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Intrauterine device or estrogen treatment after hysteroscopic uterine septum resection
International Journal of Gynecology and Obstetrics 109 (2010) 226–229
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j g o
CLINICAL ARTICLE
Intrauterine device or estrogen treatment after hysteroscopic uterine septum resection Esra Ayşin Tonguc ⁎, Turgut Var, Nafiye Yilmaz, Sertac Batioglu Department of Reproductive Endocrinology, Zekai Tahir Burak Women's Health Research and Education Hospital, Ankara, Turkey
a r t i c l e
i n f o
Article history: Received 20 October 2009 Received in revised form 11 December 2009 Accepted 14 January 2010 Keywords: Adhesions Estrogen treatment Intrauterine device Hysteroscopic metroplasty Hysteroscopic uterine septum resection Pregnancy
a b s t r a c t Objective: To investigate the effects on adhesion formation and pregnancy maintenance of an intrauterine device (IUD) and/or estrogen treatment after hysteroscopic septum resection. Methods: After septum resection 100 women received either no treatment, or estrogens, or an IUD, or an IUD plus estrogens (n = 25 per group). Most were later checked hysteroscopically for uterine cavity adhesions. All pregnancies occurring during the study period were recorded. Results: Adhesions developed in 1 of 19 (5.3%) of the untreated women, 3 of 25 (12%) of the women treated with an IUD plus estrogens, 2 of 19 (10.5%) of the women treated with an IUD only, and none of the women treated with estrogens only. None of the differences, however, were significant. Regarding pregnancy, the differences between groups were also not significant. Conclusion: Neither IUD placement, nor estrogen treatment, nor both were found to prevent intrauterine adhesions or facilitate pregnancy after hysteroscopic uterine septum resection. © 2010 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction A uterine septum is the most commonly encountered congenital müllerian anomaly [1]. Although affected women may be asymptomatic and able to conceive and give birth, a uterine septum frequently leads to habitual abortion and may cause infertility. Uterine septum resection by hysteroscopic metroplasty is fast, efficient, safe, and widely practiced. However, there remains controversy regarding the best way to prevent the postsurgical formation of adhesions. The usefulness of inserting an intrauterine device (IUD), with or without concurrent estrogen treatment, to prevent adhesion formation has been investigated [2,3]. While these methods initially seemed promising, later studies found no benefit in using them [4,5]. However, these studies were retrospective, and they did not evaluate the effects of an IUD alone. We designed a prospective study to investigate the effects of an IUD and/or estrogen treatment after hysteroscopic uterine septum resection. 2. Materials and methods All patients referred to the Infertility Unit of Zekai Tahir Burak Women's Health Research and Education Hospital for spontaneous abortion or infertility between January 1, 2006, and December 31, 2006 were assessed for possible enrollment. Those with a history of abortion were given immunologic, biochemical, and endocrinologic tests as well as genetic tests (chromosome analysis and a test for thrombophilia). All underwent a hysterosalpingographic evaluation ⁎ Corresponding author. Tunali Hilmi Cad. Binnaz sok. No:1/5 Kavaklidere/Ankara 06100, Turkey. E-mail address: [email protected] (E.A. Tonguc).
and those diagnosed as having a uterine septum underwent diagnostic laparoscopy. When no abnormality was detected other than the uterine septum, the patient was asked if she wished to join the study. The protocol and consent forms were approved by the institutional ethics committee. All eligible patients received a detailed description of the hysteroscopic septum resection procedure and gave their written informed consent before they were enrolled. The 100 original participants were aged between 20 and 39 years and wished to have children despite their primary infertility (n = 51) or abortion history (n = 49; of these, 35 had first-trimester and 14 had second-trimester spontaneous abortions). We use a rigid resectoscope (Karl Storz Endoskope, Tuttlingen, Germany) with a lens at a 30° angle. The procedure was performed under general anesthesia, in the early proliferative phase of the menstrual cycle, after administration of 1 g of cefazolin sodium (Cephamezin; Eczacibaşi Baxter, Istanbul, Turkey) as a prophylactic antibiotic. After an 11-mm cervical dilation was achieved, the uterine cavity was distended by means of a 1.5% glycine solution. The septum length was then estimated using the 1.4-cm yellow tip of the electric knife as a reference measure and classified with respect to the uterine length, as follows: less than one-third (n = 14), between one- and two-thirds (n = 31), and more than two-thirds (n = 34). Finally, the septum was resected using a monopolar dissection electrode. A statistician allotted the participants to their postsurgical treatment groups according to their application numbers. The coordinator and the investigators were blinded to treatment allotment. Following septum resection the participants either received no treatment (the control group); or were treated with 2 mg of estradiol valerate and 0.5 mg of norgestrel (Cyclo-prognova; Schering AG, Istanbul, Turkey), once daily for 2 months; or received an IUD (Multiload Cu250; Multilan, Dublin, Ireland); or received both the estrogen
0020-7292/$ – see front matter © 2010 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijgo.2009.12.015
E.A. Tonguc et al. / International Journal of Gynecology and Obstetrics 109 (2010) 226–229
treatment and an IUD. The participants who received an IUD took an oral tablet of doxycycline twice daily for 2 weeks after insertion. We are aware that a Lippes loop IUD may have been more appropriate than an IUD containing copper; however, the only types used in our country are the Copper T and the Multiload Cu250, and the latter contains less copper than the former. The reasons for seeking care were spontaneous abortion (12 participants in the untreated group, 14 in the estrogen only group, 13 in the IUD only group, and 10 in the estrogen plus IUD group) or primary infertility (13, 11, 12, and 15 participants in the corresponding groups). Participants were excluded from the study if they (1) did not report for the follow-up office hysteroscopic examination, (2) did not comply with the estrogen treatment, or (3) had their IUD removed for any reason. Two months after the treatment was initiated, the participants were checked for a residual septum and uterine cavity adhesions by the same gynecologist. This outpatient procedure was performed without any form of anesthesia using a 4-mm, 30°-angled lens Bettocchi hysteroscope system (Karl Storz). A retained septum longer than 1 cm was considered a residual septum and therefore inadequate. Adhesions were classified according to the American Fertility Society classification [6]. The follow-up continued through November 2007, and all new pregnancies occurring during the follow-up period were recorded. When the study ended, only pregnancies of at least 32 weeks' duration were considered; they were recorded as ongoing pregnancies. A power analysis had determined that, to detect a statistical difference between the control group and at least 1 of the study groups with 80% power and a type 1 error of 0.83, the numbers of participants needed in each group were 302 for adhesion rates and 202 participants for pregnancy rates. Since we could not conduct a clinical experiment with a minimum of 1200 participants, we decided to work with the number of patients we could reach within a given time. Data analysis was performed using the statistical package SPSS for Windows (SPSS, Chicago, IL, USA). The Kolmogorov-Smirnov test was used to check age and septum length for normality of distribution. Comparisons between groups were made using the Pearson χ2 test (for age) and analysis of variance (for septum length); and adhesion and pregnancy rates were compared using the Pearson χ2 test or the Fisher exact test. P < 0.05 was considered significant. 3. Results Of the 100 original participants, 21 were excluded: 6 in the control group for not reporting for follow-up; 9 in the estrogen only group (4 for not reporting for follow-up and 5 for discontinuing treatment);
227
and 6 in the IUD only group (2 for not reporting for follow-up and 4 for having their IUD removed because of severe bleeding and pain). No participants in the estrogen plus IUD group were excluded. Thus, 79 participants, 19 in the control group, 16 in the estrogen only group, 19 in the IUD only group, and 25 in the estrogen plus IUD group, were followed up for adhesions and pregnancy and included in the final analysis (Fig. 1). None developed any complications due to hysteroscopy, laparoscopy, or anesthesia. The mean± SD age was 27.13 ± 4.35 years (range, 20–39 years), and the differences between the groups were not significant (P = 0.99). The septum length was one-third, between one-third and two-thirds, and more than two-thirds of the uterine length, respectively, in 14 (17.7%), 31 (39.2%), and 34 (43.0%) of the original participants. The differences in septum length between the groups were not significant (P = 0.99). The follow-up time after surgery lasted from January 2006 through November 2007 and ranged from 10 to 22 months. At the end of November 2007, only the pregnancies with a duration of at least 32 weeks were taken into account. They were recorded as ongoing pregnancies. A retained septum longer than 1 cm was considered a residual septum. On the follow-up hysteroscopic examination, 86.4% of the participants had no residual septum. There were no significant differences between the groups regarding residual septum (P=0.42). The 9 participants with a residual septum underwent a second hysteroscopic resection. Demographic and clinical data are shown in Table 1. Of the 6 cases of adhesion, 5 were grade 1 (filmy adhesions) and 1 was grade 2 (a filmy-dense adhesion). One of these adhesions was in the fundus, 2 were on the resection line between the anterior and posterior walls of the uterus (1 was dense), 1 was anterior to the left tubal ostium, 1 was between the right lateral wall of the uterus and the resection line, and 1 was at the proximal end of the cervical canal. The adhesions were removed by hysteroscopic lysis, the filmy ones by scissor and the dense ones by sharp dissection. The rates of intrauterine adhesion were 1 of 19 (5.3%), 2 of 19 (10.5%), and 3 of 25 (12%), respectively, in the control group, the IUD only group, and the estrogen plus IUD group. There were no adhesions in the estrogen only group. Although the difference in rates between the control group and the estrogen only group was not statistically significant (P = 1.0), an absence of adhesions in the estrogen only group was a striking finding. Similarly, the difference between the control group and the estrogen plus IUD group was not statistically significant (P = 0.06), but fewer adhesions developed in the control group. On the other hand, even though the differences were not statistically significant, the participants in the IUD only and the estrogen plus IUD groups had higher rates of intrauterine adhesions than those in the control or estrogen only groups.
Fig. 1. Patients' flow chart.
228
E.A. Tonguc et al. / International Journal of Gynecology and Obstetrics 109 (2010) 226–229
Table 1 Demographic and clinical characteristics of the original 100 participants.a Characteristic
Postsurgical treatment
Age, y Septum length in relation to length of uterine cavity <1/3 1/3–2/3 >2/3 Follow-up time, mo Length of residual septum, cm a
P value
None (control group) (n = 25)
Estrogen only (n = 25)
IUD only (n = 25)
IUD + estrogen (n = 25)
26.95 ± 4.90
27.25 ± 4.30
27.05 ± 4.66
27.24 ± 3.93
0.99
3 (15.8) 8 (42.1) 8 (42.1) 19.1 ± 2.4 4 (21)
2 (12.5) 7 (43.8) 7 (43.8) 18.2 ± 1.8 2 (12.5)
4 (21.1) 7 (36.8) 8 (42.1) 18.6 ± 2.0 1 (5.3)
5 (20) 9 (36) 11 (44) 18.6 ± 2.1 2 (8)
0.99
0.69 0.42
Values are given as mean ± SD or number (percentage) unless otherwise indicated.
Among the participants who were followed-up, 35 became pregnant and 7 miscarried, 6 during the first trimester and 1 during the 24th week. The pregnancy losses were distributed as follows: 1 in the control group, 1 in the estrogen only group; 2 in the IUD only group, and 3 in the estrogen plus IUD group (Table 2). The distribution of the remaining 28 patients by groups is shown in Table 2. Although the differences between the groups were not statistically significant (P = 0.66), the highest pregnancy rate, 47.4%, was observed in the control group (Table 2). 4. Discussion Hysteroscopic metroplasty is the most widely accepted modality for uterine septum removal. However, sure ways of preventing postsurgical adhesions are still lacking. It is commonly agreed that the optimum timing for the procedure is during the early proliferative period, immediately after menstruation, and that preparing the endometrium preoperatively by administering a gonadotropin-releasing hormone analogue or danazol, a testosterone analogue, is unnecessary [7]. Although an IUD only, estrogen treatment only, or a combination of both have been used for the prevention of intrauterine adhesions, most studies indicate that treating women by these methods after hysteroscopic uterine septum removal is an unwarranted habit passed on from laparatomic metroplasty. In laparotomic metroplasty, an IUD is often placed to prevent the surgical procedure itself or retained suturing material to foster adhesions. In hysteroscopic metroplasty, resection of the septum leaves wide areas free from any endometrial tissue on both the anterior and posterior walls, and the likelihood of developing adhesions between these areas is therefore theoretically high. But studies have demonstrated that these areas are quickly covered by endometrial tissue [2,4], which explains why the development of adhesions after hysteroscopic metroplasty is rare. It should be looked for in postsurgical check-ups, however. In a 2004 study by Guida et al. [8], adhesions were detected in 4 of 16 patients who had undergone hysteroscopic septum resection. It has been suggested that IUDs may promote infertility secondary to clinical or subclinical pelvic infections in women undergoing hysteroscopic metroplasty [9]. A review article reported that the use of IUDs in women without signs of cervical infection did not result in an increase in upper genital infections [10], however, and laboratory
findings consistent with endometritis and salpingitis were not observed after IUD placement in a study of the possible benefits of IUD placement or estrogen treatment following hysteroscopic metroplasty [4]. The rationale behind estrogen use was that it stimulates endometrial development, thus promoting the epithelization of the septal areas [11], but it has been shown that postmenstrual levels of endogenous estradiol are sufficient to induce epithelization [4]. Valle and Sciarra [3] have recommended estrogen treatment but not IUD placement. On the other hand, in a 1989 study by Vercellini et al. [4], 10 of 20 patients who had undergone hysteroscopic septum resection received an IUD and were also treated with estrogens whereas the remaining 10 received no treatment. On follow-up, no adhesions were observed in any of the patients, and the study concluded that the combined IUD and estrogen treatment was unnecessary for the prevention of septal fusion. Assaf et al. [12] evaluated 17 patients postoperatively in a study published in 1990 and also suggested that neither an IUD nor estrogen treatment had any effect on adhesion formation. And in a 1996 study, Dabirashrafi et al. [13] also reported finding no significant role for estrogen treatment after hysteroscopic resection of the septum. Our results are consistent with all these findings. Although no adhesions developed in the estrogen only group, but developed in 5.3% of the participants in the untreated group, the difference was not statistically significant. Similarly, although the differences between all groups were not statically significant, the rate of participants with adhesions was slightly higher in the groups of participants who received IUDs. Pregnancy loss associated with uterine septum usually occurs as spontaneous abortion or premature delivery. Early pregnancy loss is caused by placental ischemia from an avascular septum whereas premature delivery is usually caused by an insufficiently wide uterine cavity. Hysteroscopic metroplasty has helped reduce the rates of spontaneous abortion and premature delivery due to the presence of a uterine septum, and it allows affected women to be delivered vaginally. In 2002, Nawroth et al. [5] investigated cumulative pregnancy rates after IUD placement and/or estrogen use, and found no effect of either on pregnancy. In our study, the differences in ongoing pregnancy rates at the end of the follow-up period were not statistically significant, although the untreated group had the highest pregnancy rate (47%). Although our prospective study included only 100 participants
Table 2 Comparison of outcomes between the groups.a Outcome
Pregnancy Miscarriage
Postsurgical treatment None (control group) (n = 19)
Estrogen only (n = 16)
IUD only (n = 19)
IUD + estrogen (n = 25)
9 (47.4) 1 (5.2)
5 (31.5) 1 (6.25)
6 (31.6) 2 (10.5)
8 (32) 3 (12)
Abbreviation: NS, not significant. a Values are given as number (percentage).
Total (n = 79)
P value
28 (35.4) 7 (8.8)
NS NS
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distributed among 4 groups, it is the highest number of participants and groups in any similar study to date. This larger study verifies the findings of smaller studies, that IUD placement and/or estrogen treatment play no role in the prevention of intrauterine adhesions or the maintenance of pregnancy after hysteroscopic uterine septum resection. Conflict of interest The authors declare that they have no conflict of interest. References [1] March CM, Israel R. Hysteroscopic management of recurrent abortion caused by septate uterus. Am J Obstet Gynecol 1987;156(4):834–42. [2] Israel R, March CM. Hysteroscopic incision of the septate uterus. Am J Obstet Gynecol 1984;149(1):66–73. [3] Valle RF, Sciarra JJ. Hysteroscopic treatment of septate uterus. Obstet Gynecol 1986;67(2):253–7. [4] Vercellini P, Fedele L, Arcaini L, Rognoni MT, Candiani GB. Value of intrauterine device insertion and estrogen administration after hysteroscopic metroplasty. J Reprod Med 1989;34(7):447–50.
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[5] Nawroth F, Schmidt T, Freise C, Foth D, Römer T. Is it possible to recommend an optimal postoperative management after hysteroscopic metroplasty? a retrospective study with 52 infertile patients showing a septate uterus. Acta Obstet Gynecol Scand 2002;81(1):55–7. [6] American Fertility Society. The American Fertility Society classification of adnexal adhesions, distal tubal occlusions secondary to tubal ligation, tubal pregnancy, mullerian anomalies and intrauterine adhesions. Fertil Steril 1988;49:944–55. [7] Römer T, Schmidt T, Foth D. Pre and postoperative hormonal treatment in patients with hysteroscopic surgery. Contrib Gynecol Obstet 2000;20:1–12. [8] Guida M, Acunzo G, Sardo AD, Bifulco G, Piccoli R, Pellicano M, et al. Effectiveness of auto-crosslinked hyaluronic acid gel in the prevention of intrauterine adhesions after hysteroscopic surgery: a prospective, randomized, controlled study. Hum Reprod 2004;19(6):1461–4. [9] Fayez JA. Comparison between abdominal and hysteroscopic metroplasty. Obstet Gynecol 1986;68(3):399–403. [10] Grimes DA. Intrauterine device and upper-genital-tract infection. Lancet 2000;356 (9234):1013–9. [11] Homer HA, Li TC, Cooke ID. The septate uterus: a rewiew of managment and reproductive outcome. Fertil Steril 2000;73(1):1–12. [12] Assaf A, Serour G, Elkady A, El Agizy H. Endoscopic management of the intrauterine septum. Int J Gynecol Obstet 1990;32(1):43–51. [13] Dabirashrafi H, Mohammad K, Moghadami-Tabrizi N, Zandinejad K, MoghadamiTabrizi M. Is estrogen necessary after hysteroscopic incision of the uterine septum? J Am Assoc Gynecol Laparosc 1996;3(4):623–5.
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j g o
CLINICAL ARTICLE
Intrauterine device or estrogen treatment after hysteroscopic uterine septum resection Esra Ayşin Tonguc ⁎, Turgut Var, Nafiye Yilmaz, Sertac Batioglu Department of Reproductive Endocrinology, Zekai Tahir Burak Women's Health Research and Education Hospital, Ankara, Turkey
a r t i c l e
i n f o
Article history: Received 20 October 2009 Received in revised form 11 December 2009 Accepted 14 January 2010 Keywords: Adhesions Estrogen treatment Intrauterine device Hysteroscopic metroplasty Hysteroscopic uterine septum resection Pregnancy
a b s t r a c t Objective: To investigate the effects on adhesion formation and pregnancy maintenance of an intrauterine device (IUD) and/or estrogen treatment after hysteroscopic septum resection. Methods: After septum resection 100 women received either no treatment, or estrogens, or an IUD, or an IUD plus estrogens (n = 25 per group). Most were later checked hysteroscopically for uterine cavity adhesions. All pregnancies occurring during the study period were recorded. Results: Adhesions developed in 1 of 19 (5.3%) of the untreated women, 3 of 25 (12%) of the women treated with an IUD plus estrogens, 2 of 19 (10.5%) of the women treated with an IUD only, and none of the women treated with estrogens only. None of the differences, however, were significant. Regarding pregnancy, the differences between groups were also not significant. Conclusion: Neither IUD placement, nor estrogen treatment, nor both were found to prevent intrauterine adhesions or facilitate pregnancy after hysteroscopic uterine septum resection. © 2010 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction A uterine septum is the most commonly encountered congenital müllerian anomaly [1]. Although affected women may be asymptomatic and able to conceive and give birth, a uterine septum frequently leads to habitual abortion and may cause infertility. Uterine septum resection by hysteroscopic metroplasty is fast, efficient, safe, and widely practiced. However, there remains controversy regarding the best way to prevent the postsurgical formation of adhesions. The usefulness of inserting an intrauterine device (IUD), with or without concurrent estrogen treatment, to prevent adhesion formation has been investigated [2,3]. While these methods initially seemed promising, later studies found no benefit in using them [4,5]. However, these studies were retrospective, and they did not evaluate the effects of an IUD alone. We designed a prospective study to investigate the effects of an IUD and/or estrogen treatment after hysteroscopic uterine septum resection. 2. Materials and methods All patients referred to the Infertility Unit of Zekai Tahir Burak Women's Health Research and Education Hospital for spontaneous abortion or infertility between January 1, 2006, and December 31, 2006 were assessed for possible enrollment. Those with a history of abortion were given immunologic, biochemical, and endocrinologic tests as well as genetic tests (chromosome analysis and a test for thrombophilia). All underwent a hysterosalpingographic evaluation ⁎ Corresponding author. Tunali Hilmi Cad. Binnaz sok. No:1/5 Kavaklidere/Ankara 06100, Turkey. E-mail address: [email protected] (E.A. Tonguc).
and those diagnosed as having a uterine septum underwent diagnostic laparoscopy. When no abnormality was detected other than the uterine septum, the patient was asked if she wished to join the study. The protocol and consent forms were approved by the institutional ethics committee. All eligible patients received a detailed description of the hysteroscopic septum resection procedure and gave their written informed consent before they were enrolled. The 100 original participants were aged between 20 and 39 years and wished to have children despite their primary infertility (n = 51) or abortion history (n = 49; of these, 35 had first-trimester and 14 had second-trimester spontaneous abortions). We use a rigid resectoscope (Karl Storz Endoskope, Tuttlingen, Germany) with a lens at a 30° angle. The procedure was performed under general anesthesia, in the early proliferative phase of the menstrual cycle, after administration of 1 g of cefazolin sodium (Cephamezin; Eczacibaşi Baxter, Istanbul, Turkey) as a prophylactic antibiotic. After an 11-mm cervical dilation was achieved, the uterine cavity was distended by means of a 1.5% glycine solution. The septum length was then estimated using the 1.4-cm yellow tip of the electric knife as a reference measure and classified with respect to the uterine length, as follows: less than one-third (n = 14), between one- and two-thirds (n = 31), and more than two-thirds (n = 34). Finally, the septum was resected using a monopolar dissection electrode. A statistician allotted the participants to their postsurgical treatment groups according to their application numbers. The coordinator and the investigators were blinded to treatment allotment. Following septum resection the participants either received no treatment (the control group); or were treated with 2 mg of estradiol valerate and 0.5 mg of norgestrel (Cyclo-prognova; Schering AG, Istanbul, Turkey), once daily for 2 months; or received an IUD (Multiload Cu250; Multilan, Dublin, Ireland); or received both the estrogen
0020-7292/$ – see front matter © 2010 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijgo.2009.12.015
E.A. Tonguc et al. / International Journal of Gynecology and Obstetrics 109 (2010) 226–229
treatment and an IUD. The participants who received an IUD took an oral tablet of doxycycline twice daily for 2 weeks after insertion. We are aware that a Lippes loop IUD may have been more appropriate than an IUD containing copper; however, the only types used in our country are the Copper T and the Multiload Cu250, and the latter contains less copper than the former. The reasons for seeking care were spontaneous abortion (12 participants in the untreated group, 14 in the estrogen only group, 13 in the IUD only group, and 10 in the estrogen plus IUD group) or primary infertility (13, 11, 12, and 15 participants in the corresponding groups). Participants were excluded from the study if they (1) did not report for the follow-up office hysteroscopic examination, (2) did not comply with the estrogen treatment, or (3) had their IUD removed for any reason. Two months after the treatment was initiated, the participants were checked for a residual septum and uterine cavity adhesions by the same gynecologist. This outpatient procedure was performed without any form of anesthesia using a 4-mm, 30°-angled lens Bettocchi hysteroscope system (Karl Storz). A retained septum longer than 1 cm was considered a residual septum and therefore inadequate. Adhesions were classified according to the American Fertility Society classification [6]. The follow-up continued through November 2007, and all new pregnancies occurring during the follow-up period were recorded. When the study ended, only pregnancies of at least 32 weeks' duration were considered; they were recorded as ongoing pregnancies. A power analysis had determined that, to detect a statistical difference between the control group and at least 1 of the study groups with 80% power and a type 1 error of 0.83, the numbers of participants needed in each group were 302 for adhesion rates and 202 participants for pregnancy rates. Since we could not conduct a clinical experiment with a minimum of 1200 participants, we decided to work with the number of patients we could reach within a given time. Data analysis was performed using the statistical package SPSS for Windows (SPSS, Chicago, IL, USA). The Kolmogorov-Smirnov test was used to check age and septum length for normality of distribution. Comparisons between groups were made using the Pearson χ2 test (for age) and analysis of variance (for septum length); and adhesion and pregnancy rates were compared using the Pearson χ2 test or the Fisher exact test. P < 0.05 was considered significant. 3. Results Of the 100 original participants, 21 were excluded: 6 in the control group for not reporting for follow-up; 9 in the estrogen only group (4 for not reporting for follow-up and 5 for discontinuing treatment);
227
and 6 in the IUD only group (2 for not reporting for follow-up and 4 for having their IUD removed because of severe bleeding and pain). No participants in the estrogen plus IUD group were excluded. Thus, 79 participants, 19 in the control group, 16 in the estrogen only group, 19 in the IUD only group, and 25 in the estrogen plus IUD group, were followed up for adhesions and pregnancy and included in the final analysis (Fig. 1). None developed any complications due to hysteroscopy, laparoscopy, or anesthesia. The mean± SD age was 27.13 ± 4.35 years (range, 20–39 years), and the differences between the groups were not significant (P = 0.99). The septum length was one-third, between one-third and two-thirds, and more than two-thirds of the uterine length, respectively, in 14 (17.7%), 31 (39.2%), and 34 (43.0%) of the original participants. The differences in septum length between the groups were not significant (P = 0.99). The follow-up time after surgery lasted from January 2006 through November 2007 and ranged from 10 to 22 months. At the end of November 2007, only the pregnancies with a duration of at least 32 weeks were taken into account. They were recorded as ongoing pregnancies. A retained septum longer than 1 cm was considered a residual septum. On the follow-up hysteroscopic examination, 86.4% of the participants had no residual septum. There were no significant differences between the groups regarding residual septum (P=0.42). The 9 participants with a residual septum underwent a second hysteroscopic resection. Demographic and clinical data are shown in Table 1. Of the 6 cases of adhesion, 5 were grade 1 (filmy adhesions) and 1 was grade 2 (a filmy-dense adhesion). One of these adhesions was in the fundus, 2 were on the resection line between the anterior and posterior walls of the uterus (1 was dense), 1 was anterior to the left tubal ostium, 1 was between the right lateral wall of the uterus and the resection line, and 1 was at the proximal end of the cervical canal. The adhesions were removed by hysteroscopic lysis, the filmy ones by scissor and the dense ones by sharp dissection. The rates of intrauterine adhesion were 1 of 19 (5.3%), 2 of 19 (10.5%), and 3 of 25 (12%), respectively, in the control group, the IUD only group, and the estrogen plus IUD group. There were no adhesions in the estrogen only group. Although the difference in rates between the control group and the estrogen only group was not statistically significant (P = 1.0), an absence of adhesions in the estrogen only group was a striking finding. Similarly, the difference between the control group and the estrogen plus IUD group was not statistically significant (P = 0.06), but fewer adhesions developed in the control group. On the other hand, even though the differences were not statistically significant, the participants in the IUD only and the estrogen plus IUD groups had higher rates of intrauterine adhesions than those in the control or estrogen only groups.
Fig. 1. Patients' flow chart.
228
E.A. Tonguc et al. / International Journal of Gynecology and Obstetrics 109 (2010) 226–229
Table 1 Demographic and clinical characteristics of the original 100 participants.a Characteristic
Postsurgical treatment
Age, y Septum length in relation to length of uterine cavity <1/3 1/3–2/3 >2/3 Follow-up time, mo Length of residual septum, cm a
P value
None (control group) (n = 25)
Estrogen only (n = 25)
IUD only (n = 25)
IUD + estrogen (n = 25)
26.95 ± 4.90
27.25 ± 4.30
27.05 ± 4.66
27.24 ± 3.93
0.99
3 (15.8) 8 (42.1) 8 (42.1) 19.1 ± 2.4 4 (21)
2 (12.5) 7 (43.8) 7 (43.8) 18.2 ± 1.8 2 (12.5)
4 (21.1) 7 (36.8) 8 (42.1) 18.6 ± 2.0 1 (5.3)
5 (20) 9 (36) 11 (44) 18.6 ± 2.1 2 (8)
0.99
0.69 0.42
Values are given as mean ± SD or number (percentage) unless otherwise indicated.
Among the participants who were followed-up, 35 became pregnant and 7 miscarried, 6 during the first trimester and 1 during the 24th week. The pregnancy losses were distributed as follows: 1 in the control group, 1 in the estrogen only group; 2 in the IUD only group, and 3 in the estrogen plus IUD group (Table 2). The distribution of the remaining 28 patients by groups is shown in Table 2. Although the differences between the groups were not statistically significant (P = 0.66), the highest pregnancy rate, 47.4%, was observed in the control group (Table 2). 4. Discussion Hysteroscopic metroplasty is the most widely accepted modality for uterine septum removal. However, sure ways of preventing postsurgical adhesions are still lacking. It is commonly agreed that the optimum timing for the procedure is during the early proliferative period, immediately after menstruation, and that preparing the endometrium preoperatively by administering a gonadotropin-releasing hormone analogue or danazol, a testosterone analogue, is unnecessary [7]. Although an IUD only, estrogen treatment only, or a combination of both have been used for the prevention of intrauterine adhesions, most studies indicate that treating women by these methods after hysteroscopic uterine septum removal is an unwarranted habit passed on from laparatomic metroplasty. In laparotomic metroplasty, an IUD is often placed to prevent the surgical procedure itself or retained suturing material to foster adhesions. In hysteroscopic metroplasty, resection of the septum leaves wide areas free from any endometrial tissue on both the anterior and posterior walls, and the likelihood of developing adhesions between these areas is therefore theoretically high. But studies have demonstrated that these areas are quickly covered by endometrial tissue [2,4], which explains why the development of adhesions after hysteroscopic metroplasty is rare. It should be looked for in postsurgical check-ups, however. In a 2004 study by Guida et al. [8], adhesions were detected in 4 of 16 patients who had undergone hysteroscopic septum resection. It has been suggested that IUDs may promote infertility secondary to clinical or subclinical pelvic infections in women undergoing hysteroscopic metroplasty [9]. A review article reported that the use of IUDs in women without signs of cervical infection did not result in an increase in upper genital infections [10], however, and laboratory
findings consistent with endometritis and salpingitis were not observed after IUD placement in a study of the possible benefits of IUD placement or estrogen treatment following hysteroscopic metroplasty [4]. The rationale behind estrogen use was that it stimulates endometrial development, thus promoting the epithelization of the septal areas [11], but it has been shown that postmenstrual levels of endogenous estradiol are sufficient to induce epithelization [4]. Valle and Sciarra [3] have recommended estrogen treatment but not IUD placement. On the other hand, in a 1989 study by Vercellini et al. [4], 10 of 20 patients who had undergone hysteroscopic septum resection received an IUD and were also treated with estrogens whereas the remaining 10 received no treatment. On follow-up, no adhesions were observed in any of the patients, and the study concluded that the combined IUD and estrogen treatment was unnecessary for the prevention of septal fusion. Assaf et al. [12] evaluated 17 patients postoperatively in a study published in 1990 and also suggested that neither an IUD nor estrogen treatment had any effect on adhesion formation. And in a 1996 study, Dabirashrafi et al. [13] also reported finding no significant role for estrogen treatment after hysteroscopic resection of the septum. Our results are consistent with all these findings. Although no adhesions developed in the estrogen only group, but developed in 5.3% of the participants in the untreated group, the difference was not statistically significant. Similarly, although the differences between all groups were not statically significant, the rate of participants with adhesions was slightly higher in the groups of participants who received IUDs. Pregnancy loss associated with uterine septum usually occurs as spontaneous abortion or premature delivery. Early pregnancy loss is caused by placental ischemia from an avascular septum whereas premature delivery is usually caused by an insufficiently wide uterine cavity. Hysteroscopic metroplasty has helped reduce the rates of spontaneous abortion and premature delivery due to the presence of a uterine septum, and it allows affected women to be delivered vaginally. In 2002, Nawroth et al. [5] investigated cumulative pregnancy rates after IUD placement and/or estrogen use, and found no effect of either on pregnancy. In our study, the differences in ongoing pregnancy rates at the end of the follow-up period were not statistically significant, although the untreated group had the highest pregnancy rate (47%). Although our prospective study included only 100 participants
Table 2 Comparison of outcomes between the groups.a Outcome
Pregnancy Miscarriage
Postsurgical treatment None (control group) (n = 19)
Estrogen only (n = 16)
IUD only (n = 19)
IUD + estrogen (n = 25)
9 (47.4) 1 (5.2)
5 (31.5) 1 (6.25)
6 (31.6) 2 (10.5)
8 (32) 3 (12)
Abbreviation: NS, not significant. a Values are given as number (percentage).
Total (n = 79)
P value
28 (35.4) 7 (8.8)
NS NS
E.A. Tonguc et al. / International Journal of Gynecology and Obstetrics 109 (2010) 226–229
distributed among 4 groups, it is the highest number of participants and groups in any similar study to date. This larger study verifies the findings of smaller studies, that IUD placement and/or estrogen treatment play no role in the prevention of intrauterine adhesions or the maintenance of pregnancy after hysteroscopic uterine septum resection. Conflict of interest The authors declare that they have no conflict of interest. References [1] March CM, Israel R. Hysteroscopic management of recurrent abortion caused by septate uterus. Am J Obstet Gynecol 1987;156(4):834–42. [2] Israel R, March CM. Hysteroscopic incision of the septate uterus. Am J Obstet Gynecol 1984;149(1):66–73. [3] Valle RF, Sciarra JJ. Hysteroscopic treatment of septate uterus. Obstet Gynecol 1986;67(2):253–7. [4] Vercellini P, Fedele L, Arcaini L, Rognoni MT, Candiani GB. Value of intrauterine device insertion and estrogen administration after hysteroscopic metroplasty. J Reprod Med 1989;34(7):447–50.
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[5] Nawroth F, Schmidt T, Freise C, Foth D, Römer T. Is it possible to recommend an optimal postoperative management after hysteroscopic metroplasty? a retrospective study with 52 infertile patients showing a septate uterus. Acta Obstet Gynecol Scand 2002;81(1):55–7. [6] American Fertility Society. The American Fertility Society classification of adnexal adhesions, distal tubal occlusions secondary to tubal ligation, tubal pregnancy, mullerian anomalies and intrauterine adhesions. Fertil Steril 1988;49:944–55. [7] Römer T, Schmidt T, Foth D. Pre and postoperative hormonal treatment in patients with hysteroscopic surgery. Contrib Gynecol Obstet 2000;20:1–12. [8] Guida M, Acunzo G, Sardo AD, Bifulco G, Piccoli R, Pellicano M, et al. Effectiveness of auto-crosslinked hyaluronic acid gel in the prevention of intrauterine adhesions after hysteroscopic surgery: a prospective, randomized, controlled study. Hum Reprod 2004;19(6):1461–4. [9] Fayez JA. Comparison between abdominal and hysteroscopic metroplasty. Obstet Gynecol 1986;68(3):399–403. [10] Grimes DA. Intrauterine device and upper-genital-tract infection. Lancet 2000;356 (9234):1013–9. [11] Homer HA, Li TC, Cooke ID. The septate uterus: a rewiew of managment and reproductive outcome. Fertil Steril 2000;73(1):1–12. [12] Assaf A, Serour G, Elkady A, El Agizy H. Endoscopic management of the intrauterine septum. Int J Gynecol Obstet 1990;32(1):43–51. [13] Dabirashrafi H, Mohammad K, Moghadami-Tabrizi N, Zandinejad K, MoghadamiTabrizi M. Is estrogen necessary after hysteroscopic incision of the uterine septum? J Am Assoc Gynecol Laparosc 1996;3(4):623–5.