Sesti et al., 2008; Tan et al., 2008) were significantly higher after minilaparotomy than laparoscopy, with significant heterogeneity across the studies (Figure 3b). Significant differences in blood loss (Cicinelli et al., 2009; Fanfani et al., 2005; Malzoni et al., 2010; Palomba et al., 2007a, 2007b) and haemoglobin drop (Alessandri et al., 2006; Cicinelli et al., 2009; Malzoni et al., 2010; Palomba et al., 2007a, 2007b) were detected only when not assisted minilaparotomy was compared with laparoscopy, without or with heterogeneity across the studies, respectively. When laparoscopically assisted minilaparotomy was compared with laparoscopy, no significant difference between the two techniques was detected (Prapas et al., 2009; Tan et al., 2008), with significant heterogeneity across the studies (Table 3). The rate of blood transfusions during or after the intervention was mentioned in five studies comparing minilaparotomy and laparoscopy (Alessandri et al., 2006; Cicinelli et al., 2009; Malzoni et al., 2010; Palomba et al., 2007a, 2007b; Prapas et al., 2009). In only one study (Prapas et al., 2009), one patient treated with laparoscopically assisted minilaparotomy was transfused.

Postoperative ileus The mean duration of postoperative ileus after minilaparotomy was significantly shorter than after laparotomy (Benassi et al., 2005; Cagnacci et al., 2003; Kalogiannidis et al., 2010; Wen et al., 2008, 2010), with significant heterogeneity across the studies (Figure 4a). Minilaparotomy showed an advantage on laparotomy both when it was not laparoscopically assisted

474 Table 3

S Palomba et al. Data synthesis for the main outcome measures.

Outcome Operative time (min) Minilaparotomy versus traditional laparotomy Not assisted minilaparotomy versus traditional laparotomy Laparoscopically assisted minilaparotomy versus traditional laparotomy Minilaparotomy versus laparoscopy Not assisted minilaparotomy versus traditional gas laparoscopy Laparoscopically assisted minilaparotomy versus laparoscopy Blood loss (ml) Minilaparotomy versus traditional laparotomy Not assisted minilaparotomy versus traditional laparotomy Laparoscopically assisted minilaparotomy versus traditional laparotomy Minilaparotomy versus laparoscopy Not assisted minilaparotomy versus traditional gas laparoscopy Laparoscopically assisted minilaparotomy versus laparoscopy Haemoglobin drop (g/dl) Minilaparotomy versus traditional laparotomy Not assisted minilaparotomy versus traditional laparotomy Laparoscopically assisted minilaparotomy versus traditional laparotomy Minilaparotomy versus laparoscopy Not assisted minilaparotomy versus traditional gas laparoscopy Laparoscopically assisted minilaparotomy versus laparoscopy Postoperative ileus (h) Minilaparotomy versus traditional laparotomy Not assisted minilaparotomy versus traditional laparotomy Laparoscopically assisted minilaparotomy versus traditional laparotomy Minilaparotomy versus laparoscopy Not assisted minilaparotomy versus traditional gas laparoscopy Laparoscopically assisted minilaparotomy versus laparoscopy Hospitalization length Minilaparotomy versus traditional laparotomy Not assisted minilaparotomy versus traditional laparotomy Laparoscopically assisted minilaparotomy versus traditional laparotomy Minilaparotomy versus laparoscopy

Data synthesis

WMD −7.85, 95% CI −15.94 to 0.24, P = 0.06 Cochran’s Q-test, P = 0.001, I2 = 77% WMD −8.41, 95% CI −17.02 to 0.21, P = 0.06 Cochran’s Q-test, P = 0.01, I2 = 72% WMD −2.38, 95% CI −11.76 to 7.00, P = 0.62 Cochran’s Q-test, P = 0.01, I2 = 77% WMD −7.94, 95% CI −15.61 to −0.27, P = 0.04 Cochran’s Q-test, P < 0.00001, I2 = 94% WMD −7.54, 95% CI −13.79 to −1.29, P = 0.02 Cochran’s Q-test, P < 0.00001, I2 = 91% WMD −26.51, 95% CI −32.80 to −20.22, P < 0.00001 Cochran’s Q-test, NS, I2 = 0% WMD −19.66, 95% CI −23.10 to −16.23, P < 0.00001 Cochran’s Q-test, NS, I2 = 38% WMD −19.48, 95% CI −22.93 to −16.04, P < 0.00001 Cochran’s Q-test, NS, I2 = 0% WMD −33.14, 95% CI −63.06 to −3.22, P = 0.03 Cochran’s Q-test, NS, I2 = 60% WMD 35.71, 95% CI 20.89 to 50.54, P < 0.00001 Cochran’s Q-test, P < 0.00001), I2 = 94% WMD 48.19, 95% CI 42.64 to 53.74, P < 0.00001 Cochran’s Q-test, NS, I2 = 8% WMD 36.55, 95% CI −88.20 to 161.31, P = 0.57 Cochran’s Q-test, P < 0.00001, I2 = 95% WMD −0.56, 95% CI −1.15 to 0.03, P = 0.06 Cochran’s Q-test, P = 0.002, I2 = 84% WMD −0.65, 95% CI −0.87 to −0.42, P < 0.00001 Cochran’s Q-test, NS, I 2 = 0% WMD −0.75, 95% CI −1.80 to 0.30, P = 0.16 Cochran’s Q-test, P < 0.00001, I2 = 96% WMD 0.53, 95% CI 0.21 to 0.85, P = 0.001 Cochran’s Q-test, P < 0.00001, I2 = 97% WMD 0.85, 95% CI 0.65 to 1.06, P < 0.00001 Cochran’s Q-test, P < 0.00001, I2 = 89% WMD 0.04, 95% CI −0.87 to 0.95, P = 0.94 Cochran’s Q-test, P < 0.0001, I2 = 94% WMD −17.75, 95% CI −21.90 to −13.61, P < 0.00001 Cochran’s Q-test, P = 0.0001, I2 = 82% WMD −16.20, 95% CI −23.00 to −9.40, P < 0.00001 Cochran’s Q-test, P < 0.00001, I2 = 91% WMD −19.81, 95% CI −21.95 to −17.66, P < 0.00001 Cochran’s Q-test, NS, I2 = 66% WMD 3.55, 95% CI −1.11 to 8.20, NS Cochran’s Q-test, P < 0.00001, I2 = 99% WMD 6.82, 95% CI −0.19 to 13.83, NS Cochran’s Q-test, P < 0.00001, I2 = 99% WMD −8.83, 95% CI −25.60 to 7.93, NS Cochran’s Q-test, P < 0.00001, I2 = 98% WMD −1.84, 95% CI −2.40 to −1.27, P < 0.00001 Cochran’s Q-test, P < 0.00001, I2 = 94% WMD −1.23, 95% CI −1.54 to −0.91, P < 0.00001 Cochran’s Q-test, P = 0.01, I2 = 72% WMD −2.27, 95% CI -3.09 to −1.45, P < 0.00001 Cochran’s Q-test, P < 0.00001, I2 = 96% WMD 0.77, 95% CI 0.13 to 1.40, P = 0.02 Cochran’s Q-test, P < 0.00001, I2 = 100% (continued on next page)

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Outcome Not assisted minilaparotomy versus traditional gas laparoscopy Laparoscopically assisted minilaparotomy versus laparoscopy Post-operative pain (VAS score) Minilaparotomy versus traditional laparotomy Not assisted minilaparotomy versus traditional laparotomy Laparoscopically assisted minilaparotomy versus traditional laparotomy Minilaparotomy versus laparoscopy Not assisted minilaparotomy versus traditional gas laparoscopy Laparoscopically assisted minilaparotomy versus laparoscopy Intraoperative complications (number) Minilaparotomy versus traditional laparotomy Minilaparotomy versus laparoscopy Conversions to laparotomy (number) Minilaparotomy versus laparoscopy Minilaparotomy versus traditional laparotomy Post-operative complications (number) Minilaparotomy versus traditional laparotomy Not assisted minilaparotomy versus traditional laparotomy Laparoscopically assisted minilaparotomy versus traditional laparotomy Minilaparotomy versus laparoscopy Pregnancy rate (pregnant patients/total patients) Not assisted minilaparotomy versus traditional gas laparoscopy Live-birth rate (patients with a live-birth/total patients) Not assisted minilaparotomy versus traditional gas laparoscopy Abortion rate (patients who had an abortion/total pregnant patients) Not assisted minilaparotomy versus traditional gas laparoscopy Vaginal delivery rate (patients who had a vaginal delivery/total patients who delivered) Not assisted minilaparotomy versus traditional gas laparoscopy Caesarean delivery rate (patients who had a caesarean delivery/total patients who delivered) Not assisted minilaparotomy versus traditional gas laparoscopy Preterm delivery rate (patients who had a preterm delivery/total patients who delivered) Not assisted minilaparotomy versus traditional gas laparoscopy

Data synthesis WMD 0.78, 95% CI 0.46 to 1.09, P < 0.00001 Cochran’s Q-test, P < 0.00001, I2 = 96% WMD 0.11, 95% CI −0.12 to 0.34, P = 0.35 Cochran’s Q-test, NS, I2 = 0% WMD −1.80, 95% CI −2.27 to −1.32, P < 0.00001 Cochran’s Q-test, P = 0.0003, I2 = 88% WMD −1.80, 95% CI −2.50 to −1.10, P < 0.00001 Cochran’s Q-test, P < 0.00001, I2 = 94% WMD −1.92, 95% CI −2.14 to −1.70, P < 0.00001 Cochran’s Q-test, NS, I2 = 42% WMD 0.00, 95% CI −0.41 to 0.42, NS Cochran’s Q-test, NS, I2 = 30% WMD 0.78, 95% CI 0.46 to 1.09, P < 0.00001 Cochran’s Q-test, P < 0.00001, I2 = 96% WMD 0.11, 95% CI −0.12 to 0.34, NS Cochran’s Q-test, NS, I2 = 0% OR 4.55, 95% CI 0.82 to 25.17, NS Cochran’s Q-test, NS, I2 = 51% OR 1.63, 95% CI 0.59 to 4.50, NS Cochran’s Q-test, NS, I2 = 52% OR 2.08, 95% CI 0.64 to 6.80, NS Cochran’s Q-test, NS, I2 = 29% − OR 0.71, 95% 0.44 to 1.16, NS Cochran’s Q-test, NS, I2 = 0% OR 0.78, 95% CI 0.44 to 1.40, NS Cochran’s Q-test, NS, I2 = 0% OR 0.81, 95% CI 0.46 to 1.45, NS Cochran’s Q-test, NS, I2 = 0% OR 1.53, 95% CI 1.01 to 2.32, NS Cochran’s Q-test, NS, I2 = 0% OR 0.76, 95% CI 0.47 to 1.22, NS Cochran’s Q-test, NS, I2 = 40% OR 0.57, 95% CI 0.35 to 0.90, NS Cochran’s Q-test, NS, I2 = 0% OR 2.04, 95% CI 0.91 to 4.59, NS Cochran’s Q-test, NS, I2 = 0%

OR 0.82, 95% CI 0.43 to 1.54, NS Cochran’s Q-test, NS, I2 = 6%

OR 0.68, 95% CI 0.37 to 1.24, NS Cochran’s Q-test, NS, I2 = 0%

OR 0.96, 95% CI 0.21 to 4.39, NS Cochran’s Q-test, NS, I2 = 0%

The specific studies included in the data synthesis are described in the main text. CI = coefficient interval; I2 = inconsistency; NS = not statistically significant; OR = odds ratio; VAS = visual analog scale; WMD = weighted mean differences.

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b

Figure 2

Operative time (minutes): (a) minilaparotomy versus traditional laparotomy (b) and minilaparotomy versus laparoscopy.

a

b

Figure 3 The haemoglobin drop (gr/dl): (a) minilaparotomy versus traditional laparotomy and (b) minilaparotomy versus laparoscopy.

(Benassi et al., 2005; Cagnacci et al., 2003; Wen et al., 2008, 2010) and when it was laparoscopically assisted (Cagnacci et al., 2003; Kalogiannidis et al., 2010; Wen et al., 2010), with or without significant heterogeneity across the studies, respectively (Table 3).

The mean duration of postoperative ileus after minilaparotomy was not significantly longer than after laparoscopy (Alessandri et al., 2006; Cicinelli et al., 2009; Malzoni et al., 2010; Palomba et al., 2007a, 2007b; Prapas et al., 2009; Sesti et al., 2008; Tan et al., 2008), with significant heterogeneity

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a

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Figure 4 The postoperative ileus (hours): (a) minilaparotomy versus traditional laparotomy and (b) minilaparotomy versus laparoscopy.

across the studies (Figure 4b). Those data were confirmed for not laparoscopically assisted (Alessandri et al., 2006; Cicinelli et al., 2009; Fanfani et al., 2005; Malzoni et al., 2010; Palomba et al., 2007a, 2007b) and laparoscopically assisted (Prapas et al., 2009; Tan et al., 2008) minilaparotomy, with significant heterogeneity across the studies (Table 3).

Postoperative pain Minilaparotomy resulted in significantly less pain than laparotomy (Cagnacci et al., 2003; Wen et al., 2008, 2010), with significant heterogeneity across the studies (Table 3). Those data were confirmed both when minilaparotomy was laparoscopically assisted (Cagnacci et al., 2003; Wen et al., 2010) and when it was not (Malzoni et al., 2010; Wen et al., 2008, 2010), without and with significant heterogeneity across the studies, respectively (Table 3). No significant difference in postoperative pain (VAS score at 24 h) was detected between minilaparotomy and laparoscopy (Alessandri et al., 2006; Sesti et al., 2008; Tan et al., 2008), without significant heterogeneity across the studies (Table 3).

Hospitalization length After minilaparotomy, the hospitalization length was significantly shorter than after laparotomy (Benassi et al., 2005; Cagnacci et al., 2003; Kalogiannidis et al., 2010; Wen et al., 2008, 2010) but significantly longer than after laparoscopy (Alessandri et al., 2006; Cicinelli et al., 2009; Fanfani et al.,

2005; Malzoni et al., 2010; Palomba et al., 2007a, 2007b; Prapas et al., 2009; Sesti et al., 2008; Tan et al., 2008), with significant heterogeneity across the studies for both comparisons (Figures 5a and 5b). The increased duration of hospital stay was confirmed both when laparoscopically assisted (Cagnacci et al., 2003; Kalogiannidis et al., 2010; Wen et al., 2010) and not assisted minilaparotomy (Benassi et al., 2005; Cagnacci et al., 2003; Wen et al., 2008, 2010) were compared with traditional laparotomy, without and with significant heterogeneity across the studies, respectively (Table 3). When compared with laparoscopy, a longer hospitalization after minilaparotomy was confirmed only for not assisted minilaparotomy (Alessandri et al., 2006; Cicinelli et al., 2009; Fanfani et al., 2005; Malzoni et al., 2010; Palomba et al., 2007a, 2007b), with significant heterogeneity across the studies (Table 3). No statistically significant difference in time to discharge was detected when laparoscopically assisted minilaparotomy was compared with laparoscopy (Prapas et al., 2009; Tan et al., 2008), without significant heterogeneity across the studies (Table 3).

Intra- and postoperative complications No difference in intra-operative complications (including the conversions to laparotomy) was detected between minilaparotomy compared with traditional laparotomy (Malzoni et al., 2010; Wen et al., 2008) and between minilaparotomy versus laparoscopy (Alessandri et al., 2006; Cicinelli et al., 2009; Fanfani et al., 2005; Palomba et al., 2007a, 2007b; Prapas et al., 2009; Sesti et al., 2008; Tan et al., 2008), without significant heterogeneity across the studies (Table 3).

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Figure 5 Hospitalization length (days): (a) minilaparotomy versus traditional laparotomy and (b) minilaparotomy versus laparoscopy.

No difference in postoperative complications (including postoperative fever) was detected between minilaparotomy compared traditional laparotomy (Cagnacci et al., 2003; Kalogiannidis et al., 2010; Malzoni et al., 2010; Wen et al., 2008) and between mini-aparotomy compared with laparoscopy (Alessandri et al., 2006; Ciavattini et al., 2010; Cicinelli et al., 2009; Fanfani et al., 2005; Malzoni et al., 2010; Palomba et al., 2007a, 2007b; Prapas et al., 2009; Sesti et al., 2008; Tan et al., 2008), without significant heterogeneity across the studies (Table 3). Those data were confirmed when both laparoscopically assisted (Cagnacci et al., 2003; Kalogiannidis et al., 2010; Wen et al., 2010) and not assisted minilaparotomy was compared with traditional laparotomy (Table 3).

recurrence rate of leiomyomas. No data synthesis was carried out because the former (Wen et al., 2008) reported no case of recurrence of leiomyomas in both treatment arms after 1 year of follow-up. The latter study (Wen et al., 2010) showed no difference in recurrence rate between minilaparotomy and traditional laparotomy (38/145 versus 24/79, respectively), even if the interval between the operation and the detection of recurrence was significantly longer after laparoscopically assisted minilaparotomy. Leiomyoma recurrence was assessed in three studies comparing minilaparotomy and laparoscopy (Alessandri et al., 2006; Cicinelli et al., 2009; Malzoni et al., 2010). No data synthesis was carried out because no case of recurrence of leiomyoma was observed at 6 months’ follow-up.

Reproductive and obstetric data Economic costs No studies have assessed reproductive and obstetric outcomes after the intervention of minilaparotomy compared with traditional laparotomy, whereas only two studies (Malzoni et al., 2010; Palomba et al., 2007b) evaluated the difference between minilaparotomy and laparoscopy according to reproductive and obstetric end-points. No significant difference between techniques was detected in the rates of pregnancies, live births, abortions, vaginal and caesarean deliveries, and preterm deliveries (Table 3).

A meta-analytic comparison of economic costs among techniques was not possible because one (Benassi et al., 2005) of the two trials (Benassi et al., 2005; Wen et al., 2008) comparing minilaparotomy and traditional laparotomy lacked the information needed. No data synthesis was also possible to compare minilaparotomy and laparoscopy because only one trial (Alessandri et al., 2006), reported the costs of the procedures.

Recurrence of leiomyomas

Discussion

Only two studies (Wen et al., 2008, 2010) comparing minilaparotomy and traditional laparotomy assessed the

To our knowledge, this is the first systematic review with a meta-analysis of randomized and non-randomized

Minilaparotomy for myomectomy controlled studies that has evaluated the safety and the efficacy of the minilaparotomy myomectomy. Surprisingly, although the myomectomy is one of the most frequent gynaecological surgery procedures, only seven RCTs were available, and no further RCT was registered on the main worldwide registers for clinical trials. In addition, the only minimally invasive surgical technique compared with minilaparotomy in a randomized fashion was the laparoscopy, using both traditional gas and gasless isobaric laparoscopy. The number of the studies were few and the sample size of the populations investigated remained small even after further systematic research aimed at including and analyse prospective non-randomized and retrospective studies. The included studies were also of suboptimal quality considering the many biases and confounders present. The scientific transparency of the RCTs was very low. In fact, although all included papers were published after 2001 (Begg et al., 1996; Moher et al., 2001) only one RCT (Palomba et al., 2007a, 2007b) followed the international guidelines for improving the quality of the reporting of clinical trials. In particular, only four of the RCTs (Alessandri et al., 2006; Palomba et al., 2007a, 2007b; Sesti et al., 2008; Tan et al., 2008) reported the study flowchart diagram, and none reported data commonly considered fundamental in non-pharmacological trials, such as the efforts to standardize interventions, the characteristics and descriptions of the care providers, centres, or both, the blinding or masking procedures (Boutron et al., 2008) and especially the assessment of safety and reproductive outcomes (Palomba, 2013). In one RCT (Alessandri et al., 2006), the data analysis erroneously (Fergusson et al., 2002) excluded the data from two patients randomized to laparoscopy; one who converted to laparotomy and one who required a subsequent surgery. Considering the consolidated role of myomectomy for women of reproductive age interested in future childbearing, and its potential beneficial effects for women with unexplained infertility (Metwally et al., 2011), it is also surprising that only two studies (Malzoni et al., 2010; Palomba et al., 2007a, 2007b), both comparing not laparoscopically assisted minilaparotomy with traditional gas laparoscopy, were available. Although consensus has been reached that myomectomy should be carried out through a minimally invasive surgical procedure, our data demonstrated a lack of scientific evidence about the best surgical procedure in terms of preservation of reproductive potential. In fact, no significant difference between surgical techniques in the rates of pregnancies, live births, abortions, vaginal and caesarean deliveries, and preterm deliveries was detected. The quality of the evidence was low, as only one study (Palomba et al., 2007b) was conducted in a randomized controlled fashion. In this RCT (Palomba et al., 2007b), the pregnancy and live birth rates per cycle were significantly lower after minilaparotomy compared with traditional laparoscopy (Palomba et al., 2007b). Moreover, the time to first pregnancy and live birth after minilaparotomy, even if significantly different from laparoscopy, resulted longer of only one month. That difference cannot be considered clinically relevant. In addition, no difference between the minilaparotomy and laparoscopy techniques was detected in women who received a myomectomy with unexplained infertility (Palomba et al., 2007b), confirming that myomectomy, independently from the surgical route, is effective in selected infertile patients (Seracchioli et al., 2000). On the other hand, in patients who received

479 myomectomy for symptomatic-leiomyomas and with proven fertility, the laparoscopy had better reproductive outcome compared with the minilaparotomy (Palomba et al., 2007b). Our meta-analysis showed that, when compared with laparotomy, minilaparotomy is characterized by lower intraoperative blood loss and shorter canalization times. The time of discharge was also significantly lower in patients treated with minilaparotomy. Unfortunately, no trials pragmatically assessed the real feasibility of the minilaparotomy approach in unselected patients who were candidates to laparotomy. On the other hand, the main result emerging from the metaanalytic comparison between the minilaparotomy and laparoscopy techniques was the significant advantage of minilaparotomy in operative time compared with laparoscopy. The shorter anaesthesia time is an important advantage for all patients, and particularly for those who, for anesthesiologic reasons, cannot stand long surgical interventions. In these cases, the minilaparotomy should be considered the technique of choice for myomectomy. Moreover, no findings can be formally extrapolated from the available studies about the safety of the different surgical (and anaesthethic) techniques in high-risk patients, including obese patients. Even if no significant difference was demonstrated in intraoperative, postoperative complications, or both, the laparoscopy technique seemed formally to be a safer technique with less blood loss, haemoglobin drop, postoperative ileus duration and time of hospitalization. These data can be the results of the better quality of vision and dissection. Moreover, a careful analysis of these results highlights very little clinical differences between the two techniques. In fact, no effect of the reduced blood loss on the transfusion rate was observed, and a difference of less than 1 day of hospitalization between techniques cannot be absolutely considered again as clinically relevant. Because of the impossibility of palpating the uterus and detecting the smallest leiomyomas during laparoscopy, a higher risk of recurrence after laparoscopic myomectomy has been reported (Fauconnier et al., 2000). Unfortunately, in only few studies (Alessandri et al., 2006; Cicinelli et al., 2009; Malzoni et al., 2010; Wen et al., 2008, 2010) the recurrence of the leiomyomas was assessesed, and in only one study (Wen et al., 2010) it was reported. No recurrence was observed in any patient in four studies (Alessandri et al., 2006; Cicinelli et al., 2009; Malzoni et al., 2010; Wen et al., 2008), probably because of the careful selection of the patients. This issue highlights again the need of a wide pragmatic clinical trial comparing different surgical procedures for the myomectomy technique, including also patients with multiple intramural and submucosal tumours. A specific advantage of the minilaparotomy could be to avoid the use of morcellation and to be safer in terms of oncologic risk in case of undiagnosed malignancy. Moreover, in all studies included in the current analysis, in which a traditional gas laparoscopy was carried out (Alessandri et al., 2006; Ciavattini et al., 2010; Cicinelli et al., 2009; Fanfani et al., 2005; Malzoni et al., 2010; Palomba et al., 2007a, 2007b; Prapas et al., 2009), the leiomyomas were always extracted from abdomen with the use of laparoscopic electrosurgical morcellator but no case of sarcoma was reported. The present study has several strengths but also important limitations. In particular, this was the first attempt to produce, using systematic review and meta-analysis of

480 randomized and non-randomized studies, evidence-based suggestions about the safety and efficacy of the minimally invasive minilaparotomy technique. In addition, the absence of further clinical trials or RCTs in progress make the current finding conclusive for the next few years. As discussed earlier, our study has also limitations regarding the limited number of studies and participants included in the final analysis, the lack of a powered analysis in almost all trials, the heterogeneity of the populations studied and the dearth descriptions of the surgical techniques assessed. A significant proportion of the included studies were conducted in Europe; this could also introduce a publication bias that limits the generalizability of the current findings. In conclusion, the current systematic review with a metaanalysis suggested that the minilaparotomy myomectomy is safer than laparotomy and provides results clinically comparable to laparoscopy. The quantity and quality of the scientific evidence, however, did not permit a definitive conclusion to be drawn about reproductive outcomes. Further welldesigned, powered and transparent RCTs are needed to clarify the risk–benefit ratio of the minilaparotomy myomectomy technique compared with the other minimally invasive surgical procedures for myomectomy in order to provide clinical recommendations with strong scientific evidence.

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Declaration: The authors report no conflict of interest. This study was supported by internal funding.

Received 4 September 2014; refereed 19 January 2015; accepted 21 January 2015.