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Hysteroscopy for Infertile Women: A Review
Review Article
Hysteroscopy for Infertile Women: A Review Aarathi Cholkeri-Singh, MD, FACOG*, and Kirsten J. Sasaki, MD, FACOG From the Department of Obstetrics and Gynecology, Advocate Lutheran General Hospital, Park Ridge, Illinois (Dr. Cholkeri-Singh), and Department of Obstetrics and Gynecology, University of Illinois at Chicago, Chicago, Illinois (Dr. Cholkeri).
ABSTRACT Hysteroscopy is widely performed in infertile women. A review of peer-reviewed, published literature from the PubMed database on uterine intracavitary pathology, proximal tubal occlusion, failed in vitro fertilization procedures, and first trimester miscarriages of infertile women was performed to examine the importance, feasibility, and success rates of diagnostic and operative hysteroscopy when evaluating and treating these conditions. Journal of Minimally Invasive Gynecology (2015) 22, 353–362 Ó 2015 AAGL. All rights reserved. Keywords:
DISCUSS
Asherman’s syndrome; Chronic endometritis; Endometrial polyps; Hysteroscopy; Infertile women; In vitro fertilization; Missed abortion; Proximal tubal occlusion; Recurrent pregnancy loss; Retained products of conception; Submucous myoma; Uterine septum
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In 2002, approximately 2.1 million US women were infertile. According to the National Center for Health Statistics, between 2006 and 2010, rates of infertility ranged from 8% to 30% in married women aged 15 to 44 years [1]. Assisted reproductive technology has been applied to treat many of these women; however, the peer-reviewed published literature has identified hysteroscopy as a valuable tool for diagnosis and treatment of some infertile women before or after undergoing an assisted reproductive technique. Indications for hysteroscopy in infertile women include intracavitary abnormalities, such as submucous fibroids, endometrial polyps, uterine septum, adhesions, chronic endometritis, and retained products of conception. The use of hysteroscopy has been evaluated in proximal tubal occlusion, failed in vitro fertilization (IVF) cycle, and firsttrimester miscarriage as well.
Corresponding author: Aarathi Cholkeri-Singh, MD, FACOG, Advanced Gynecologic Surgery Institute, 120 Olser Drive, Suite 100, Naperville, IL 60540. E-mail: [email protected] Submitted September 23, 2014. Accepted for publication December 19, 2014. Available at www.sciencedirect.com and www.jmig.org 1553-4650/$ - see front matter Ó 2015 AAGL. All rights reserved. http://dx.doi.org/10.1016/j.jmig.2014.12.163
Materials and Methods A PubMed search of the literature was performed using the following Medical Subject Headings (MeSH) alone or in combination: hysteroscopy, infertility, myomectomy, polypectomy, uterine septum or metroplasty, Asherman’s syndrome or intrauterine adhesions, uterine septum, retained products of conception, chronic endometritis, proximal tubal occlusion, failed in vitro fertilization, first trimester miscarriage, and embryoscopy. Our search was then filtered by selecting papers published in English from 1970 through 2014. Only prospective trials and meta-analyses were reviewed initially; however, for topics with a limited number of prospective studies, the search was expanded to include retrospective studies. Intracavitary Pathology Submucous Fibroids Submucous fibroids are categorized as type 0, 1, and 2. A type 0 fibroid is located completely within the uterine cavity; type 1 fibroid, R50% within the uterine cavity (Fig. 1A); and type 2, ,50% within the uterine cavity [2]. Postulated mechanisms by which fibroids cause infertility include the following:
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Fig. 1 (A) Submucous myoma. (B) Hysteroscopic resection of submucous myoma restoring normal cavity architecture.
Interference with normal patterns of endocrine function [3] Distortion of the endometrium [4,5] Dysfunctional uterine contractility [6] Distortion or obstruction of tubal ostia [7] Chronic endometrial inflammation [6] Abnormal uterine vascularization [8,9] Impaired endometrial receptivity [10] Implantation failure due to atrophy or venous ectasia over or opposite a submucous fibroid [11]. Pregnancy wastage rates frequently exceed 70% for submucous fibroids [12]. A small prospective cohort study published in 2005 by Shokeir [13] followed 29 consecutive women with submucous fibroids who desired pregnancy. Primary infertility was diagnosed in 14 women, and the other 15 had a history of poor obstetrical outcomes. All women were treated with a hysteroscopic myomectomy (Fig. 1B). Intraoperatively, all 29 women were found to have a single fibroid, 25 type 0 and 4 type 1, all no larger than 5 cm. Twenty-one of the 29 women (72%) achieved at total of 30 pregnancies; 13 of these women had live births. The rate of live birth increased from 3.8% to 63.2%, and the rate of abortion decreased from 61.6% to 26.3% after hysteroscopic myomectomy. In 2009, Pritts et al [14] published a meta-analysis of 23 studies evaluating women with fibroids and infertility. Nine of these 23 studies looked at submucous fibroids. These 9 studies included 6 retrospective studies, 2 prospective studies, and 1 randomized control study. A comparison of infertile women with submucous fibroids and those without submucous fibroids revealed clinically significant differences in pregnancy, implantation, and ongoing pregnancy/ live birth rates, as well as the spontaneous abortion rate. The clinical pregnancy rate was greated in the women who underwent a hysteroscopic myomectomy compared with those with fibroids left in situ. This study also found that the pregnancy rate in women after hysteroscopic myomectomy was comparable to that in women with no evidence of fibroids.
To date, only 1 prospective control study, published by Casini et al [4] in 2005, has analyzed whether the removal of fibroids before conception improves pregnancy rates and outcomes compared with no surgery. That study included a total of 181 patients age %35 years with infertility for at least 12 months and a fibroid ,4 cm in diameter. Ninety-two of the 181 patients underwent myomectomy, via either hysteroscopy or laparotomy, and 89 patients did not undergo surgery. All patients were followed up for 12 months to determine the rate of clinical pregnancy. Pregnancy rates were statistically higher in the patients who underwent myomectomy with submucous fibroids (43.35% vs 27.2% in the nonsurgical group) or submucous and intramural fibroids (36.4% vs 15% in the nonsurgical group) (p , .05). There was no statistically significant increase in pregnancy rate in the patients with only intramural or intramural and subserosal fibroids (p . .05). Despite the findings of Casini et al [4], a further review of their data by the Cochrane Database found that in a subset of women with a submucous fibroid (n 5 94), there was a statistically insignificant increased odds of clinical pregnancy (odds ratio, 2.4; 95% confidence interval, 0.97–6.2; p 5 .06) [15]. One other prospective study in the literature, by Shokeir et al [16], seemed to indicate a benefit to myomectomy in subfertile patients, but this paper was pulled from publication by the journal editor. Endometrial Polyps (Fig. 2) Postulated mechanisms by which polyps cause infertility include irregular endometrial bleeding, inflammatory endometrial response, obstructive inhibition of sperm transport, physical obstruction of exposure of the embryo to the endometrium, interference with normal patterns of endocrine function, and increasing glycodelin concentration, which inhibits sperm binding to the zona pellucida [17,18]. In 2005, Perez-Medina et al [19] published a prospective study evaluating 204 women with infertility for R24 months. Exclusion criteria were age .39 years, anovulation, uncorrected tubal disease, previous unsuccessful use of recombinant follicle-stimulating hormone, and an azoospermic partner. The study group (n 5 101) underwent hysteroscopic
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Fig. 2 Endometrial polyp.
polypectomy, whereas the control group (n 5 103) underwent hysteroscopic polyp biopsy only. After either procedure, participants were to receive up to 4 intrauterine insemination cycles. However, 65% of the study group participants achieved pregnancy before undergoing an intrauterine insemination cycle, a significant finding of that study. There were no significant between-group differences in polyp size and pregnancy conception rates (p 5 .32). A retrospective study in 2008 by Stamatellos et al [20] evaluated the impact on fertility of the size and number of polyps within the uterine cavity. The study included women age ,35 years with primary or secondary infertility for .12 months. The participants were divided into 2 groups, those with a polyp %1 cm and those with a polyp .1 cm or multiple polyps. The findings of this study correlated with those of Perez-Medina et al [19], with polyp size and number of polyps having no significant association with pregnancy rate. The pregnancy rate was 61.4% for the entire study population undergoing hysteroscopic polypectomy, irrespective of whether the patient had primary or secondary infertility.
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Consequently, with the understanding that polyps may impact fertility, Yahaihara et al [21] conducted a retrospective study of 230 women to determine the significance of the location of endometrial polyps. The locations were defined as anterior wall, posterior wall, lateral wall, uterotubal junction, and multiple polyps. Similar to previously reported findings, polyp size in any area of the uterus did not significantly impact pregnancy rate; however, the highest pregnancy rate, 50% to 60%, was achieved in those who had polyps removed from the utero-tubal junction. Uterine Septum The uterine septum has been associated with pregnancy wastage rates as high as 90%, most likely related to the structural alterations in the endometrium of the septum, which affects implantation (Fig. 3A) [22,23]. The American Fertility Association, now known as the American Society of Reproductive Medicine, has published a subclassification with 12 variations of uterine septum anatomy [24]. Four prospective trials have evaluated the effect of hysteroscopic metroplasty (Fig. 3B) on clinical pregnancy rates [22,25–27]. In these studies, live birth rates after hysteroscopic metroplasty ranged from 30% to 54%. Mollo et al [27] studied 2 groups with unexplained fertility, a group of women with septate uteri who underwent hysteroscopic metroplasty and a control group without septate uteri. The 2 groups were similar in terms of age, duration of infertility, and body mass index. The pregnancy rate and live birth rate were significantly higher in the hysteroscopic metroplasty group compared with the control group (38.6% vs 20.4%; p 5 .016 and 34.1% vs 18.9%; p , .05, respectively). Pabuc¸cu and Gomel [25] evaluated women aged 21– 35 years with unexplained primary fertility and septate uteri who underwent hysteroscopic metroplasty. Five women (8.2%) underwent repeat surgery for a residual septum .1 cm. The outcome of that study was a 41% pregnancy rate, with a 29.5% live birth rate. In 13 of the 18 pregnancies that carried to term, 2 patients had a total septum and 11 had a subtotal septum resected.
Fig. 3 (A) Uterine septum. (B) Hysteroscopic transection of uterine septum restoring normal anatomy of the cavity.
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Fig. 4 (A) Intrauterine adhesions blocking the right tubal ostia. (B) Hysteroscopic lysis of adhesions restoring normal uterine cavity anatomy.
Considering that some women have a residual septum after their initial metroplasty, Kormanyos et al [22] investigated whether a residual septum impacts fertility. After the first hysteroscopic metroplasty, 1 patient had .1 cm of residual septum, which was further resected, and 35 patients (37%) had a residual septum of %1 cm. If no pregnancy was conceived within 24 months for those with a residual septum %1 cm, then the patients underwent a second hysteroscopic metroplasty for removal of the residual septum. The increase in pregnancy rate after the second hysteroscopy was not significant. Looking further at septum length, Shokeir et al [26] studied women with septum length of R2.5 cm and compared them with women with a septum length of ,2.5 cm. All of f the 42 women (47.7%) who achieved pregnancy were age ,40 years with ,3 years of infertility; 8% of these pregnancies were spontaneous. The pregnancy rate was 66.7% in those with a septum length of R2.5 cm and 42.8% in those with a septum length of ,2.5 cm. The overall live birth rate was 40.1%. Uterine septum length has a potential impact not only on the rate of conception, but also on the rate of pregnancy loss. A retrospective study published in 2009 by Ban-Frangez et al [28] evaluated the affect of septum length on pregnancy loss. A comparison of women with a large (.1.5 cm) or small partial (1.3 to 1.5 cm) septum with women without a septum revealed a significantly higher pregnancy loss rate in those with a septum. Women in both septum groups who underwent hysteroscopic metroplasty had a pregnancy loss rate comparable to that of the control group. Other studies, although not prospective, also have confirmed the significant impact of septum with infertility. Grimbizis et al [29] reviewed 6 studies published before 2001 that reported a live birth rate of 6.1% in women with intact septums compared with 82% in those women who underwent hysteroscopic metroplasty. Nouri et al [30] performed a more recent literature search that revealed live birth rates ranging from 26% to 73%, with a cumulative rate of 45%, after hysteroscopic metroplasty. Both of these reviews evaluated studies in women with a septate uterus,
and both unexplained primary infertility and recurrent abortions. Although hysteroscopic metroplasty appears to improve fertility, the role of surgical correction in patients with primary fertility remains under debate [25]. An older prospective study identified a reduction in pregnancy wastage from 87.5% to 44.4% and recommended hysteroscopic metroplasty as the treatment of choice in patients experiencing recurrent abortions [31]. Intrauterine Adhesions Intrauterine adhesions, also known as Asherman’s syndrome, are caused by postsurgical or infectious damage to the basalis layer of the endometrium. This can cause granulation tissue, which can create tissue bridges, leading to cavity obliteration (Fig. 4A), and is associated with increased risks of ectopic pregnancy, recurrent miscarriage, preterm labor, and abnormal placentation. Pregnancy wastage rates as high as 90% have been reported [31–36]. The severity of intrauterine adhesions is defined as follows: mild, ,25% of the uterine cavity containing thin or filmy adhesions; moderate, 25% to 75% of the cavity containing adhesions, causing partial occlusion of ostium and upper fundus; and severe, .75% of the cavity with agglutination of walls or thick bands [37]. One prospective study evaluated 24 women with infertility (12 of whom had previously delivered) and 12 women with a history of recurrent abortions. Of these 24 women, 48% conceived after hysteroscopic adhesiolysis. Among the 12 women with recurrent abortions, pregnancy wastage was reduced from 86.5% to 42.8% postoperatively [31]. Several retrospective studies in patients with unexplained fertility and recurrent abortions diagnosed with mild adhesive disease recorded pregnancy rates between 58% and 88% after the adhesions were treated by hysteroscopic adhesiolysis. Similarly, women who underwent hysteroscopic adhesiolysis (Fig. 4B) for moderate and severe intrauterine adhesions had pregnancy rates of 30% to 75% and 14% to 33%, respectively [36,38–40].
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Fig. 5 Retained products of conception.
Two retrospective studies of women with severe adhesions found live birth rates of 32.1% and 32.8%, respectively, after undergoing hysteroscopic adhesiolysis. Cappella-Allouc et al [41] reported that among 31 patients who underwent hysteroscopic adhesiolysis, a functional uterine cavity was restored after 1 surgical procedure in 16 patients, after 2 procedures in 7 patients, after 3 procedures in 7 patients, and after 4 procedures in 1 patient. For Fernandez et al [42], final reconstruction resulting in a normal uterine cavity was noted after 1 surgical procedure in 31 patients, after 2 procedures in 20 patients, after 3 procedures in 15 patients, and after 4 or more procedures in 5 patients. These 2 studies also found a significant difference between women aged ,35 years and those aged .35 years after hysteroscopic treatment of severe intrauterine adhesions. Pregnancy rates from both studies were 62% to 67% for women aged ,35 years, compared with 16% to 24% for those aged .35 years. It is important to note that all of the foregoing studies used a combination of 1 to 3 months of estrogen and progesterone hormonal therapy with or without a distended intrauterine Foley bulb for 3 to 5 days or an intrauterine device postoperatively. At the completion of the hormonal therapy, most patients either underwent hysterosalpingography and/ or hysteroscopy to assess and treat recurrent adhesions if necessary. Retained Products of Conception Retained products of conception can lead to an inflammatory state within the uterine cavity, potentially causing intrauterine adhesions and infertility (Fig. 5). Typically, a diagnosis can be made with a history of a pregnancy loss with or without undergoing a dilatation and curettage (D&C), complaints of irregular vaginal bleeding, and abnormal cavity appearance on transvaginal ultrasound, hysterosonogram, or hysterosalpingogram [43].
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Cohen et al [43] retrospectively examined patients who were diagnosed with residual trophoblastic tissue. Patients underwent either hysteroscopy or D&C for removal of retained tissue. The time from pregnancy termination to surgery was not significant between the 2 groups. The time to a subsequent conception after management was significantly shorter for those who underwent hysteroscopic resection compared with those who underwent D&C (7 months vs 11 months). Five of the 24 patients (20.8%) who underwent a D&C initially required subsequent hysteroscopic resection owing to persistent residual trophoblastic tissue. A more recent study by Rein et al [44] in 2011 prospectively studied patients who underwent dilatation and evacuation (D&E) with ultrasound guidance vs hysteroscopic resection for removal of residual trophoblastic tissue. A second-look hysteroscopy was performed at 3 months to evaluate intrauterine adhesions. Significantly more patients with mild adhesions underwent ultrasound-guided D&E than hysteroscopic resection (30.8% vs 4.2%), and 1 D&E recipient was diagnosed with severe adhesions. Conception rate and time to conception also differed significantly between the 2 groups, with a conception rate of 59.9% in the D&E group vs 68.8% in the hysteroscopic resection group and a respective time to conception of 14.5 months vs 11.5 months. Two studies, 1 prospective and 1 retrospective, evaluated conception and live birth rates after hysteroscopic resection of residual trophoblastic tissue [45,46]. Conception rates in these studies were 76% and 82%, respectively, with live birth rates of 70% and 75%. The prospective study found a conception rate of 88% in women aged %35 years, compared with 66% in those aged .35 years [45]. Chronic Endometritis Chronic endometritis often occurs as an asymptomatic inflammation of the endometrium. Some studies have demonstrated an association with infertility, recurrent miscarriage, and implantation failure, although not all of the literature is in agreement [47–51]. Zolghadri et al [48] prospectively demonstrated evidence of chronic endometritis on hysteroscopy in 67% of subjects with recurrent miscarriage, compared with 27.3% in controls (p , .0001). In addition, Johnston-MacAnanny et al [50] prospectively demonstrated a lower implantation rate in a chronic endometritis group compared with controls (15% vs 46.2%; p 5 .0024). Conversely, in a small case-control study by Kasius et al [51], among 17 women diagnosed with chronic endometritis by histology, there was no difference in clinical pregnancy or live birth rate compared with controls. Methods for diagnosing chronic endometritis include culture, hysteroscopy, and histology specimens. On hysteroscopy, the endometrium often contains micropolyps (,1 mm), is edematous, and demonstrates focal or diffuse endometrial hyperemia [52] (Fig. 6). Compared with histological specimens, which exhibit stromal edema and
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Fig. 6 (A) Chronic endometritis showing micropolyps (photo courtesy of Morris Wortman, MD). (B) Chronic endometritis showing hyperemia (photo courtesy of Morris Wortman, MD).
plasma cells in the endometrial stroma [53], hysteroscopy has demonstrated a high sensitivity and negative predictive value. In a prospective study of 142 patients with unexplained recurrent pregnancy loss and 154 fertile patients, the sensitivity and negative predictive value of hysteroscopy were 98.4% and 97.82%, respectively, compared with histology [48]. The specificity and positive predictive value in the same study were fair, at 56.23% and 63.5%, respectively. Based on the presence of hyperemia, edema, and micropolyps on hysteroscopy in 158 patients, Cicinelli et al [54] retrospectively demonstrated a sensitivity of 55.4%, specificity of 99.9%, positive predictive value of 98.4%, and negative predictive value of 94.5%. Furthermore, a prospective controlled study by the same lead author of 438 patients with evidence of chronic endometritis on hysteroscopy found positive histological findings in 388 (88.6%) and positive culture results in 320 (73.1%) [55]. Another discrepancy regarding the clinical implications of chronic endometritis is the mixed evidence that treatment with antibiotics improves pregnancy rates and outcomes compared with controls when diagnosed based on histology [50,51]. In a prospective study, Yang et al [56] failed to identify differences in implantation, clinical, or ongoing pregnancy rates in patients diagnosed with chronic endometritis on histology and treated (n 5 68) compared with those who went untreated (n 5 20). But when comparing patients diagnosed and treated based on hysteroscopy evidence alone (n 5 41) and those receiving no treatment (n 5 27), Yang et al [56] found higher rates of implantation (18.6% vs 4.9%) and ongoing pregnancy (29.3% vs 7.4%) in the treatment group (p , .05). Proximal Tubal Occlusion Proximal tubal occlusion, leading to obstruction of the anatomic pathway for fertilization, occurs in 10% to 25% of infertile women. Tubal spasms, mucus plugs, debris, salpingitis isthmica nodosa, chronic salpingitis, intratubal endometriosis, tubal polyps, and hypoplasia are all known causes of proximal tubal occlusion. A false-positive diag-
nosis has led to unnecessary tubal resection in 16% to 50% of women [57–60]. A meta-analysis published in 1999 by Honore et al [60] examined 7 articles reporting studies of patients undergoing tubal microsurgery and macrosurgery, 9 articles reporting on selective salpingography and 4 articles on hysteroscopic management of proximal tubal occlusion. The average pregnancy rate was higher in women managed by hysteroscopic tubal recanalization compared with those managed with tubal microsurgery and macrosurgery or selective salpingography (48.9% vs 38% vs 28.8%, respectively). A more recent review in 2010 by Allahbadia and Merchant [61] evaluated success and pregnancy rates of tubal recanalization with hysteroscopy. Success rates ranged from 57% to 88% with partially occluded tubes or with complete occlusion in the cornual, proximal, and intramural/ interstitial portions of the fallopian tube. One study that was reviewed reported a success rate of 13.3% for distal tubal occlusion after hysteroscopic tubal cannulation. Failed IVF Hysteroscopy in women unable to conceive a pregnancy after undergoing IVF has been shown to have a twofold effect. First, hysteroscopy will allow the diagnosis and treatment of intrauterine pathology, as described above, for those who may have had a normal hysterosalpingogram before their IVF cycle. Second, uterine instrumentation with hysteroscopy through the cervical canal may facilitate future embryo transfers as well as trigger an immunologic mechanism in the endometrium, which may improve pregnancy rates [57,62]. Four prospective trials evaluated the impact of hysteroscopy on women with R2 failed IVF cycles [63–66]. All of these patients had a normal hysterosalpingogram before their IVF cycles. The most common findings in these studies were polyps and intrauterine adhesions; other hysteroscopic findings included fibroids, endometritis, hyperplasia, and uterine septum. Oliveira et al [65] reported significantly higher pregnancy rates in patients with
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Fig. 7 (A) Pregnancy at 7 weeks gestation with failure to develop beyond 5 weeks. Image is of fetus and yolk sac. (B) Two-vessel cord of aborted fetus at 8 weeks gestation.
intrauterine pathology identified and treated during hysteroscopy compared with those with normal hysteroscopy findings. This finding is consistent with the findings of most of the literature reviewed in this paper. Of interest, however, is that 2 separate randomized studies, by Demirol and Gurgan [63] and Raju et al [64], found significantly higher pregnancy rates in patients who underwent hysteroscopy even with normal findings compared with those who never underwent hysteroscopy before their IVF cycle (approximately 32%–44% vs 21%–26%). A meta-analysis published in 2008 [67] evaluated 4 studies, including the 2 aforementioned studies by Demirol and Gurgan [63] and Raju et al [64]. The other 2 studies were nonrandomized, but all 4 studies showed a significant improvement in pregnancy rates in women with normal cavities who underwent diagnostic hysteroscopy before an IVF cycle compared with those who did not. The number needed to treat (NNT) to achieve an additional pregnancy was 7. The most recent meta-analysis, published in 2014 by Pundir et al [68], reached a similar conclusion, with an NNT of 10. First Trimester Miscarriage Approximately 15% to 20% of pregnancies result in spontaneous abortions, with approximately 60% to 70% of these miscarriages secondary to chromosomal abnormalities. Hysteroscopy performed during the first trimester after confirmation of pregnancy failure is known as embryoscopy. Embryoscopy may allow the physician to evaluate embryonic maldevelopment for those genetic lesions currently undetectable by cytogenetic techniques (Fig. 7). Direct biopsy of the demised embryo through embyroscopy improves cytogenetic testing by avoiding maternal blood/tissue contamination. Genetic counseling for those with chromosomal abnormalities may be offered to reduce the risk of recurrent abortion [69–71]. In 2003, Ferro et al [72] evaluated 68 women who had experienced first trimester abortions and underwent direct
biopsy followed by suction curettage. Biopsy was successful in 97.2% of the gestational sacs. Karyotyping was accomplished in 79.7% of cases. Among the 36 cases for which cytogenic results were available from both the biopsy and curettage, 12 (33%) had maternal contamination and 8 (22%) had only maternal tissue in the curettage specimen. Another study in 2003, by Philipp et al [70], performed embryoscopy in 233 women with a missed abortion. Visualization was successful in all 233 women, and karyotyping was successful in 221 women. The mean age of the study population was 35.2 years, and 89.7% were nulliparous. This population conceived mainly with assisted reproductive techniques (75.4%), and the remainder had a history of R2 previous spontaneous abortions. Of the 31 patients identified with normal morphology who underwent karyotyping, 48.4% had an abnormal karyotype. Abnormal morphology, defined as growth disorganization, combined defects, and isolated defects, was detected in 200 (86%) of the fetuses. A normal karyotype was found in 30% of the fetuses with growth disorganization, in 14% with combined defects, and in 40% with isolated defects. Three fetuses with normal morphology and karyotype had amniotic band syndrome. Although cytogenetics provides information on chromosomal causes for pregnancy, embryoscopy helps reduce maternal contamination to provide a higher yield of fetal chromosomes, and also allows direct visualization of morphologic causes of a pregnancy failure. This information is valuable for infertile couples and their treating physicians to help understand the probable cause of miscarriage and enable steps to reduce the risk of another unsuccessful outcome. Conclusion Based on the current published literature, including a meta-analysis published by Pritts et al [14] in 2009, infertile women who undergo hysteroscopic myomectomy have improved clinical pregnancy rates compared with those with fibroids left in situ. The use of universal hysteroscopy
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for removal of submucous fibroids in those with unexplained infertility cannot be strongly recommended, however, given the current lack of no good-quality prospective studies. Similarly, only 1 randomized controlled prospective study evaluating and favoring hysteroscopic polypectomy has been published to date. In a retrospective study, Yahaihara et al [21] found that uterotubal polypectomy was associated with the highest pregnancy rates. Thus, based on limited data, it does seem that hysteroscopic polypectomy may improve fertility, especially when performed near the uterotubal junction. None of the publications reviewed identified polyp size or multiple polyps as a significant factor in improving fertility. Hysteroscopic metroplasty has short operative and hospitalization times, with advantages for women with unexplained primary fertility and those with recurrent abortions. Based on oue review of the literature, the greatest benefit is achieved in patients experiencing recurrent abortions. Septum length %1 cm does not appear to affect reproductive outcome, and thus hysteroscopic metroplasty is not recommended to correct these uteri. One small prospective and several retrospective studies have indicated that hysteroscopic adhesiolysis can increase clinical pregnancy rates and reduce pregnancy wastage. Owing to the lack of randomized controlled trials, a strong recommendation for hysteroscopic adhesiolysis cannot be made, however. Retained products of conception are a recognizable pathology seen on uterine imaging. The studies reviewed provide good evidence that hysteroscopic removal of retained products of conception is superior to D&C. Clinical pregnancy rates and time to conception are both improved with hysteroscopic resection. The data on the clinical significance and implications for treatment of chronic endometritis is currently inconclusive, but there is some evidence that diagnosis and treatment based on hysteroscopy may improve outcomes in infertile patients. Proximal tubal occlusion can result from multiple causes. Irrespective of the cause, however, the meta-analysis and review evaluated here deemed hysteroscopic tubal recanalization to be successful. Hysteroscopic outcomes reportedly increase clinical pregnancy rates to a greater degree than other methods of tubal correction and, because of its minimally invasive approach, is a recommended technique for treating proximal tubal occlusion. The current literature indicates improved clinical pregnancy rates in those women who undergo a diagnostic hysteroscopy before an IVF cycle. The ability to diagnose and treat intracavitary pathology appears to have a positive effect; however, women with normal uterine cavities who undergo diagnostic hysteroscopy before their IVF cycle also may benefit from the procedure, and have significantly higher clinical pregnancy rates compared with women who do not undergo hysteroscopy. Finally, we reviewed the role of hysteroscopy in women who achieve pregnancy but miscarry in the first trimester.
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Based on our literature search, embryoscopy can be an additional tool in the workup of first trimester losses by evaluating for abnormal anatomic development. Direct tissue biopsy also helps reduce maternal contamination, yielding better success for resulting fetal chromosomes. Both evaluations can help direct the couple to the possible need for genetic evaluation and counseling. In conclusion, hysteroscopy may play an important role before or in conjunction with assisted reproductive techniques to help infertile women and couples achieve their goals of a pregnancy and live birth of a child. References 1. Centers for Disease Control and Prevention. Fertility, family planning, and reproductive health of US women: data from the 2002 National Survey of Family Growth. Vital Health Stat. 2005;23:1–160. 2. Bajekal N, Li TC. Fibroids, infertility and pregnancy wastage. Hum Reprod Update. 2000;6:614–620. 3. Deligdish L, Lowenthal M. Endometrial changes associated with myomata of the uterus. J Clin Pathol. 1970;23:676–680. 4. Casini ML, Rossi F, Agostini R, et al. Effects of the position of fibroids on fertility. Gynecol Endocrinol. 2006;22:106–109. 5. Richards PA, Richards PD, Tiltman AJ. The ultrastructure of fibromyomatous myometrium and its relationship to infertility. Hum Reprod Update. 1998;4:520–525. 6. Yoshin O, Hayashi T, Osuga Y, et al. Decreased pregnancy rate is linked to abnormal uterine peristalsis caused by intramural fibroids. Hum Reprod. 2010;25:2475–2479. 7. Oliveira FG, Abdelmassih VG, Diamond MP, et al. Impact of subserosal and intramural uterine fibroids that do not distort the endometrial cavity on the outcome of in vitro fertilization-intracytoplasmic sperm injection. Fertil Steril. 2004;81:582–587. 8. Check JH, Choe JK, Lee G, et al. The effect on IVF outcome of small intramural fibroids not compressing the uterine cavity as determined by a prospective matched control study. Hum Reprod. 2002;17:1244–1248. 9. Hart R, Khalaf Y, Yeong CT, et al. A prospective controlled study of the effect of intramural uterine fibroids on the outcome of assisted conception. Hum Reprod. 2001;16:2411–2417. 10. Rackow BW, Taylor HS. Submucosal uterine leiomyomas have a global effect on molecular determinants of endometrial receptivity. Fertil Steril. 2010;93:2027–2034. 11. Practice Committee. American Society for Reproductive Medicine. Myomas and reproductive function. Fertil Steril. 2008;90:S125–S130. 12. Ezzati M, Norian J, Segars JH. Management of uterine fibroids in the patient pursuing assisted reproductive technologies. Womens Health (Lond Engl). 2009;5:413–421. 13. Shokeir TA. Hysteroscopic management in submucous fibroids to improve fertility. Arch Gynecol Obstet. 2005;273:50–54. 14. Pritts EA, Parker WH, Olive DL. Fibroids and infertility: an updated systematic review of the evidence. Fertil Steril. 2009;9:1215–1223. 15. Bosteels J, Kasius J, Weyers S, Broekmans FJ, Mol BWJ, D’Hooghe TM. Hysteroscopy for treating subfertility associated with suspected major uterine cavity abnormalities. Cochrane Database Syst Rev. 2013;(1):CD009461. 16. Shokeir T, El-Shafei M, Yousef H, et al. Submucous myomas and their implications in the pregnancy rate of patients with otherwise unexplained primary infertility undergoing hysteroscopic myomectomy: a randomized matched control study. Fertil Steril. 2010;94:724–729. 17. Richlin SS, Ramachandran S, Shanti A, et al. Glycodelin levels in uterine flushings and in plasma of patients with leiomyomas and polyps: implications for implantation. Hum Reprod. 2002;17:2742–2747. 18. Oehninger S, Coddington CC, Hodgen GD, et al. Factors affecting fertilization: endometrial placental protein 14 reduces the capacity of
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human spermatozoa to bind to the human zona pellucida. Fertil Steril. 1995;63:377–383. Perez-Medina T, Bajo-Arenas J, Salazar F, et al. Endometrial polyps and their implication in the pregnancy rates of patients undergoing intrauterine insemination: a prospective, randomized study. Hum Reprod. 2005;20:163–165. Stamatellos I, Apostolides A, Stamatopoulos P, et al. Pregnancy rates after hysteroscopic polypectomy depending on the size or number of the polyps. Arch Gynecol Obstet. 2008;277:395–399. Yahaihara A, Yorimitsu T, Motoyama H, Iwasaki S, Kawamura T. Location of endometrial polyp and pregnancy rate in infertility patients. Fertil Steril. 2008;90:180–182. Kormanyos Z, Molnar BG, Pal A. Removal of a residual portion of a uterine septum in women of advanced reproductive age: obstetric outcome. Hum Reprod. 2006;21:1047–1051. Fedele L, Bianchi S, Marchini M, et al. Ultrastructural aspects of endometrium in infertile women with septate uterus. Fertil Steril. 1996;65: 750–752. Gubbini G, Sardo ADS, Nascetti D, et al. New outpatient subclassification system for American Fertility Society classes V and VI uterine anomalies. J Minim Invasive Gynecol. 2009;16:554–561. Pabuc¸cu R, Gomel V. Reproductive outcome after hysteroscopic metroplasty in women with septate uterus and otherwise unexplained infertility. Fertil Steril. 2004;81:1675–1678. Shokeir T, Abdelshaheed M, El-Shafie M, et al. Determinants of fertility and reproductive success after hysteroscopic septoplasty for women with unexplained primary infertility: a prospective analysis of 88 cases. Eur J Obstet Gynecol Reprod Biol. 2011;155:54–57. Mollo A, De Franciscis P, Colacuci N, et al. Hysteroscopic resection of the septum improves the pregnancy rate of women with unexplained infertility: a prospective controlled trial. Fertil Steril. 2009;91: 2628–2631. Ban-Frangez H, Tomazevic T, Virant-Klun I, Verdenik I, RibicPucelj M, Bokal EV. The outcome of singleton pregnancies after IVF/ICSI in women before and after hysteroscopic resection of a uterine septum compared to normal controls. Eur J Obstet Gynecol Reprod Biol. 2009;146:184–187. Grimbizis GF, Camus M, Tarlatzis BC, Bontis JN, Devroey P. Clinical implications of uterine malformations and hysteroscopic treatment results. Hum Reprod Update. 2001;7:161–174. Nouri K, Ott J, Huber JC, et al. Reproductive outcome after hysteroscopic septoplasty in patients with septate uterus: a retrospective cohort study and systematic review of the literature. Reprod Biol Endocrinol. 2010;8:52. Goldenberg M, Sivan E, Sharabi Z, et al. Reproductive outcome following hysteroscopic management of intrauterine septum and adhesions. Hum Reprod. 1995;10:2663–2665. Robinson J, Colimon LM, Isaacson KB. Postoperative adhesiolysis therapy for intrauterine adhesions (Asherman’s syndrome). Fertil Steril. 2008;90:409–414. Valle RF, Sciarra JJ. Intrauterine adhesions: hysteroscopic diagnosis, classification, treatment, and reproductive outcome. Am J Obstet Gynecol. 1988;158(6 Pt 1):1459–1470. Schenker JG, Margalioth EJ. Intrauterine adhesions: an updated appraisal. Fertil Steril. 1982;37:593–610. Orhue AA, Aziken ME, Igbefoh JO. A comparison of two adjunctive treatments for intrauterine adhesions following lysis. Int J Gynaecol Obstet. 2003;82:49–56. Klein SM, Garcia CR. Asherman’s syndrome: a critique and current review. Fertil Steril. 1973;24:722–735. March C. Hysteroscopy for infertility. In: Baggish M, editor. Diagnostic and Pperative Hysteroscopy. Chicago: Year Book Medical; 1989. p. 136–144. Pabuc¸cu R, Atay V, Orhon E, et al. Hyssteroscopic treatment of intrauterine adhesions is safe and effective in the restoration of normal menstruation and fertility. Fertil Steril. 1997;68:1141–1143.
361 39. Roy KK, Baruah J, Sharma JB, et al. Reproductive outcome following hysteroscopic adhesiolysis in patients with infertility due to Asherman’s syndrome. Arch Gynecol Obstet. 2010;281:355–361. 40. Yu D, Li TC, Huang X, et al. Factors affecting reproductive outcome of hysteroscopic adhesiolysis for Asherman’s syndrome. Fertil Steril. 2008;89:715–722. 41. Capella-Alouc S, Morsad F, Rongieres-Bertrand C. Hysteroscopic treatment of severe Asherman’s syndrome and subsequent fertility. Hum Reprod. 1999;14:1230–1233. 42. Fernandez H, Al-Najjar F, Chauveaud-Lambling A, et al. Fertility after treatment of Asherman’s syndrome stage 3 and 4. J Minim Invasive Gynecol. 2006;13:398–402. 43. Cohen SB, Kalter-Ferber A, Weisz B, et al. Hysteroscopy may be the method of choice for management of residual trophoblastic tissue. J Am Assoc Gynecol Laparosc. 2001;8:199–202. 44. Rein DT, Schmidt T, Hess AP, Volkmer A, Sch€ondorf T, Breidenbach M. Hysteroscopic management of residual trophoblastic tissue is superior to ultrasound-guided curettage. J Minim Invasive Gynecol. 2011;18:774–778. 45. Faivre E, Deffieux X, Mrazguia C, et al. Hysteroscopic management of residual trophoblastic tissue and reproductive outcome: a pilot study. J Minim Invasive Gynecol. 2009;16:487–490. 46. Golan A, Dishi M, Shalev A, Keidar R, Ginath S, Sagiv R. Operative hysteroscopy to remove retained products of conception: novel treatment of an old problem. J Minim Invasive Gynecol. 2011;18:100–103. 47. Cicinelli E, Matteo M, Tinelli R, et al. Chronic endometritis due to common bacteria is prevalent in women with recurrent miscarriage as confirmed by improved pregnancy outcome after antibiotic treatment. Reprod Sci. 2014;21:640–647. 48. Zolghadri J, Momtahan M, Aminian K, et al. The value of hysteroscopy in diagnosis of chronic endometritis in patients with unexplained recurrent spontaneous abortion. Eur J Obstet Gynecol. 2011;155:217–220. 49. Romero R, Espinoza J, Mazor M. Can endometrial infection/inflammation explain implantation failure, spontaneous abortion and preterm birth after in vitro fertilization? Fertil Steril. 2004;82:799–804. 50. Johnston-MacAnanny E, Hartnett J, Engmann L, et al. Chronic endometritis is a frequent finding in women with recurrent implantation failure after in vitro fertilization. Fertil Steril. 2010;93:437–441. 51. Kasius J, Fatemi H, Bourgain C, et al. The impact of chronic endometritis on reproductive outcome. Fertil Steril. 2011;96:1451–1456. 52. Cicinelli E, Resta L, Nicoletti R, Zappimbulso V, Tartagni M, Saliani N. Endometrial micropolyps at fluid hysteroscopy suggest the existence of chronic endometritis. Hum Reprod. 2005;20:1386–1389. 53. Greenwood S, Moran J. Chronic endometritis: morphologic and clinical observations. Obstet Gynecol. 1981;58:176–184. 54. Cicinelli E, Resta L, Nicoletti R, et al. Detection of chronic endometritis at fluid hysteroscopy. J Minim Invasive Gynecol. 2005;12:514–518. 55. Cicinelli E, De Ziegler D, Nicoletti R, et al. Chronic endometritis: correlation among hysteroscopic, histologic, and bacteriologic findings in a prospective trial with 2190 consecutive office hysteroscopies. Fertil Steril. 2008;89:7677–7684. 56. Yang R, Du X, Wang Y, et al. The hysteroscopy and histological diagnosis and treatment value of chronic endometritis in recurrent implantation failure patients. Arch Gynecol Obstet. 2014;289:1363–1369. 57. McManus J, McClure N, Traub AI. The effect of cervical dilatation in patients with previous difficult embryo transfer. Fertil Steril. 2000;74:159. 58. Thurmond AS. Fallopian tube catheterization. Semin Intervent Radiol. 2008;25:425–431. 59. Sulak PJ, Letterie GS, Coddington CC, et al. Histology of proximal tubal occlusion. Fertil Steril. 1987;48:437–440. 60. Honore G, Holden A, Schenken R. Pathophysiology and management of proximal tubal blockage. Fertil Steril. 1999;71:785–795. 61. Allahbadia G, Merchant R. Fallopian tube recanalization: lessons learnt and future challenges. Womens Health. 2010;6:531–548. 62. Mansour R, Aboulghar M. Optimizing the embryo transfer technique. Hum Reprod. 2002;17:1149–1153.
362 63. Demirol A, Gurgan T. Effect of treatment of intrauterine pathologies with office hysteroscopy in patients with recurrent IVF failure. Reprod Biomed Online. 2004;8:590–594. 64. Raju G, Kumari G, Krishna K, et al. Assessment of uterine cavity by hysteroscopy in an assisted reproduction programme and its influence on pregnancy outcome. Arch Gynecol Obstet. 2006;274:160–164. 65. Oliveira F, Abdelmassih V, Diamond M, et al. Uterine cavity findings and hysteroscopic interventions in patients undergoing in vitro fertilization-embryo transfer who repeatedly cannot conceive. Fertil Steril. 2003;80:1371–1375. 66. Makrakis E, Hassiakos D, Stathis D, et al. Hysteroscopy in women with implantation failures after in vitro fertilization: findings and effect on subsequent pregnancy rates. J Minim Invasive Gynecol. 2009;16:181–187. 67. El-Touky T. Outpatient hysteroscopy and subsequent IVF cycle outcome: a systematic review and meta-analysis. Reprod Biomed Online. 2008;16:712–719.
Journal of Minimally Invasive Gynecology, Vol 22, No 3, March/April 2015 68. Pundir J, Pundir V, Omanwa K, et al. Hysteroscopy prior to the first IVF cycle: a systematic review and mate-analysis. Reprod Biomed Online. 2014;28:151–161. 69. Philipp T, Feichtinger W, Van Allen M, Separovic E, Reiner A, Kalousek DK. Abnormal embryonic development diagnosed embryoscopically in early intrauterine deaths after in vitro fertilization: a preliminary report of 23 cases. Fertil Steril. 2004;82:1337–1342. 70. Philipp T, Philipp K, Reiner A, Beer F, Kalousek DK. Embryoscopic and cytogenetic analysis of 233 missed abortions: factors involved in the pathogenesis of developmental defects of early failed pregnancies. Hum Reprod. 2003;28:1724–1732. 71. Paschopoulos M, Meridis EN, Tanos V, O’Donovan PJ, Paraskevaidis E. Embryofetoscopy: a new ‘‘old’’ tool. Gynecol Surg. 2006;3:79–83. 72. Ferro J, Martınez MC, Lara C, Pellicer A, Remohı J, Serra V. Improved accuracy of hysteroembryoscopic biopsies for karyotyping early missed abortions. Fertil Steril. 2003;80:1260–1264.
Hysteroscopy for Infertile Women: A Review Aarathi Cholkeri-Singh, MD, FACOG*, and Kirsten J. Sasaki, MD, FACOG From the Department of Obstetrics and Gynecology, Advocate Lutheran General Hospital, Park Ridge, Illinois (Dr. Cholkeri-Singh), and Department of Obstetrics and Gynecology, University of Illinois at Chicago, Chicago, Illinois (Dr. Cholkeri).
ABSTRACT Hysteroscopy is widely performed in infertile women. A review of peer-reviewed, published literature from the PubMed database on uterine intracavitary pathology, proximal tubal occlusion, failed in vitro fertilization procedures, and first trimester miscarriages of infertile women was performed to examine the importance, feasibility, and success rates of diagnostic and operative hysteroscopy when evaluating and treating these conditions. Journal of Minimally Invasive Gynecology (2015) 22, 353–362 Ó 2015 AAGL. All rights reserved. Keywords:
DISCUSS
Asherman’s syndrome; Chronic endometritis; Endometrial polyps; Hysteroscopy; Infertile women; In vitro fertilization; Missed abortion; Proximal tubal occlusion; Recurrent pregnancy loss; Retained products of conception; Submucous myoma; Uterine septum
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In 2002, approximately 2.1 million US women were infertile. According to the National Center for Health Statistics, between 2006 and 2010, rates of infertility ranged from 8% to 30% in married women aged 15 to 44 years [1]. Assisted reproductive technology has been applied to treat many of these women; however, the peer-reviewed published literature has identified hysteroscopy as a valuable tool for diagnosis and treatment of some infertile women before or after undergoing an assisted reproductive technique. Indications for hysteroscopy in infertile women include intracavitary abnormalities, such as submucous fibroids, endometrial polyps, uterine septum, adhesions, chronic endometritis, and retained products of conception. The use of hysteroscopy has been evaluated in proximal tubal occlusion, failed in vitro fertilization (IVF) cycle, and firsttrimester miscarriage as well.
Corresponding author: Aarathi Cholkeri-Singh, MD, FACOG, Advanced Gynecologic Surgery Institute, 120 Olser Drive, Suite 100, Naperville, IL 60540. E-mail: [email protected] Submitted September 23, 2014. Accepted for publication December 19, 2014. Available at www.sciencedirect.com and www.jmig.org 1553-4650/$ - see front matter Ó 2015 AAGL. All rights reserved. http://dx.doi.org/10.1016/j.jmig.2014.12.163
Materials and Methods A PubMed search of the literature was performed using the following Medical Subject Headings (MeSH) alone or in combination: hysteroscopy, infertility, myomectomy, polypectomy, uterine septum or metroplasty, Asherman’s syndrome or intrauterine adhesions, uterine septum, retained products of conception, chronic endometritis, proximal tubal occlusion, failed in vitro fertilization, first trimester miscarriage, and embryoscopy. Our search was then filtered by selecting papers published in English from 1970 through 2014. Only prospective trials and meta-analyses were reviewed initially; however, for topics with a limited number of prospective studies, the search was expanded to include retrospective studies. Intracavitary Pathology Submucous Fibroids Submucous fibroids are categorized as type 0, 1, and 2. A type 0 fibroid is located completely within the uterine cavity; type 1 fibroid, R50% within the uterine cavity (Fig. 1A); and type 2, ,50% within the uterine cavity [2]. Postulated mechanisms by which fibroids cause infertility include the following:
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Fig. 1 (A) Submucous myoma. (B) Hysteroscopic resection of submucous myoma restoring normal cavity architecture.
Interference with normal patterns of endocrine function [3] Distortion of the endometrium [4,5] Dysfunctional uterine contractility [6] Distortion or obstruction of tubal ostia [7] Chronic endometrial inflammation [6] Abnormal uterine vascularization [8,9] Impaired endometrial receptivity [10] Implantation failure due to atrophy or venous ectasia over or opposite a submucous fibroid [11]. Pregnancy wastage rates frequently exceed 70% for submucous fibroids [12]. A small prospective cohort study published in 2005 by Shokeir [13] followed 29 consecutive women with submucous fibroids who desired pregnancy. Primary infertility was diagnosed in 14 women, and the other 15 had a history of poor obstetrical outcomes. All women were treated with a hysteroscopic myomectomy (Fig. 1B). Intraoperatively, all 29 women were found to have a single fibroid, 25 type 0 and 4 type 1, all no larger than 5 cm. Twenty-one of the 29 women (72%) achieved at total of 30 pregnancies; 13 of these women had live births. The rate of live birth increased from 3.8% to 63.2%, and the rate of abortion decreased from 61.6% to 26.3% after hysteroscopic myomectomy. In 2009, Pritts et al [14] published a meta-analysis of 23 studies evaluating women with fibroids and infertility. Nine of these 23 studies looked at submucous fibroids. These 9 studies included 6 retrospective studies, 2 prospective studies, and 1 randomized control study. A comparison of infertile women with submucous fibroids and those without submucous fibroids revealed clinically significant differences in pregnancy, implantation, and ongoing pregnancy/ live birth rates, as well as the spontaneous abortion rate. The clinical pregnancy rate was greated in the women who underwent a hysteroscopic myomectomy compared with those with fibroids left in situ. This study also found that the pregnancy rate in women after hysteroscopic myomectomy was comparable to that in women with no evidence of fibroids.
To date, only 1 prospective control study, published by Casini et al [4] in 2005, has analyzed whether the removal of fibroids before conception improves pregnancy rates and outcomes compared with no surgery. That study included a total of 181 patients age %35 years with infertility for at least 12 months and a fibroid ,4 cm in diameter. Ninety-two of the 181 patients underwent myomectomy, via either hysteroscopy or laparotomy, and 89 patients did not undergo surgery. All patients were followed up for 12 months to determine the rate of clinical pregnancy. Pregnancy rates were statistically higher in the patients who underwent myomectomy with submucous fibroids (43.35% vs 27.2% in the nonsurgical group) or submucous and intramural fibroids (36.4% vs 15% in the nonsurgical group) (p , .05). There was no statistically significant increase in pregnancy rate in the patients with only intramural or intramural and subserosal fibroids (p . .05). Despite the findings of Casini et al [4], a further review of their data by the Cochrane Database found that in a subset of women with a submucous fibroid (n 5 94), there was a statistically insignificant increased odds of clinical pregnancy (odds ratio, 2.4; 95% confidence interval, 0.97–6.2; p 5 .06) [15]. One other prospective study in the literature, by Shokeir et al [16], seemed to indicate a benefit to myomectomy in subfertile patients, but this paper was pulled from publication by the journal editor. Endometrial Polyps (Fig. 2) Postulated mechanisms by which polyps cause infertility include irregular endometrial bleeding, inflammatory endometrial response, obstructive inhibition of sperm transport, physical obstruction of exposure of the embryo to the endometrium, interference with normal patterns of endocrine function, and increasing glycodelin concentration, which inhibits sperm binding to the zona pellucida [17,18]. In 2005, Perez-Medina et al [19] published a prospective study evaluating 204 women with infertility for R24 months. Exclusion criteria were age .39 years, anovulation, uncorrected tubal disease, previous unsuccessful use of recombinant follicle-stimulating hormone, and an azoospermic partner. The study group (n 5 101) underwent hysteroscopic
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Fig. 2 Endometrial polyp.
polypectomy, whereas the control group (n 5 103) underwent hysteroscopic polyp biopsy only. After either procedure, participants were to receive up to 4 intrauterine insemination cycles. However, 65% of the study group participants achieved pregnancy before undergoing an intrauterine insemination cycle, a significant finding of that study. There were no significant between-group differences in polyp size and pregnancy conception rates (p 5 .32). A retrospective study in 2008 by Stamatellos et al [20] evaluated the impact on fertility of the size and number of polyps within the uterine cavity. The study included women age ,35 years with primary or secondary infertility for .12 months. The participants were divided into 2 groups, those with a polyp %1 cm and those with a polyp .1 cm or multiple polyps. The findings of this study correlated with those of Perez-Medina et al [19], with polyp size and number of polyps having no significant association with pregnancy rate. The pregnancy rate was 61.4% for the entire study population undergoing hysteroscopic polypectomy, irrespective of whether the patient had primary or secondary infertility.
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Consequently, with the understanding that polyps may impact fertility, Yahaihara et al [21] conducted a retrospective study of 230 women to determine the significance of the location of endometrial polyps. The locations were defined as anterior wall, posterior wall, lateral wall, uterotubal junction, and multiple polyps. Similar to previously reported findings, polyp size in any area of the uterus did not significantly impact pregnancy rate; however, the highest pregnancy rate, 50% to 60%, was achieved in those who had polyps removed from the utero-tubal junction. Uterine Septum The uterine septum has been associated with pregnancy wastage rates as high as 90%, most likely related to the structural alterations in the endometrium of the septum, which affects implantation (Fig. 3A) [22,23]. The American Fertility Association, now known as the American Society of Reproductive Medicine, has published a subclassification with 12 variations of uterine septum anatomy [24]. Four prospective trials have evaluated the effect of hysteroscopic metroplasty (Fig. 3B) on clinical pregnancy rates [22,25–27]. In these studies, live birth rates after hysteroscopic metroplasty ranged from 30% to 54%. Mollo et al [27] studied 2 groups with unexplained fertility, a group of women with septate uteri who underwent hysteroscopic metroplasty and a control group without septate uteri. The 2 groups were similar in terms of age, duration of infertility, and body mass index. The pregnancy rate and live birth rate were significantly higher in the hysteroscopic metroplasty group compared with the control group (38.6% vs 20.4%; p 5 .016 and 34.1% vs 18.9%; p , .05, respectively). Pabuc¸cu and Gomel [25] evaluated women aged 21– 35 years with unexplained primary fertility and septate uteri who underwent hysteroscopic metroplasty. Five women (8.2%) underwent repeat surgery for a residual septum .1 cm. The outcome of that study was a 41% pregnancy rate, with a 29.5% live birth rate. In 13 of the 18 pregnancies that carried to term, 2 patients had a total septum and 11 had a subtotal septum resected.
Fig. 3 (A) Uterine septum. (B) Hysteroscopic transection of uterine septum restoring normal anatomy of the cavity.
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Fig. 4 (A) Intrauterine adhesions blocking the right tubal ostia. (B) Hysteroscopic lysis of adhesions restoring normal uterine cavity anatomy.
Considering that some women have a residual septum after their initial metroplasty, Kormanyos et al [22] investigated whether a residual septum impacts fertility. After the first hysteroscopic metroplasty, 1 patient had .1 cm of residual septum, which was further resected, and 35 patients (37%) had a residual septum of %1 cm. If no pregnancy was conceived within 24 months for those with a residual septum %1 cm, then the patients underwent a second hysteroscopic metroplasty for removal of the residual septum. The increase in pregnancy rate after the second hysteroscopy was not significant. Looking further at septum length, Shokeir et al [26] studied women with septum length of R2.5 cm and compared them with women with a septum length of ,2.5 cm. All of f the 42 women (47.7%) who achieved pregnancy were age ,40 years with ,3 years of infertility; 8% of these pregnancies were spontaneous. The pregnancy rate was 66.7% in those with a septum length of R2.5 cm and 42.8% in those with a septum length of ,2.5 cm. The overall live birth rate was 40.1%. Uterine septum length has a potential impact not only on the rate of conception, but also on the rate of pregnancy loss. A retrospective study published in 2009 by Ban-Frangez et al [28] evaluated the affect of septum length on pregnancy loss. A comparison of women with a large (.1.5 cm) or small partial (1.3 to 1.5 cm) septum with women without a septum revealed a significantly higher pregnancy loss rate in those with a septum. Women in both septum groups who underwent hysteroscopic metroplasty had a pregnancy loss rate comparable to that of the control group. Other studies, although not prospective, also have confirmed the significant impact of septum with infertility. Grimbizis et al [29] reviewed 6 studies published before 2001 that reported a live birth rate of 6.1% in women with intact septums compared with 82% in those women who underwent hysteroscopic metroplasty. Nouri et al [30] performed a more recent literature search that revealed live birth rates ranging from 26% to 73%, with a cumulative rate of 45%, after hysteroscopic metroplasty. Both of these reviews evaluated studies in women with a septate uterus,
and both unexplained primary infertility and recurrent abortions. Although hysteroscopic metroplasty appears to improve fertility, the role of surgical correction in patients with primary fertility remains under debate [25]. An older prospective study identified a reduction in pregnancy wastage from 87.5% to 44.4% and recommended hysteroscopic metroplasty as the treatment of choice in patients experiencing recurrent abortions [31]. Intrauterine Adhesions Intrauterine adhesions, also known as Asherman’s syndrome, are caused by postsurgical or infectious damage to the basalis layer of the endometrium. This can cause granulation tissue, which can create tissue bridges, leading to cavity obliteration (Fig. 4A), and is associated with increased risks of ectopic pregnancy, recurrent miscarriage, preterm labor, and abnormal placentation. Pregnancy wastage rates as high as 90% have been reported [31–36]. The severity of intrauterine adhesions is defined as follows: mild, ,25% of the uterine cavity containing thin or filmy adhesions; moderate, 25% to 75% of the cavity containing adhesions, causing partial occlusion of ostium and upper fundus; and severe, .75% of the cavity with agglutination of walls or thick bands [37]. One prospective study evaluated 24 women with infertility (12 of whom had previously delivered) and 12 women with a history of recurrent abortions. Of these 24 women, 48% conceived after hysteroscopic adhesiolysis. Among the 12 women with recurrent abortions, pregnancy wastage was reduced from 86.5% to 42.8% postoperatively [31]. Several retrospective studies in patients with unexplained fertility and recurrent abortions diagnosed with mild adhesive disease recorded pregnancy rates between 58% and 88% after the adhesions were treated by hysteroscopic adhesiolysis. Similarly, women who underwent hysteroscopic adhesiolysis (Fig. 4B) for moderate and severe intrauterine adhesions had pregnancy rates of 30% to 75% and 14% to 33%, respectively [36,38–40].
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Fig. 5 Retained products of conception.
Two retrospective studies of women with severe adhesions found live birth rates of 32.1% and 32.8%, respectively, after undergoing hysteroscopic adhesiolysis. Cappella-Allouc et al [41] reported that among 31 patients who underwent hysteroscopic adhesiolysis, a functional uterine cavity was restored after 1 surgical procedure in 16 patients, after 2 procedures in 7 patients, after 3 procedures in 7 patients, and after 4 procedures in 1 patient. For Fernandez et al [42], final reconstruction resulting in a normal uterine cavity was noted after 1 surgical procedure in 31 patients, after 2 procedures in 20 patients, after 3 procedures in 15 patients, and after 4 or more procedures in 5 patients. These 2 studies also found a significant difference between women aged ,35 years and those aged .35 years after hysteroscopic treatment of severe intrauterine adhesions. Pregnancy rates from both studies were 62% to 67% for women aged ,35 years, compared with 16% to 24% for those aged .35 years. It is important to note that all of the foregoing studies used a combination of 1 to 3 months of estrogen and progesterone hormonal therapy with or without a distended intrauterine Foley bulb for 3 to 5 days or an intrauterine device postoperatively. At the completion of the hormonal therapy, most patients either underwent hysterosalpingography and/ or hysteroscopy to assess and treat recurrent adhesions if necessary. Retained Products of Conception Retained products of conception can lead to an inflammatory state within the uterine cavity, potentially causing intrauterine adhesions and infertility (Fig. 5). Typically, a diagnosis can be made with a history of a pregnancy loss with or without undergoing a dilatation and curettage (D&C), complaints of irregular vaginal bleeding, and abnormal cavity appearance on transvaginal ultrasound, hysterosonogram, or hysterosalpingogram [43].
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Cohen et al [43] retrospectively examined patients who were diagnosed with residual trophoblastic tissue. Patients underwent either hysteroscopy or D&C for removal of retained tissue. The time from pregnancy termination to surgery was not significant between the 2 groups. The time to a subsequent conception after management was significantly shorter for those who underwent hysteroscopic resection compared with those who underwent D&C (7 months vs 11 months). Five of the 24 patients (20.8%) who underwent a D&C initially required subsequent hysteroscopic resection owing to persistent residual trophoblastic tissue. A more recent study by Rein et al [44] in 2011 prospectively studied patients who underwent dilatation and evacuation (D&E) with ultrasound guidance vs hysteroscopic resection for removal of residual trophoblastic tissue. A second-look hysteroscopy was performed at 3 months to evaluate intrauterine adhesions. Significantly more patients with mild adhesions underwent ultrasound-guided D&E than hysteroscopic resection (30.8% vs 4.2%), and 1 D&E recipient was diagnosed with severe adhesions. Conception rate and time to conception also differed significantly between the 2 groups, with a conception rate of 59.9% in the D&E group vs 68.8% in the hysteroscopic resection group and a respective time to conception of 14.5 months vs 11.5 months. Two studies, 1 prospective and 1 retrospective, evaluated conception and live birth rates after hysteroscopic resection of residual trophoblastic tissue [45,46]. Conception rates in these studies were 76% and 82%, respectively, with live birth rates of 70% and 75%. The prospective study found a conception rate of 88% in women aged %35 years, compared with 66% in those aged .35 years [45]. Chronic Endometritis Chronic endometritis often occurs as an asymptomatic inflammation of the endometrium. Some studies have demonstrated an association with infertility, recurrent miscarriage, and implantation failure, although not all of the literature is in agreement [47–51]. Zolghadri et al [48] prospectively demonstrated evidence of chronic endometritis on hysteroscopy in 67% of subjects with recurrent miscarriage, compared with 27.3% in controls (p , .0001). In addition, Johnston-MacAnanny et al [50] prospectively demonstrated a lower implantation rate in a chronic endometritis group compared with controls (15% vs 46.2%; p 5 .0024). Conversely, in a small case-control study by Kasius et al [51], among 17 women diagnosed with chronic endometritis by histology, there was no difference in clinical pregnancy or live birth rate compared with controls. Methods for diagnosing chronic endometritis include culture, hysteroscopy, and histology specimens. On hysteroscopy, the endometrium often contains micropolyps (,1 mm), is edematous, and demonstrates focal or diffuse endometrial hyperemia [52] (Fig. 6). Compared with histological specimens, which exhibit stromal edema and
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Fig. 6 (A) Chronic endometritis showing micropolyps (photo courtesy of Morris Wortman, MD). (B) Chronic endometritis showing hyperemia (photo courtesy of Morris Wortman, MD).
plasma cells in the endometrial stroma [53], hysteroscopy has demonstrated a high sensitivity and negative predictive value. In a prospective study of 142 patients with unexplained recurrent pregnancy loss and 154 fertile patients, the sensitivity and negative predictive value of hysteroscopy were 98.4% and 97.82%, respectively, compared with histology [48]. The specificity and positive predictive value in the same study were fair, at 56.23% and 63.5%, respectively. Based on the presence of hyperemia, edema, and micropolyps on hysteroscopy in 158 patients, Cicinelli et al [54] retrospectively demonstrated a sensitivity of 55.4%, specificity of 99.9%, positive predictive value of 98.4%, and negative predictive value of 94.5%. Furthermore, a prospective controlled study by the same lead author of 438 patients with evidence of chronic endometritis on hysteroscopy found positive histological findings in 388 (88.6%) and positive culture results in 320 (73.1%) [55]. Another discrepancy regarding the clinical implications of chronic endometritis is the mixed evidence that treatment with antibiotics improves pregnancy rates and outcomes compared with controls when diagnosed based on histology [50,51]. In a prospective study, Yang et al [56] failed to identify differences in implantation, clinical, or ongoing pregnancy rates in patients diagnosed with chronic endometritis on histology and treated (n 5 68) compared with those who went untreated (n 5 20). But when comparing patients diagnosed and treated based on hysteroscopy evidence alone (n 5 41) and those receiving no treatment (n 5 27), Yang et al [56] found higher rates of implantation (18.6% vs 4.9%) and ongoing pregnancy (29.3% vs 7.4%) in the treatment group (p , .05). Proximal Tubal Occlusion Proximal tubal occlusion, leading to obstruction of the anatomic pathway for fertilization, occurs in 10% to 25% of infertile women. Tubal spasms, mucus plugs, debris, salpingitis isthmica nodosa, chronic salpingitis, intratubal endometriosis, tubal polyps, and hypoplasia are all known causes of proximal tubal occlusion. A false-positive diag-
nosis has led to unnecessary tubal resection in 16% to 50% of women [57–60]. A meta-analysis published in 1999 by Honore et al [60] examined 7 articles reporting studies of patients undergoing tubal microsurgery and macrosurgery, 9 articles reporting on selective salpingography and 4 articles on hysteroscopic management of proximal tubal occlusion. The average pregnancy rate was higher in women managed by hysteroscopic tubal recanalization compared with those managed with tubal microsurgery and macrosurgery or selective salpingography (48.9% vs 38% vs 28.8%, respectively). A more recent review in 2010 by Allahbadia and Merchant [61] evaluated success and pregnancy rates of tubal recanalization with hysteroscopy. Success rates ranged from 57% to 88% with partially occluded tubes or with complete occlusion in the cornual, proximal, and intramural/ interstitial portions of the fallopian tube. One study that was reviewed reported a success rate of 13.3% for distal tubal occlusion after hysteroscopic tubal cannulation. Failed IVF Hysteroscopy in women unable to conceive a pregnancy after undergoing IVF has been shown to have a twofold effect. First, hysteroscopy will allow the diagnosis and treatment of intrauterine pathology, as described above, for those who may have had a normal hysterosalpingogram before their IVF cycle. Second, uterine instrumentation with hysteroscopy through the cervical canal may facilitate future embryo transfers as well as trigger an immunologic mechanism in the endometrium, which may improve pregnancy rates [57,62]. Four prospective trials evaluated the impact of hysteroscopy on women with R2 failed IVF cycles [63–66]. All of these patients had a normal hysterosalpingogram before their IVF cycles. The most common findings in these studies were polyps and intrauterine adhesions; other hysteroscopic findings included fibroids, endometritis, hyperplasia, and uterine septum. Oliveira et al [65] reported significantly higher pregnancy rates in patients with
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Fig. 7 (A) Pregnancy at 7 weeks gestation with failure to develop beyond 5 weeks. Image is of fetus and yolk sac. (B) Two-vessel cord of aborted fetus at 8 weeks gestation.
intrauterine pathology identified and treated during hysteroscopy compared with those with normal hysteroscopy findings. This finding is consistent with the findings of most of the literature reviewed in this paper. Of interest, however, is that 2 separate randomized studies, by Demirol and Gurgan [63] and Raju et al [64], found significantly higher pregnancy rates in patients who underwent hysteroscopy even with normal findings compared with those who never underwent hysteroscopy before their IVF cycle (approximately 32%–44% vs 21%–26%). A meta-analysis published in 2008 [67] evaluated 4 studies, including the 2 aforementioned studies by Demirol and Gurgan [63] and Raju et al [64]. The other 2 studies were nonrandomized, but all 4 studies showed a significant improvement in pregnancy rates in women with normal cavities who underwent diagnostic hysteroscopy before an IVF cycle compared with those who did not. The number needed to treat (NNT) to achieve an additional pregnancy was 7. The most recent meta-analysis, published in 2014 by Pundir et al [68], reached a similar conclusion, with an NNT of 10. First Trimester Miscarriage Approximately 15% to 20% of pregnancies result in spontaneous abortions, with approximately 60% to 70% of these miscarriages secondary to chromosomal abnormalities. Hysteroscopy performed during the first trimester after confirmation of pregnancy failure is known as embryoscopy. Embryoscopy may allow the physician to evaluate embryonic maldevelopment for those genetic lesions currently undetectable by cytogenetic techniques (Fig. 7). Direct biopsy of the demised embryo through embyroscopy improves cytogenetic testing by avoiding maternal blood/tissue contamination. Genetic counseling for those with chromosomal abnormalities may be offered to reduce the risk of recurrent abortion [69–71]. In 2003, Ferro et al [72] evaluated 68 women who had experienced first trimester abortions and underwent direct
biopsy followed by suction curettage. Biopsy was successful in 97.2% of the gestational sacs. Karyotyping was accomplished in 79.7% of cases. Among the 36 cases for which cytogenic results were available from both the biopsy and curettage, 12 (33%) had maternal contamination and 8 (22%) had only maternal tissue in the curettage specimen. Another study in 2003, by Philipp et al [70], performed embryoscopy in 233 women with a missed abortion. Visualization was successful in all 233 women, and karyotyping was successful in 221 women. The mean age of the study population was 35.2 years, and 89.7% were nulliparous. This population conceived mainly with assisted reproductive techniques (75.4%), and the remainder had a history of R2 previous spontaneous abortions. Of the 31 patients identified with normal morphology who underwent karyotyping, 48.4% had an abnormal karyotype. Abnormal morphology, defined as growth disorganization, combined defects, and isolated defects, was detected in 200 (86%) of the fetuses. A normal karyotype was found in 30% of the fetuses with growth disorganization, in 14% with combined defects, and in 40% with isolated defects. Three fetuses with normal morphology and karyotype had amniotic band syndrome. Although cytogenetics provides information on chromosomal causes for pregnancy, embryoscopy helps reduce maternal contamination to provide a higher yield of fetal chromosomes, and also allows direct visualization of morphologic causes of a pregnancy failure. This information is valuable for infertile couples and their treating physicians to help understand the probable cause of miscarriage and enable steps to reduce the risk of another unsuccessful outcome. Conclusion Based on the current published literature, including a meta-analysis published by Pritts et al [14] in 2009, infertile women who undergo hysteroscopic myomectomy have improved clinical pregnancy rates compared with those with fibroids left in situ. The use of universal hysteroscopy
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for removal of submucous fibroids in those with unexplained infertility cannot be strongly recommended, however, given the current lack of no good-quality prospective studies. Similarly, only 1 randomized controlled prospective study evaluating and favoring hysteroscopic polypectomy has been published to date. In a retrospective study, Yahaihara et al [21] found that uterotubal polypectomy was associated with the highest pregnancy rates. Thus, based on limited data, it does seem that hysteroscopic polypectomy may improve fertility, especially when performed near the uterotubal junction. None of the publications reviewed identified polyp size or multiple polyps as a significant factor in improving fertility. Hysteroscopic metroplasty has short operative and hospitalization times, with advantages for women with unexplained primary fertility and those with recurrent abortions. Based on oue review of the literature, the greatest benefit is achieved in patients experiencing recurrent abortions. Septum length %1 cm does not appear to affect reproductive outcome, and thus hysteroscopic metroplasty is not recommended to correct these uteri. One small prospective and several retrospective studies have indicated that hysteroscopic adhesiolysis can increase clinical pregnancy rates and reduce pregnancy wastage. Owing to the lack of randomized controlled trials, a strong recommendation for hysteroscopic adhesiolysis cannot be made, however. Retained products of conception are a recognizable pathology seen on uterine imaging. The studies reviewed provide good evidence that hysteroscopic removal of retained products of conception is superior to D&C. Clinical pregnancy rates and time to conception are both improved with hysteroscopic resection. The data on the clinical significance and implications for treatment of chronic endometritis is currently inconclusive, but there is some evidence that diagnosis and treatment based on hysteroscopy may improve outcomes in infertile patients. Proximal tubal occlusion can result from multiple causes. Irrespective of the cause, however, the meta-analysis and review evaluated here deemed hysteroscopic tubal recanalization to be successful. Hysteroscopic outcomes reportedly increase clinical pregnancy rates to a greater degree than other methods of tubal correction and, because of its minimally invasive approach, is a recommended technique for treating proximal tubal occlusion. The current literature indicates improved clinical pregnancy rates in those women who undergo a diagnostic hysteroscopy before an IVF cycle. The ability to diagnose and treat intracavitary pathology appears to have a positive effect; however, women with normal uterine cavities who undergo diagnostic hysteroscopy before their IVF cycle also may benefit from the procedure, and have significantly higher clinical pregnancy rates compared with women who do not undergo hysteroscopy. Finally, we reviewed the role of hysteroscopy in women who achieve pregnancy but miscarry in the first trimester.
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Based on our literature search, embryoscopy can be an additional tool in the workup of first trimester losses by evaluating for abnormal anatomic development. Direct tissue biopsy also helps reduce maternal contamination, yielding better success for resulting fetal chromosomes. Both evaluations can help direct the couple to the possible need for genetic evaluation and counseling. In conclusion, hysteroscopy may play an important role before or in conjunction with assisted reproductive techniques to help infertile women and couples achieve their goals of a pregnancy and live birth of a child. References 1. Centers for Disease Control and Prevention. Fertility, family planning, and reproductive health of US women: data from the 2002 National Survey of Family Growth. Vital Health Stat. 2005;23:1–160. 2. Bajekal N, Li TC. Fibroids, infertility and pregnancy wastage. Hum Reprod Update. 2000;6:614–620. 3. Deligdish L, Lowenthal M. Endometrial changes associated with myomata of the uterus. J Clin Pathol. 1970;23:676–680. 4. Casini ML, Rossi F, Agostini R, et al. Effects of the position of fibroids on fertility. Gynecol Endocrinol. 2006;22:106–109. 5. Richards PA, Richards PD, Tiltman AJ. The ultrastructure of fibromyomatous myometrium and its relationship to infertility. Hum Reprod Update. 1998;4:520–525. 6. Yoshin O, Hayashi T, Osuga Y, et al. Decreased pregnancy rate is linked to abnormal uterine peristalsis caused by intramural fibroids. Hum Reprod. 2010;25:2475–2479. 7. Oliveira FG, Abdelmassih VG, Diamond MP, et al. Impact of subserosal and intramural uterine fibroids that do not distort the endometrial cavity on the outcome of in vitro fertilization-intracytoplasmic sperm injection. Fertil Steril. 2004;81:582–587. 8. Check JH, Choe JK, Lee G, et al. The effect on IVF outcome of small intramural fibroids not compressing the uterine cavity as determined by a prospective matched control study. Hum Reprod. 2002;17:1244–1248. 9. Hart R, Khalaf Y, Yeong CT, et al. A prospective controlled study of the effect of intramural uterine fibroids on the outcome of assisted conception. Hum Reprod. 2001;16:2411–2417. 10. Rackow BW, Taylor HS. Submucosal uterine leiomyomas have a global effect on molecular determinants of endometrial receptivity. Fertil Steril. 2010;93:2027–2034. 11. Practice Committee. American Society for Reproductive Medicine. Myomas and reproductive function. Fertil Steril. 2008;90:S125–S130. 12. Ezzati M, Norian J, Segars JH. Management of uterine fibroids in the patient pursuing assisted reproductive technologies. Womens Health (Lond Engl). 2009;5:413–421. 13. Shokeir TA. Hysteroscopic management in submucous fibroids to improve fertility. Arch Gynecol Obstet. 2005;273:50–54. 14. Pritts EA, Parker WH, Olive DL. Fibroids and infertility: an updated systematic review of the evidence. Fertil Steril. 2009;9:1215–1223. 15. Bosteels J, Kasius J, Weyers S, Broekmans FJ, Mol BWJ, D’Hooghe TM. Hysteroscopy for treating subfertility associated with suspected major uterine cavity abnormalities. Cochrane Database Syst Rev. 2013;(1):CD009461. 16. Shokeir T, El-Shafei M, Yousef H, et al. Submucous myomas and their implications in the pregnancy rate of patients with otherwise unexplained primary infertility undergoing hysteroscopic myomectomy: a randomized matched control study. Fertil Steril. 2010;94:724–729. 17. Richlin SS, Ramachandran S, Shanti A, et al. Glycodelin levels in uterine flushings and in plasma of patients with leiomyomas and polyps: implications for implantation. Hum Reprod. 2002;17:2742–2747. 18. Oehninger S, Coddington CC, Hodgen GD, et al. Factors affecting fertilization: endometrial placental protein 14 reduces the capacity of
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