Spontaneous pregnancy rates after reproductive surgery

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Article

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Spontaneous pregnancy rates after reproductive surgery

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Helena Ban Frangez *, Sara Korošec, Barbara Pozlep, Nina Jancar, Vesna Salamun, Andrej Vogler, Tanja Burnik Papler, Tea Terezija Cvetko, Eda Vrtacnik Bokal Department of Human Reproduction, Division of Gynaecology, University Medical Center Ljubljana, Slajmerjeva 3, Slovenia

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Helena Ban Frangez, MD, PhD, is an Associate Professor at the Department of Human Reproduction, University Medical Centre Ljubljana, where she performs endoscopic surgical procedures to investigate infertility and benign gynaecological pathology on a daily basis as well as IVF procedures. She works at the outpatient unit for endometriosis and operates on women with deep infiltrating endometriosis. Her main areas of interests are uterine anomalies, on which she has published numerous manuscripts, and endometriosis.

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KEY MESSAGE Spontaneous pregnancy rates after reproductive surgery are relatively high, and therefore the role of surgery in the treatment of infertility should be re-evaluated.

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A B S T R A C T

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With the development of IVF procedures, the role of reproductive surgery in the management of infertile couples has been questioned. Pregnancy rates (PR) after IVF procedures are well known, but recent data on spontaneous PR after reproductive surgery are scarce. This study aimed to prospectively evaluate how often fertility is restored by reproductive surgery and to identify which independent factors influence spontaneous pregnancy after reproductive surgery. Eight hundred eighty-eight infertile women who underwent surgery for infertility were prospectively included. Women who were referred to IVF after surgery, ceased to plan pregnancy and were lost to follow-up were excluded. Spontaneous PR was analysed for 519 women. A total of 252 (48.6%) women, including 30 treated with clomiphene citrate, conceived spontaneously in the 12–18 months observation period following surgery. Multivariate logistic regression showed that woman’s age (OR 0.95, 95% CI 0.90–0.99) and duration of infertility (OR 0.86, 95% CI 0.74–0.99) significantly influence spontaneous PR. Each year of infertility lowers spontaneous PR following surgery by 14% and each year of woman’s age by 5%. The study shows a relatively high percentage of women conceived spontaneously after reproductive surgery. The role of reproductive surgery in the management of infertility should be re-evaluated. © 2017 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

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* Corresponding author. E-mail address: [email protected] (H Ban Frangez). http://dx.doi.org/10.1016/j.rbmo.2017.05.007 1472-6483/© 2017 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. Please cite this article in press as: Helena Ban Frangez, et al., Spontaneous pregnancy rates after reproductive surgery, Reproductive BioMedicine Online (2017), doi: 10.1016/ j.rbmo.2017.05.007

ARTICLE IN PRESS REPRODUCTIVE BIOMEDICINE ONLINE ■■ (2017) ■■–■■

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Introduction

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Counselling an infertile couple starts with a careful medical history, semen analysis, transvaginal ultrasound, serum hormone concentration analysis and sometimes a tubal patency test. After the results of these tests are known, a decision is made whether to refer the woman to reproductive surgery or to advise the couple to progress to an assisted reproductive technique. Until a few years ago, endoscopic surgical procedures were considered a gold standard for infertility investigation as they are minimally invasive and serve as a diagnostic and therapeutic method at the same time (Yanamandra and Gundabattula, 2015). They can be used as a primary treatment of infertility as well as to enhance outcomes in IVF procedures. However, with the development of IVF procedures, the role of reproductive surgery has been questioned (Erel and Senturk, 2005; Feinberg et al., 2008). There is an opinion that investigations of infertile couples should be fast and cheap (Gomel and McComb, 2010) and therefore, reproductive surgery should only be performed as an initial part of infertility evaluation in cases where there is a suspicion of underlying gynaecological pathology according to the woman’s history and initial examination (Bosteels et al., 2007). On the other hand, it has been reported that careful selection of patients for reproductive surgery enables couples to conceive spontaneously and yields high cumulative pregnancy rates (PR) (Gordts, 2013). Pregnancy rates after IVF procedures are well known because European IVF centres report them to European IVF Monitoring (EIM). At our department, verifying PR after IVF procedures several times a year has become part of the routine. We believe this approach is necessary for maintaining the quality of the IVF programme. Analysing PR after IVF procedures is relatively easy in comparison to analysing spontaneous PR after surgery for infertility. In an IVF programme, the feedback information comes back after 2–3 weeks, whereas after reproductive surgery the time period is measured in months or years in cases where spontaneous conception is expected. Pregnancy rates after reproductive surgery are usually known for groups of patients with particular diagnosis, for example different stages of endometriosis, polycystic ovary syndrome (PCOS) or unexplained infertility (Lee et al., 2013; Shimizu et al., 2011; Yanamandra and Gundabattula, 2015). Taking into account the longer expectation period for feedback information, it is understandable that analyses considering spontaneous PR after reproductive surgery are usually retrospective and include a relatively small number of patients. Continuous monitoring of IVF success rates on the one hand and a lack of continuous verification of pregnancy rates after surgery for infertility on the other hand has led us to design a computerized database that enables periodic verification of PR after reproductive surgery. The database contains a meticulous medical history, preoperative clinical assessment, detailed description of the performed surgical procedure and operative diagnosis; these are all recorded at the time of surgery. Pregnancy data are added to the database after a 12–18-month observation period. The database therefore enables us to verify surgical work as part of quality control management. In our institution, a woman is referred directly to IVF only if there is an obvious indication for IVF such as male factor of infertility, inoperable bilateral tubal factor and the need for preimplantation genetic diagnosis. Women aged 38 years or over can decide for IVF without previous diagnostic laparoscopy if an ultrasound scan shows no pathology that indicates operative treatment. Women younger than 38 years are always referred to diagnostic laparoscopy, despite a normal

ultrasound scan and normal partner’s semen analysis. In case of previous spontaneous abortions or ultrasound suspicious for intrauterine pathology, hysteroscopy is performed as part of the same operative procedure. The aim of the present analysis was to prospectively evaluate how often fertility is restored by reproductive surgery alone and how many couples still need to be referred to an IVF programme. Furthermore, this study aimed to identify which parameters best predict spontaneous PR after reproductive surgery.

103 104 105 106 107 108 109 110 111

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Materials and methods

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Computerized database

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Some data that are prospectively collected include:

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– general patient information (patient’s name, date of birth, address, phone and e-mail, body weight and height) – medical history (chronic illnesses, previous non-gynaecological surgical procedures) – gynaecological history (previous pregnancies with outcomes, menstrual cycle, gynaecological ultrasound, previous surgical procedures) – duration of infertility, semen and hormone analysis, results of a tubal patency test if performed, previous IVF cycles or treatment with clomiphene citrate, previous use of hormone therapy – data about the performed operative procedure according to the diagnosis: – fibroids: number, location, size of fibroid(s) and type of operation – endometriosis: peritoneal, ovarian (unilateral or bilateral and size of endometriomas), deep infiltrating endometriosis (DIE), rAFS Q3 stage (ASRM, 1996) and Enzian stage for DIE (Haas et al., 2011) Q4 – tubal factor: status of each tube (classified using rAFS classifiQ5 cation; ASRM, 1988) and procedure performed – PCOS: with performance of laparoscopic ovarian drilling – ovarian cysts (excluding endometrioma):size and histological type – congenital uterine anomalies (classified using rAFS classification; ASRM, 1988) and procedure performed – endometrial polyps: size and number – intrauterine adhesions with stage of Asherman’s syndrome – other (descriptional)

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Patients Between June 2012 and December 2013, 888 patients were operated due to infertility at the Department of Human Reproduction, Division of Obstetrics and Gynaecology, University Medical Centre Ljubljana, Slovenia. After the procedure, the woman’s potential for spontaneous conception was evaluated; patients where spontaneous conception was not expected (male factor infertility, bilateral tubal damage, the need for preimplantation genetic diagnostic) were referred directly to IVF. Out of 888 operated women, 238 were immediately referred to IVF. This group of women consisted of those with an additional male factor of infertility (n = 140), bilateral tubal damage (n = 47) and women who already had previous unsuccessful IVF and pathology that demanded surgical treatment prior to the next IVF was seen on ultrasound (intracavitary fibroids, polyps, sactosalpinx) (n = 51). Among

Please cite this article in press as: Helena Ban Frangez, et al., Spontaneous pregnancy rates after reproductive surgery, Reproductive BioMedicine Online (2017), doi: 10.1016/ j.rbmo.2017.05.007

146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161

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162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202

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Table 2 – Group description: preoperative diagnostic procedures and treatments. Tubal patency test n (%)

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Previous CC treatment n (%)

Group (n)

Normal

Tubal pathology suspected

Not performed

Yes

Diagnostic laparoscopy (152) Endometriosis mild – moderate (104) Endometriosis severe (70) Intramural fibroids (26) PCOS (51) Tubal factor – unilateral (27) Tubal factor – bilateral (41) Miscellaneous (48) Total (519)

54 35 13 7 15 3 1 8 136

0 1 6 1 1 9 10 3 31

98 68 51 18 35 15 30 37 352

32 27 9 3 41 6 13 5 136

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3

(35.5) (33.7) (18.6) (26.9) (29.4) (11.1) (2.4) (16.7) (26.2)

(0) (1.0) (8.6) (3.8) (2) (33.3) (24.4) (6.3) (6.0)

(64.5) (65.4) (72.9) (69.2) (68.6) (55.6) (73.2) (77.1) (67.8)

Previous laparoscopy

Previous hysteroscopy

12 9 14 7 2 9 7 12 72

6 2 2 3 3 1 1 1 19

No (21.1) (26) (12.9) (11.5) (80.4) (22.2) (31.7) (10.4) (26.2)

120 77 61 23 10 21 28 43 383

(78.9) (74) (87.1) (88.5) (19.6) (77.8) (68.3) (89.6) (73.8)

CC = clomiphene citrate; PCOS = polycystic ovary syndrome.

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the remaining 650 women, 65 (10%) ceased to plan pregnancy and 66 women (10.2%) were lost from follow-up. Pregnancy rates and surgical data were analysed for 519 women who tried to conceive spontaneously after the surgical procedure. The observation period was 12–18 months. All patients signed an informed consent prior to the surgical procedure allowing their data to be collected and analysed for the purposes of this study. The study did not have to be notified in the Ethics Committee according to the Slovene law, as it was entirely a register based study where all participants signed individual personal approval and permission (Personal Data Protection Act, Official Gazette of the Republic of Slovenia No 94/07, 2004). The flow diagram of patient selection is presented in Figure 1. Data about pregnancies and/or deliveries after the surgical procedure were obtained from the National Perinatal Information System, the IVF database at our department, by e-mail or by phone. All 519 included women had undergone laparoscopy, with hysteroscopy performed at the same time in 314 women. Women were divided to subgroups according to operative diagnosis. Some diagnoses were merged due to small subgroups:

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Diagnostic laparoscopy (n = 152) – women with diagnostic laparoscopy (n = 126), removal of subserous or intraligamentary fibroids

(n = 14) and removal of benign unilateral ovarian cysts (excluding endometriotic cysts) (n = 12). Endometriosis was divided into mild to moderate – AFS stage I and II (n = 104) – and severe endometriosis (AFS stage III and IV) (n = 70). Intramural fibroids (n = 26) – women with intramural fibroids between 2 and 8 cm in diameter that were removed. Thirteen women had a single fibroid and 13 had multiple fibroids. PCOS (n = 51) – anovulatory women with PCOS in whom ovarian drilling was performed. Tubal factor – unilateral (n = 27) – women with one normal tube and one damaged tube before surgery. Tubal factor – bilateral (n = 41) – women with both tubes affected before surgery, with at least one surgically repaired. Miscellaneous (n = 48) – women with more than one diagnosis; usually a combination of endometriosis, fibroids and adhesions.

205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228

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Data considering average age, duration of infertility and primary/ secondary infertility ratio in the subgroups are presented in Table 1. Preoperative diagnostic procedures and treatments are presented in Table 2. Data about previous pregnancies were as follows: 71 deliveries, 40 terminations of pregnancies, 163 spontaneous miscarriages and 11 ectopic pregnancies. Operative procedures that were performed in 519 women are presented in Table 3.

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229 888 women operated due to infertility Referred to IVF program (n = 238) male factor (n = 140) IVF bilateral tubal factor (n = 47) IVF failure (n = 51)

203

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650 women (73.2%) where natural conception was expected Not planning pregnancy after operation (n = 65) Lost from follow-up (n = 66) 519 women included in the study

204

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Table 1 – Group description: basic data.

Figure 1 – Flow diagram of patient selection.

Group (n)

Diagnostic laparoscopy (152) Endometriosis mild – moderate (104) Endometriosis severe (70) Intramural fibroids (26) PCOS (51) Tubal factor – unilateral (27) Tubal factor – bilateral (41) Miscellaneous (48) Total (519)

Woman’s age mean (SD)

Years of planning pregnancy mean (SD)

Primary infertility n (%)

31.4 (4.4) 30.5 (3.4)

2.2 (1.2) 2.2 (1.2)

101 (66.4) 81 (77.9)

31 35.4 28.7 30.7 31 31.7 31.1

2.3 2.5 2.3 2.1 2.4 2 2.2

57 16 42 15 30 25 367

(4.2) (3.8) (4.6) (3.6) (4.4) (4.7) (4.3)

(1.1) (1.3) (1.3) (0.6) (1.3) (1.0) (1.2)

(81.4) (61.5) (82.4) (55.6) (73.2) (52.1) (70.7)

PCOS = polycystic ovary syndrome; SD = standard deviation.

Please cite this article in press as: Helena Ban Frangez, et al., Spontaneous pregnancy rates after reproductive surgery, Reproductive BioMedicine Online (2017), doi: 10.1016/ j.rbmo.2017.05.007

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248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309

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Table 3 – Description of performed reproductive surgical procedures in infertile patients. Group (n)

Laparoscopya (n)

Hysteroscopy (n)

Diagnostic laparoscopy (152)

Diagnostic laparoscopy (126) Removal of subserous or intraligamentary fibroids (14) Removal of unilateral ovarian cysts (excluding endometriomas) (12)

Endometriosis mild – moderate (104)

Electrocoagulation or excision of peritoneal endometriosis (104) Enucleation of endometrioma <3 cm (17)

Endometriosis severe (70)

Removal of unilateral or bilateral endometrioma (62) Salpingo ovariolysis due to endometriotic adhesions (28) Excision of endometriotic nodule in the bladder (1) Ureterolysis (2) Excision of endometriotic nodule from sacrouterine ligaments (4) Segmental resection of rectosigmae (3) Excision (shaving) of endometriotic nodule from rectovaginal septum (2) Removal of single intramural fibroid between 2–8 cm (13) Removal of multiple intramural fibroids (13)

Diagnostic (14) Resection of small septum (43) Resection of large septum (32) Other operative hysteroscopyb (7) Diagnostic (6) Resection of small septum (35) Resection of large septum (13) Other operative hysteroscopyb (4) Diagnostic (3) Resection of small septum (16) Resection of large septum (9) Other operative hysteroscopyb (4)

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Intramural fibroids (26)

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PCOS (51)

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Tubal factor – unilateral (27)

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Laparoscopic ovarian drilling (51) Removal of mild peritoneal endometriosis (1) Fimbrioplasty due to unilateral distal subocclusion of the tube (1) Removal of subserosal fibroid (1) Unilateral neostomy and eversion with sutures (2) or with bipolar electrocoagulation (1) Unilateral salpingectomy (15) Previous salpingectomy due to ectopic pregnancy (9)

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Tubal factor – bilateral (41)

Bilateral neostomy with sutures (3) Unilateral salpingectomy and contralateral neostomy (38)

Miscellaneous (48)

Endometriosis and additional intramural or submucous fibroids (12) Endometriosis and severe damage of at least one tube (28) Severe adhesions of one tube and additional intramural or submucous fibroids (8)

Total (519)

519

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Diagnostic (1) Resection of small septum (4) Resection of large septum (3) Other operative hysteroscopyb (3) Diagnostic (1) Resection of small septum (19) Resection of large septum (9) Other operative hysteroscopyb (5) Diagnostic (1) Resection of small septum (10) Resection of large septum (5) Other operative hysteroscopyb (2) Diagnostic (1) Resection of small septum (13) Resection of large septum (8) Other operative hysteroscopyb (2) Diagnostic (3) Resection of small septum (23) Resection of large septum (11) Other operative hysteroscopyb (4) 314

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Some women had more than one pathology found and corrected at laparoscopy. b Other operative hysteroscopy: removal of submucous fibroids, polyps or synechiae. PCOS = polycystic ovary syndrome.

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Statistical analysis

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Multivariate logistic regression was used to identify independent parameters for PR. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated with two-sided probability (P) values, where a P-value of <0.05 was considered as significant. Statistical analysis was performed using IBM SPSS Statistics, version 20 (IBM Corp., Armonk, NY).

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Results

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The average age of women included in the study was 31.1 ± 4.3 years. There were 367 (70.7%) women with primary infertility and 152 with secondary infertility. Duration of infertility ranged from 1–7 years (average 2.28 ± 1.04 years) in the primary infertility group and 1–8 years (average 2.13 ± 1.08 years) in the secondary infertility group. After reproductive surgery, the percentage of women who conceived spontaneously and with the use of clomiphene citrate in the

12–18-month period ranged from 34.1% to 62.7%. Spontaneous PR after surgery for all subgroups are presented in Table 4. Spontaneous PR after reproductive surgery presented as Life Table Analysis are shown in Supplemental Figure S1. The last two columns of Table 4 show adjusted P and OR for hysteroscopy, secondary infertility, age and duration of infertility. After adjustments, the bilateral tubal factor group showed significantly lower PR compared with the diagnostic group (adjusted P = 0.042; adjusted OR 0.49 [95%CI 0.25–0.97]). All other groups have PR comparable to the diagnostic group. Pathology that was found and removed/corrected at laparoscopy was not the only parameter that influenced postoperative PR. The impact of other parameters is presented in Table 5. Women who failed to conceive 12 months after the reproductive surgery (n = 279) were advised to undergo an IVF procedure or ovarian stimulation with clomiphene citrate. Pregnancy rates of 205 women who chose to undergo IVF procedures are presented in Table 6. A comparison of PR in the subgroups in the IVF programme revealed that the intramural fibroid group and unilateral tubal damage group have PR comparable to the diagnostic laparoscopy group. The endometriosis group, including mild to moderate

Please cite this article in press as: Helena Ban Frangez, et al., Spontaneous pregnancy rates after reproductive surgery, Reproductive BioMedicine Online (2017), doi: 10.1016/ j.rbmo.2017.05.007

310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329

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330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389

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Table 4 – Pregnancy rates in natural or clomiphene-citrate-stimulated cycles in each subgroup 12–18 months after reproductive surgery. Group (n)

Spontaneous conception (n) + ovarian stimulation with CC (n)

Total n (%)

OR (95% CI)

Adjusteda OR

Diagnostic laparoscopy (152) Endometriosis mild-moderate (104) Endometriosis severe (70) Intramural fibroid (26) PCOS (51) Tubal factor – unilateral (27) Tubal factor – bilateral (41) Miscellaneous (48) Total

71 44 30 10 24 12 12 19 222

77 50 34 10 32 15 14 20 252

1 0.90 0.92 0.61 1.60 1.2 0.51 0.70 –

– 1.10 1.30 0.89 1.90 1.10 0.49 0.54 –

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5

+ + + + + + + + +

6 6 4 0 8 3 2 1 30

(50.7) (48.1) (48.6) (38.5) (62.7) (55.6) (34.1) (41.7) (48.6)

(0.55–1.5) (0.52–1.6) (0.26–1.4) (0.86–3.1) (0.54–2.8) (0.25–1.0) (0.36–1.3)

(0.63–1.8) (0.71–2.4) (0.35–2.2) (0.93–3.8) (0.47–2.7) (0.25–0.97)b (0.26–1.1)

CC = clomiphene citrate; CI =confidence interval; OR = odds ratio; PCOS = polycystic ovary syndrome. a Combined model adjusted for hysteroscopy, secondary infertility, age and duration of infertility. b Adjusted P-value is 0.042.

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(P = 0.001) and severe cases (P = 0.041), the PCOS group (P = 0.034), the bilateral tubal damage group (P = 0.003) and the miscellaneous group (P < 0.001) showed significantly higher PR compared with the diagnostic laparoscopy group. These differences remained significant after adjustment for secondary infertility and duration of infertility and were as follows: mild – moderate endometriosis (adj P < 0.001), severe endometriosis (adj P = 0.013), PCOS (adj P = 0.009), bilateral tubal factor (adj P = 0.001), miscellaneous (adj P = 0.001). The

impact of other parameters influencing PR in IVF patients is presented in Table 7.

Discussion This study presents the results of the first prospective analysis of PR after reproductive surgery since the introduction of a computerized database at our Department of Human Reproduction. Women under 38 years of age who have no obvious indication for immediate referral to an IVF programme are routinely referred to a diagnostic or operative endoscopic surgical procedure. In the group of 519 women that had undergone surgery for infertility, 222 (42.8%) conceived spontaneously and 30 (5.8%) conceived with the use of clomiphene citrate 12–18 months after surgery. Of the 279 women who did not conceive 12 months after surgery, 205 underwent IVF treatment resulting in an additional 91 (44.4%) pregnancies in the 12–18-month follow-up period. Since pathology is very different, patients were divided into subgroups according to the pathology established at laparoscopy. Due to the low number of women, some subgroups were merged where this was not expected to importantly influence the results (Table 3). It has been shown that the presence of subserous or intraligamentary

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Table 5 – Multivariate logistic regression for parameters influencing natural conception after reproductive surgery. Parameter – general data

OR

95% CI

P-value

Age Secondary infertility BMI <20 BMI 20–24.99 BMI 25–29.99 BMI ≥30 Duration of infertility Hysteroscopy performed with laparoscopy

0.95 2.07 1 1.16 0.94 1.44 0.86 1.60

0.90–0.99 1.37–3.13

0.031 0.001

0.73–1.84 0.52–1.68 0.70–2.94 0.74–0.99 1.20–2.71

NS NS NS 0.037 0.035

394 395

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BMI – body mass index, CI =confidence interval; NS–not statistically significant; OR = odds ratio.

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Table 6 – Pregnancy rates in women who failed to conceive spontaneously 12 months after reproductive surgery and subsequently underwent IVF procedures. Group (No. of women treated with IVF)

No. of cycles

PR per cycle (%)

Cumulative PR n (%)

Diagnostic laparoscopy (58) Endometriosis mild-moderate (43) Endometriosis severe (28) Intramural fibroid (8) PCOS (15) Tubal factor –unilateral (10) Tubal factor –bilateral (20) Miscellaneous (23) Total (205)

91 70 40 12 25 14 28 35

15.4 34.3 27.5 25.0 32.0 28.6 39.3 45.7

14 24 11 3 8 4 11 16 91

(24.1) (55.8) (39.3) (37.5) (53.3) (40.0) (55.0) (69.6) (44.4)

P-value

OR (95% CI)

Adjusted P-valuea

Adjusteda OR

0.001 0.041 NS 0.034 NS 0.003 <0.001

1 4.0 2.9 2.4 3.6 2.5 5.8 9.4

0.003 <0.001 0.013 NS 0.009 NS 0.001 0.001

5.6 4.1 4.1 5.5 3.3 7.5 8.9

(1.7–9.3) (1.0–8.0) (0.47–11.8) (1.1–11.7) (0.59–10.7) (1.8–18.4) (2.9–30.6)

(2.2–13.9) (1.3–12.3) (0.7–23.5) (1.5–20.1) (0.7–15.5) (2.2–25.9) (2.6–30.7)

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390 391 392 393

Combined model adjusted for secondary infertility and duration of infertility. CI =confidence interval; NS = not statistically significant; OR = odds ratio; PCOS = polycystic ovary syndrome; PR = pregnancy rate.

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Please cite this article in press as: Helena Ban Frangez, et al., Spontaneous pregnancy rates after reproductive surgery, Reproductive BioMedicine Online (2017), doi: 10.1016/ j.rbmo.2017.05.007

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396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412

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Table 7 – Multivariate logistic regression for parameters influencing PR in IVF procedure. Parameter – general data

OR

95% CI

P-value

Age Secondary infertility Duration of infertility Hysteroscopy performed with laparoscopy

0.96 2.49 0.81 1.51

0.90–1.03 1.18–5.25 0.74–0.99 0.82–2.66

NS 0.017 0.043 NS

CI =confidence interval; NS = not statistically significant; OR = odds ratio; PR = pregnancy rate.

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fibroids and benign ovarian cysts does not affect fertility (Taskin et al., 2013). Women with these diagnoses were merged with those women where no pathology was found at laparoscopy to the diagnostic laparoscopy group. In this group, 50.7% of women conceived spontaneously after the surgical procedure. It is not known, however, what the PR in this group would be if laparoscopy had not been performed. Badawy et al. (2010) reported a similar PR after ovarian stimulation in women with unexplained infertility who had diagnostic laparoscopy prior to ovarian stimulation and those that did not have it. Is confirming normal anatomy at laparoscopy good or bad news for the patient considering postoperative PR? In general, women are reassured when it is explained that a pathology was found and successfully removed during laparoscopy and that they can expect to get pregnant. However, multivariate analysis has shown that PR after reproductive surgery of different pathologies was comparable to PR after diagnostic laparoscopy. Restoring the normal anatomy and eliminating pathology gives a spontaneous PR of 39% to 47% in cases where at least one healthy tube is found at laparoscopy. Additional pregnancies can be achieved with the use of clomiphene citrate, especially in the PCOS group. The only group with a significantly lower PR after reproductive surgery is the group with bilateral tubal factor. The combined spontaneous PR and PR after the use of clomiphene citrate following surgery for endometriosis was 48.1% in the mild and moderate endometriosis group and 48.6% in the severe endometriosis group. Pregnancy rates after the surgery of women with minimal–mild endometriosis are comparable to previous reports. In the study of Barri et al. (2010), 54.2% of women conceived spontaneously after surgery for endometriosis. Lee et al. (2013) reported a 37.5–44.4% and Parazzini (1999) a 24% spontaneous PR in a one year follow-up period after the surgical procedure. In a nine-month followup period, Moini et al. (2012) reported a 23.7% and Marcoux et al. (1997) a 30% spontaneous PR. However, these findings again do not answer the question of whether the treatment of minimal to mild endometriosis truly improves PR. There is the question of ethics in performing randomized controlled trials in women with endometriosis, because one group of women would be left untreated despite the presence of endometriosis. The data from randomized trials are scarce, include a small number of patients and the results are controversial (Marcoux et al., 1997; Moini et al., 2012; Parazzini, 1999). In the PCOS group, spontaneous PR after the surgical procedure was 47.1%. An additional 15.7% of women conceived with the use of clomiphene citrate, making the total spontaneous PR 62.7%. Results from this study are comparable to Yanamandra and Gundabattula (2015) who reported 24.3% spontaneous pregnancies and additional 37.8% pregnancies after ovulation induction with clomiphene citrate in the 18-month follow-up period, and Felemban et al. (2000) who reported 68% PR in the 18-month follow-up period.

The value of tubal surgery became questionable with the optimization of IVF procedures that yield fast and good results. It has been suggested that hydrosalpinges should be removed or at least proximally occluded as they lower the success of IVF procedures (ASRM, 2008). In younger patients, however, it seems that tubal surgery is Q6 effective and worth performing. Milingos et al. (2000) reported spontaneous pregnancy rates between 20% and 29% after laparoscopic bilateral neosalpingostomy for complete bilateral distal occlusion. In this study, 29.3% of women conceived spontaneously after surgical repair of bilateral tubal damage. Audebert et al. (2014) reported a 28.8% spontaneous pregnancy rate after laparoscopic neosalpingostomy and found that pregnancy and delivery rate was dependent on the tubal stage, with Stage 4 having the lowest rate. This study also showed that eversion of fimbriae with sutures yields better results than eversion with bipolar electrocoagulation. Similarly, Kasia et al. (2016) showed comparable pregnancy rates to ours and also presented the tubal stage as the most important prognostic factor for spontaneous conception. Currently, the group of patients from this study is too small to show the importance of tubal stage on PR or to draw conclusions considering operative technique for tubal neostomy. According to multivariate logistic regression analysis, hysteroscopy performed at the same time as laparoscopy significantly increased spontaneous conception (OR = 1.60, P = 0.035) (Table 5). Hysteroscopy was performed in addition to laparoscopy in 61% of infertile women. In 90% of women, at least one minor hysteroscopic operation was performed: resection of a small uterine septum (52%), resection of a large septum (29%) and in 10% a polyp or submucous fibroid. Our previous studies have shown that resection of a small uterine septum improves PR and outcomes in an IVF programme (Ban Frangez et al., 2009; Tomaževič et al., 2007, 2010). For this reason, we believe that resection of even small uterine septa is also beneficial in spontaneous conceptions. Some other authors support these observations. Seyam et al. (2015) confirmed that performing hysteroscopy improves spontaneous PR in unexplained infertility (28% versus 15%). Bakas et al. (2012) reported a 44% PR in one year after hysteroscopic resection of uterine septa in primary infertile women with unexplained infertility. A similar PR (43.1%) was reported by Tonguc et al. (2011). Venetis et al. (2014) performed a meta-analysis and found that in septate, but not in arcuate uterus, the probability for spontaneous conception is significantly decreased. Most women analysed in this study had a small septum that was not thought to affect fertility. Recently, there was a debate that diagnostic hysteroscopy and endometrial scratching improve PR in women after IVF failure (Campo et al., 2014; Carneiro, 2014). If this is true, perhaps resections of small uterine septa in this study increase PR because we actually performed a diagnostic hysteroscopy and a sort of scratching at the same time. However, the beneficial role of diagnostic hysteroscopy performed in the cycle immediately before the IVF treatment cycle was not confirmed by the TROPHY study (El-Toukhy et al., 2016). CONUTA Q7 Q8 classification (Grimbizis et al., 2013) offers instructions on how to distinguish between a normal uterine fundus and a small septum on the three-dimensional ultrasound, but at hysteroscopy this decision is mostly subjective. It is possible that hysteroscopy performed by gynaecologists who already have a positive experience with resections of small septa more often end up as an operative procedure and not only diagnostic. We expect to have more insight into this question in the future when we will be able to evaluate the role of diagnostic and operative hysteroscopy on a larger group of women with otherwise unexplained infertility. The number of women that only had

Please cite this article in press as: Helena Ban Frangez, et al., Spontaneous pregnancy rates after reproductive surgery, Reproductive BioMedicine Online (2017), doi: 10.1016/ j.rbmo.2017.05.007

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diagnostic hysteroscopy in this study is currently too small to draw conclusions about the sole effect of diagnostic hysteroscopy on spontaneous conception. Multivariate analysis results show that the duration of infertility and the woman’s age more importantly influence spontaneous PR than the pathology itself (Table 5). For each additional year of infertility, the chances for spontaneous pregnancy are lowered by approximately 14% (OR = 0.86, P = 0.037) and for each year of woman’s age, the PR is lowered by approximately 5% (OR = 0.95, P = 0.031). The influence of woman’s age and duration of infertility in women from this study is a bit lower than reported in unexplained infertility by Glazener et al. (2000). Women with secondary infertility have double chances for spontaneous pregnancy (OR = 2.07, P = 0.001). Women who failed to conceive spontaneously in the 12 months after the operation were referred to the IVF programme. The lowest PR after IVF was established occured in the diagnostic laparoscopy group (Table 7). This group can also be considered as unexplained infertility, as no pathology was found at laparoscopy and any potential pathology of the uterine cavity was previously corrected by hysteroscopy. This group had significantly lower PR compared with mild to moderate endometriosis, severe endometriosis, PCOS, bilateral tubal factor and the miscellaneous group. Removal of mild to moderate endometriosis was already confirmed to be beneficial before IVF procedure (Opoien et al., 2011). Unexplained infertility has once again proven to be difficult to deal with. The same low PR as in the diagnostic laparoscopy group is seen also in women after removal of intramural fibroids and in women with one normal tube. Removal of fibroids actually normalizes the anatomy and if a woman fails to conceive spontaneously, she has the same low prognosis in IVF as unexplained infertility patients. The same trend is observed in the unilateral tubal factor group. Spontaneous PR of the unilateral tubal factor group after reproductive surgery was comparable to all other groups (except the bilateral tubal factor group that showed lower PR). But if they fail to conceive and progress to IVF, they fall into the low prognostic group together with the diagnostic laparoscopy and intramural fibroid groups. It seems that one healthy tube is enough to achieve spontaneous pregnancy; if this fails, we are dealing with the same unexplained reason that is more difficult to overcome also in IVF. Multivariate analysis of parameters influencing PR in the IVF programme shows slight differences compared with the influence on spontaneous PR after surgery (Table 7). Duration of infertility is still an important factor since each additional year of infertility lowers the chances for pregnancy by 19% (OR = 0.81, P = 0.043). Secondary infertility elevates the chances for pregnancy by 2.5 times (OR = 2.49, P = 0.017). Interestingly, woman’s age in this group was not significant, but currently the groups are very small and this will have to be verified on larger numbers. Hysteroscopy which, was a significant factor in achieving spontaneous PR after surgery, was not significant in women undergoing IVF procedure. Since our previous results (Ban Frangez et al., 2009; Tomaževič et al., 2007, 2010) showed that hysteroscopy prior to IVF procedure improved implantation and term delivery rate in IVF patients, we included a careful investigation of the uterine cavity with ultrasound and diagnostic or operative hysteroscopy if indicated at the beginning of infertility investigation in every patient. We presume that a resection of small septa enables these women to achieve spontaneous pregnancy. To sum up, there seems to be a lack of prospective studies Q9 analysing spontaneous pregnancies after reproductive surgery. The advantage of IVF compared with surgery is in the large number of

7

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cycles performed, which enable evidence-based analyses of large databases. Furthermore, fast results after IVF procedure suit some patients as well, putting surgery in a disadvantaged position. At least this is how some patients feel until the first unsuccessful IVF. Good surgery gives patients the possibility of conceiving every month, with fewer side effects compared with IVF. In our institution, IVF was introduced over 30 years ago and was always considered as a backup plan when surgical treatment yielded no results and for male factor infertility. Contrary to IVF data, the operative procedure data have never been systematically prospectively collected and we were not aware how often we actually solved the problem of infertility with surgery. The presented data from this study are prospectively collected on the entire group of patients over a certain time period and provide insight in the real situation and not only selected pathology that is usually presented in scarce prospective analyses. This group of analysed patients is highly heterogeneous which is understandable since every woman has a unique situation. Therefore, forming subgroups was the most difficult part of this analysis. But the basic question is answered – of 519 women in total, 48.6% achieved spontaneous pregnancy and in 205 women who did not achieve spontaneous pregnancy after 12 months an additional 91 pregnancies were achieved following IVF in the 12–18 months observation period, resulting in an overall pregnancy rate of 66.1%. Although this analysis answered our basic question, it also created many others, like what is the impact of a uterine septum or diagnostic hysteroscopy in unexplained infertility and what do we find at laparoscopy when all preoperative diagnostic is normal? Considering tubal surgery, the difficult decision still exists of when to preserve or remove the tube. We will perhaps be able to answer these questions in a few years’ time as the database enlarges. This prospective analysis confirmed the benefit of reproductive surgery in infertile patients. Although we have to be aware of some specificity of reproductive surgery: gentle tissue handling, ovarian tissue sparing, minimal electrocoagulation of the tissue to avoid necrosis and enable optimal healing, precise restoration of normal anatomy and prevention of adhesions. These skills are not easy to gain and should be practiced since they have to be applied not only when treating infertility but in all young women who will one day plan their pregnancies.

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631 632

Acknowledgement

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We thank Ivan Verdenik for performing statistical analyses.

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Uncited references

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American Fertility Society, 1988, Practice Committee of American Society for Reproductive Medicine in collaboration with Society of Reproductive Surgeons, 2008

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Appendix: Supplementary material

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Supplementary data to this article can be found online at doi:10.1016/j.rbmo.2017.05.007.

Please cite this article in press as: Helena Ban Frangez, et al., Spontaneous pregnancy rates after reproductive surgery, Reproductive BioMedicine Online (2017), doi: 10.1016/ j.rbmo.2017.05.007

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A R T I C L E

I N F O

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Article history: Received 6 November 2016 Received in revised form 8 May 2017 Accepted 9 May 2017

Declaration: The authors report no financial or commercial conflicts of interest.

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Keywords: Infertility IVF Reproductive surgery Spontaneous pregnancy

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REFERENCES

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