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A randomized controlled trial of tubal flushing with lipiodol for unexplained infertility
FERTILITY AND STERILITY威 VOL. 77, NO. 1, JANUARY 2002 Copyright ©2002 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A.
TECHNIQUES AND INSTRUMENTATION
A randomized controlled trial of tubal flushing with lipiodol for unexplained infertility David Nugent, M.R.C.O.G.,a Andrew J. Watson, M.R.C.O.G.,b Stephen R. Killick, M.D.,c Adam H. Balen, M.D.,d and Anthony J. Rutherford, F.R.C.O.G.d Reproductive Medicine Unit, Leeds General Infirmary, Leeds, and Department of Obstetrics and Gynaecology, The Princess Royal Hospital, Hull, United Kingdom
Received April 11, 2001; revised and accepted June 27, 2001. Reprint requests: David Nugent, M.R.C.O.G., Centre for Reproduction, Growth and Development, University of Leeds, D floor, Clarendon Wing, LGI, Belmont Grove, Leeds LS2 9NS, United Kingdom (FAX: 44-0113-292-6021; E-mail: dnhello@hotmail. com). a Centre for Reproduction, Growth and Development, University of Leeds, LGI, Belmont Grove, Leeds, United Kingdom. b Department of Obstetrics and Gynaecology, Tameside General Hospital, Ashton under Lyme, United Kingdom. c Department of Obstetrics and Gynaecology, The Princess Royal Hospital, Hull, United Kingdom. d Reproductive Medicine Unit, University of Leeds, LGI, Belmont Grove, Leeds, United Kingdom. 0015-0282/02/$22.00 PII S0015-0282(01)02925-9
Objective: To test the hypothesis that, in couples with unexplained infertility, tubal flushing with an oil-soluble media (lipiodol) would increase the pregnancy rate within 6 months compared with expectant management. Design: A prospective, randomized, controlled study in which couples were allocated to either a single treatment with lipiodol or no further action. Setting: Two tertiary referral centers for assisted reproduction. Patient(s): Couples with a diagnosis of primary or secondary unexplained infertility based on a normal semen analysis according to World Health Organization criteria, patent fallopian tubes at hysterosalpingography or laparoscopy, and ovulatory menstrual cycles based on midluteal phase progesterone levels or ultrasonic follicle tracking. Intervention(s): In those patients randomized to lipiodol, a single treatment was performed. Main Outcome Measure(s): Biochemical (i.e., positive pregnancy test) and clinical (i.e., fetal heart on ultrasound scan) pregnancy rates. Result(s): Seventeen couples were randomized to lipiodol and 17 to expectant treatment. The higher pregnancy rate after lipiodol was statistically significant. There were no complications after lipiodol treatment. Conclusion(s): There was a statistically significantly higher pregnancy rate in couples with unexplained infertility randomized to a single tubal flush with lipiodol compared with no treatment. (Fertil Steril威 2002; 77:173–5. ©2002 by American Society for Reproductive Medicine.) Key Words: Lipiodol, tubal flushing media, unexplained infertility
Oil-based tubal insufflation media, of which lipiodol is a present-day equivalent, have been widely used to investigate tubal patency during hysterosalpingography (HSG). Meta-analyses comparing oil-based and water-based media have shown a statistically significant increase in pregnancy rate with the former, and subgroup analysis has suggested the therapeutic benefits to be in couples with unexplained infertility (1). The use of a relatively inexpensive single tubal flush could be an attractive treatment option in these patients because of its simplicity and cost-effectiveness. Accordingly, a prospective, randomized, controlled trial was performed to investigate the therapeutic use of an oil-based tubal flushing medium in couples with unexplained infertility.
Couples with ⬎12 months of primary or secondary unexplained infertility were prospectively recruited for study participation from 1995 to 1998 at the Princess Royal Hospital (Hull, United Kingdom) and the General Infirmary (Leeds, United Kingdom). The local ethics committees at both sites approved the study. Both hospitals have assisted conception units and are tertiary referral centers for the management of subfertility. All couples had undergone prior investigations including, as a minimum, a recent normal semen analysis as defined by World Health Organization criteria, a hysterosalpingogram (or laparoscopy and dye test) demonstrating patent fallopian tubes with no evidence of adhesions, and an ovulatory midluteal serum progesterone level (⬎30 173
TABLE 1 Characteristics of patients randomized in the study. Variable Total patients (secondary infertility only) Mean ⫾ SEM female age (y) Mean ⫾ SEM duration of infertility (y) Mean ⫾ SEM volume injected (mL) No. of complications No. (%) of biochemical pregnancies No. (%) of clinical pregnancies No. (%) of total pregnancies
Lipiodol
No treatment
17 (5) 30.6 ⫾ 1.1 4.1 ⫾ 0.5 5.8 ⫾ 0.7 0 1 (6) 4 (23.5) 5 (29.4)a
17 (7) 31.9 ⫾ 8.7 3.1 ⫾ 0.3 N/A 0 0 (0) 0 (0) 0 (0)
N/A ⫽ not applicable. P⬍.05 (vs. no treatment).
a
Nugent. Lipidol tubal flushing in unexplained fertility. Fertil Steril 2002.
nmol/l) or ovulation confirmed with ultrasonographic follicle tracking. All of the female partners had regular menstrual cycles (K ⫽ 28 ⫾ 4 days), and other tests such as prolactin, thyroid function, and endometrial sampling were not, therefore, performed routinely. After informed, written consent had been obtained, patients were randomized via third-party sealed envelope entry to receive either a single treatment with lipiodol tubal flushing medium or no further treatment for 6 months. In those patients randomized to receive lipiodol, the hysterosalpingogram was performed by Leech-Wilkinson cervical cannulation and gentle injection of prewarmed (37°C) contrast media under fluoroscopic control. No further treatment or advice about coital frequency was given to patients in either the treatment or control group. Outcome measures assessed at 6 months were the biochemical (defined by a positive urinary or serum HCG pregnancy test) and clinical (defined by the presence of a fetal heart on transvaginal ultrasound scan) pregnancy rates and the occurrence of any complications. For dichotomous outcomes, a 2 ⫻ 2 contingency table was constructed and a two-tailed Fisher’s exact probability test applied. For continuous outcomes, a Student’s t test was applied. Thirty-four patients were randomized, 17 to lipiodol and
17 to expectant management. None of the patients counseled about the study declined to enter randomization, and none were excluded after randomization. There were no significant differences between the patients treated with lipiodol and those managed conservatively in terms of age, duration of infertility, and incidence of primary or secondary infertility (Table 1). Patients randomized to the lipiodol tubal insufflation received a mean volume of 5.8 ⫾ 0.7 mL (mean ⫾ SEM), and in all cases there were no abnormalities (tubal or uterine) seen on the HSG. No complications were reported in any of the patients who received lipiodol. Five patients (29.4%) conceived in the group that underwent lipiodol tubal insufflation (P⬍.05). One of these pregnancies miscarried following two positive hospital-basedpregnancy tests, and the remaining four proceeded uneventfully to term (23.5%). None of the patients conceived in the group randomized to receive no treatment. Of the patients who conceived, one did so within four ovulations (three menses) from treatment, whereas the other four each conceived within two ovulations (Table 2). Each patient who conceived had a minimum of 40 months of infertility, and in one case there was 12 years of secondary infertility in a couple who also had undergone a failed IVF cycle. Four of these patients had undergone a normal laparoscopy and dye
TABLE 2 Characteristics of patients who conceived after a single treatment with lipiodol. Patient
Female age (y)
Infertility
Duration of infertility (mo)
No. of menses before conception
Outcome
31 36 33 26 24
Primary Secondary Secondary Primary Primary
40 144 48 40 48
0 1 3 1 0
Livebirth Livebirth Livebirth Livebirth Miscarriage
1 2 3 4 5
Nugent. Lipidol tubal flushing in unexplained fertility. Fertil Steril 2002.
174
Nugent et al.
Lipiodol tubal flushing in unexplained infertility
Vol. 77, No. 1, January 2002
test before treatment and the other, a normal HSG. In all cases these investigations took place at least 18 months before randomization. The results presented constitute the first prospective, randomized study to specifically examine the benefit of tubal flushing with an oil-soluble medium in couples with unexplained infertility. Important prognostic factors in unexplained infertility are the age of the female partner and the duration of infertility (2). In our study there was no significant difference between the mean ages of the patients randomized. In the patients who conceived after treatment, the age range was 23–36 years, and the two youngest patients had no other favorable prognostic factors, being primiparous and with at least 4 years of subfertility. Another important prognostic factor is the duration of infertility. As the spontaneous conception rate only starts to decrease significantly after 3 years, conservative treatment may be considered until then if the female partner is ⬍35 years of age (2). In one study the cumulative pregnancy rate in couples with unexplained infertility was 46% at 2 years in couples with infertility for ⬍3 years, compared with 27% at 2 years in couples with infertility for ⱖ3 years (2). In our study there was no significant difference between groups in terms of duration of infertility. Furthermore, all of the patients who conceived after treatment had longstanding infertility ranging from 40 –144 months’ duration. Differences in outcome may also exist for patients with primary and secondary infertility. In patients with primary and secondary unexplained infertility, Lenton and colleagues (3) found the pregnancy rates to be 36% and 79%, respectively, at 7 years, whereas Templeton and Penney (4) found them to be 64% and 79% at 9 years. In our study there was no significant difference between the proportion of patients with primary and secondary infertility in the treatment arms. In addition, three of the five patients who conceived had primary subfertility. In our study all of the patients who conceived did so shortly after treatment, consistent with other reports. When used for infertility treatment, tubal flushing was often repeated at three monthly intervals because of the perception that few patients conceived after this time (1). In addition, it has been suggested that hysteroscopic tubal flushing with lipiodol during laparosopy for endometriosis-associated infertility had a significant therapeutic benefit during the first 4 months only (1). One reason given for avoiding oil-based media is the relative slowness of its absorption that may potentially lead
FERTILITY & STERILITY威
to granuloma formation when trapped within hydrosalpinges. However, this complication has not been reported in patients with patent fallopian tubes and has not been found to have long-term consequences (1). In addition, a potential advantage of oil-soluble media is that they may cause less pain than water-soluble media, possibly because of less chemical irritation of the peritoneum (1). The mechanism of action of lipiodol remains unknown and warrants further investigation. Tubal debris has been noted as amorphous matter on histological examination of the tube (1) and has also been seen in vivo during falloposcopy, even in the absence of tubal obstruction (1). It has been postulated that the increased pregnancy rate after oil-based tubal flushing may be due to the removal of this debris (1). However, in our study, all patients had a preceding normal result from tubal patency assessment, which suggests that another mechanism exists. Although oil-based media contain bacteriostatic iodine (1), it is unlikely that this is an important factor because consistently lower pregnancy rates were found in previous studies when lipiodol was used in the presence of tubal damage (1). Another possible explanation is that there is an underlying unrecognized immunological cause for the subfertility. Evidence for this derives from in vitro studies that have shown lipiodol to prevent peritoneal mast cell phagocytosis of spermatozoa (1). It has also been found that lipiodol (but not saline or water-soluble media) injected into the peritoneal cavity increases fecundity in inbred strains of mice with subfertility (1). Regardless of the mechanism, we conclude that lipiodol could prove a useful treatment in couples with unexplained infertility, particularly in circumstances in which there are limited resources available for more expensive and invasive reproductive technologies. In relation to the patients who conceived in this study, this may include patients with primary or secondary subfertility, those who have been trying for a number of years, and those who have had failures with more advanced reproductive technologies. References 1. Watson A, Vandekerckhove P, Lilford R, Vail A, Brosens I, Hughes E. A meta-analysis of the therapeutic role of oil soluble contrast media at hysterosalpingography: a surprising result? Fertil Steril 1994;61:470 –7. 2. Wichmann L, Isola J, Tuohimaa P. Prognostic variables in predicting pregnancy. A prospective follow up study of 907 couples with an infertility problem. Hum Reprod 1994;9:1102– 8. 3. Lenton EA, Weston GA, Cooke ID. Long-term follow-up of the apparently normal couple with a complaint of infertility. Fertil Steril 1977; 28:913–9. 4. Templeton AA, Penney GC. The incidence, characteristics, and prognosis of patients whose infertility is unexplained. Fertil Steril 1982;37:175– 82.
175
TECHNIQUES AND INSTRUMENTATION
A randomized controlled trial of tubal flushing with lipiodol for unexplained infertility David Nugent, M.R.C.O.G.,a Andrew J. Watson, M.R.C.O.G.,b Stephen R. Killick, M.D.,c Adam H. Balen, M.D.,d and Anthony J. Rutherford, F.R.C.O.G.d Reproductive Medicine Unit, Leeds General Infirmary, Leeds, and Department of Obstetrics and Gynaecology, The Princess Royal Hospital, Hull, United Kingdom
Received April 11, 2001; revised and accepted June 27, 2001. Reprint requests: David Nugent, M.R.C.O.G., Centre for Reproduction, Growth and Development, University of Leeds, D floor, Clarendon Wing, LGI, Belmont Grove, Leeds LS2 9NS, United Kingdom (FAX: 44-0113-292-6021; E-mail: dnhello@hotmail. com). a Centre for Reproduction, Growth and Development, University of Leeds, LGI, Belmont Grove, Leeds, United Kingdom. b Department of Obstetrics and Gynaecology, Tameside General Hospital, Ashton under Lyme, United Kingdom. c Department of Obstetrics and Gynaecology, The Princess Royal Hospital, Hull, United Kingdom. d Reproductive Medicine Unit, University of Leeds, LGI, Belmont Grove, Leeds, United Kingdom. 0015-0282/02/$22.00 PII S0015-0282(01)02925-9
Objective: To test the hypothesis that, in couples with unexplained infertility, tubal flushing with an oil-soluble media (lipiodol) would increase the pregnancy rate within 6 months compared with expectant management. Design: A prospective, randomized, controlled study in which couples were allocated to either a single treatment with lipiodol or no further action. Setting: Two tertiary referral centers for assisted reproduction. Patient(s): Couples with a diagnosis of primary or secondary unexplained infertility based on a normal semen analysis according to World Health Organization criteria, patent fallopian tubes at hysterosalpingography or laparoscopy, and ovulatory menstrual cycles based on midluteal phase progesterone levels or ultrasonic follicle tracking. Intervention(s): In those patients randomized to lipiodol, a single treatment was performed. Main Outcome Measure(s): Biochemical (i.e., positive pregnancy test) and clinical (i.e., fetal heart on ultrasound scan) pregnancy rates. Result(s): Seventeen couples were randomized to lipiodol and 17 to expectant treatment. The higher pregnancy rate after lipiodol was statistically significant. There were no complications after lipiodol treatment. Conclusion(s): There was a statistically significantly higher pregnancy rate in couples with unexplained infertility randomized to a single tubal flush with lipiodol compared with no treatment. (Fertil Steril威 2002; 77:173–5. ©2002 by American Society for Reproductive Medicine.) Key Words: Lipiodol, tubal flushing media, unexplained infertility
Oil-based tubal insufflation media, of which lipiodol is a present-day equivalent, have been widely used to investigate tubal patency during hysterosalpingography (HSG). Meta-analyses comparing oil-based and water-based media have shown a statistically significant increase in pregnancy rate with the former, and subgroup analysis has suggested the therapeutic benefits to be in couples with unexplained infertility (1). The use of a relatively inexpensive single tubal flush could be an attractive treatment option in these patients because of its simplicity and cost-effectiveness. Accordingly, a prospective, randomized, controlled trial was performed to investigate the therapeutic use of an oil-based tubal flushing medium in couples with unexplained infertility.
Couples with ⬎12 months of primary or secondary unexplained infertility were prospectively recruited for study participation from 1995 to 1998 at the Princess Royal Hospital (Hull, United Kingdom) and the General Infirmary (Leeds, United Kingdom). The local ethics committees at both sites approved the study. Both hospitals have assisted conception units and are tertiary referral centers for the management of subfertility. All couples had undergone prior investigations including, as a minimum, a recent normal semen analysis as defined by World Health Organization criteria, a hysterosalpingogram (or laparoscopy and dye test) demonstrating patent fallopian tubes with no evidence of adhesions, and an ovulatory midluteal serum progesterone level (⬎30 173
TABLE 1 Characteristics of patients randomized in the study. Variable Total patients (secondary infertility only) Mean ⫾ SEM female age (y) Mean ⫾ SEM duration of infertility (y) Mean ⫾ SEM volume injected (mL) No. of complications No. (%) of biochemical pregnancies No. (%) of clinical pregnancies No. (%) of total pregnancies
Lipiodol
No treatment
17 (5) 30.6 ⫾ 1.1 4.1 ⫾ 0.5 5.8 ⫾ 0.7 0 1 (6) 4 (23.5) 5 (29.4)a
17 (7) 31.9 ⫾ 8.7 3.1 ⫾ 0.3 N/A 0 0 (0) 0 (0) 0 (0)
N/A ⫽ not applicable. P⬍.05 (vs. no treatment).
a
Nugent. Lipidol tubal flushing in unexplained fertility. Fertil Steril 2002.
nmol/l) or ovulation confirmed with ultrasonographic follicle tracking. All of the female partners had regular menstrual cycles (K ⫽ 28 ⫾ 4 days), and other tests such as prolactin, thyroid function, and endometrial sampling were not, therefore, performed routinely. After informed, written consent had been obtained, patients were randomized via third-party sealed envelope entry to receive either a single treatment with lipiodol tubal flushing medium or no further treatment for 6 months. In those patients randomized to receive lipiodol, the hysterosalpingogram was performed by Leech-Wilkinson cervical cannulation and gentle injection of prewarmed (37°C) contrast media under fluoroscopic control. No further treatment or advice about coital frequency was given to patients in either the treatment or control group. Outcome measures assessed at 6 months were the biochemical (defined by a positive urinary or serum HCG pregnancy test) and clinical (defined by the presence of a fetal heart on transvaginal ultrasound scan) pregnancy rates and the occurrence of any complications. For dichotomous outcomes, a 2 ⫻ 2 contingency table was constructed and a two-tailed Fisher’s exact probability test applied. For continuous outcomes, a Student’s t test was applied. Thirty-four patients were randomized, 17 to lipiodol and
17 to expectant management. None of the patients counseled about the study declined to enter randomization, and none were excluded after randomization. There were no significant differences between the patients treated with lipiodol and those managed conservatively in terms of age, duration of infertility, and incidence of primary or secondary infertility (Table 1). Patients randomized to the lipiodol tubal insufflation received a mean volume of 5.8 ⫾ 0.7 mL (mean ⫾ SEM), and in all cases there were no abnormalities (tubal or uterine) seen on the HSG. No complications were reported in any of the patients who received lipiodol. Five patients (29.4%) conceived in the group that underwent lipiodol tubal insufflation (P⬍.05). One of these pregnancies miscarried following two positive hospital-basedpregnancy tests, and the remaining four proceeded uneventfully to term (23.5%). None of the patients conceived in the group randomized to receive no treatment. Of the patients who conceived, one did so within four ovulations (three menses) from treatment, whereas the other four each conceived within two ovulations (Table 2). Each patient who conceived had a minimum of 40 months of infertility, and in one case there was 12 years of secondary infertility in a couple who also had undergone a failed IVF cycle. Four of these patients had undergone a normal laparoscopy and dye
TABLE 2 Characteristics of patients who conceived after a single treatment with lipiodol. Patient
Female age (y)
Infertility
Duration of infertility (mo)
No. of menses before conception
Outcome
31 36 33 26 24
Primary Secondary Secondary Primary Primary
40 144 48 40 48
0 1 3 1 0
Livebirth Livebirth Livebirth Livebirth Miscarriage
1 2 3 4 5
Nugent. Lipidol tubal flushing in unexplained fertility. Fertil Steril 2002.
174
Nugent et al.
Lipiodol tubal flushing in unexplained infertility
Vol. 77, No. 1, January 2002
test before treatment and the other, a normal HSG. In all cases these investigations took place at least 18 months before randomization. The results presented constitute the first prospective, randomized study to specifically examine the benefit of tubal flushing with an oil-soluble medium in couples with unexplained infertility. Important prognostic factors in unexplained infertility are the age of the female partner and the duration of infertility (2). In our study there was no significant difference between the mean ages of the patients randomized. In the patients who conceived after treatment, the age range was 23–36 years, and the two youngest patients had no other favorable prognostic factors, being primiparous and with at least 4 years of subfertility. Another important prognostic factor is the duration of infertility. As the spontaneous conception rate only starts to decrease significantly after 3 years, conservative treatment may be considered until then if the female partner is ⬍35 years of age (2). In one study the cumulative pregnancy rate in couples with unexplained infertility was 46% at 2 years in couples with infertility for ⬍3 years, compared with 27% at 2 years in couples with infertility for ⱖ3 years (2). In our study there was no significant difference between groups in terms of duration of infertility. Furthermore, all of the patients who conceived after treatment had longstanding infertility ranging from 40 –144 months’ duration. Differences in outcome may also exist for patients with primary and secondary infertility. In patients with primary and secondary unexplained infertility, Lenton and colleagues (3) found the pregnancy rates to be 36% and 79%, respectively, at 7 years, whereas Templeton and Penney (4) found them to be 64% and 79% at 9 years. In our study there was no significant difference between the proportion of patients with primary and secondary infertility in the treatment arms. In addition, three of the five patients who conceived had primary subfertility. In our study all of the patients who conceived did so shortly after treatment, consistent with other reports. When used for infertility treatment, tubal flushing was often repeated at three monthly intervals because of the perception that few patients conceived after this time (1). In addition, it has been suggested that hysteroscopic tubal flushing with lipiodol during laparosopy for endometriosis-associated infertility had a significant therapeutic benefit during the first 4 months only (1). One reason given for avoiding oil-based media is the relative slowness of its absorption that may potentially lead
FERTILITY & STERILITY威
to granuloma formation when trapped within hydrosalpinges. However, this complication has not been reported in patients with patent fallopian tubes and has not been found to have long-term consequences (1). In addition, a potential advantage of oil-soluble media is that they may cause less pain than water-soluble media, possibly because of less chemical irritation of the peritoneum (1). The mechanism of action of lipiodol remains unknown and warrants further investigation. Tubal debris has been noted as amorphous matter on histological examination of the tube (1) and has also been seen in vivo during falloposcopy, even in the absence of tubal obstruction (1). It has been postulated that the increased pregnancy rate after oil-based tubal flushing may be due to the removal of this debris (1). However, in our study, all patients had a preceding normal result from tubal patency assessment, which suggests that another mechanism exists. Although oil-based media contain bacteriostatic iodine (1), it is unlikely that this is an important factor because consistently lower pregnancy rates were found in previous studies when lipiodol was used in the presence of tubal damage (1). Another possible explanation is that there is an underlying unrecognized immunological cause for the subfertility. Evidence for this derives from in vitro studies that have shown lipiodol to prevent peritoneal mast cell phagocytosis of spermatozoa (1). It has also been found that lipiodol (but not saline or water-soluble media) injected into the peritoneal cavity increases fecundity in inbred strains of mice with subfertility (1). Regardless of the mechanism, we conclude that lipiodol could prove a useful treatment in couples with unexplained infertility, particularly in circumstances in which there are limited resources available for more expensive and invasive reproductive technologies. In relation to the patients who conceived in this study, this may include patients with primary or secondary subfertility, those who have been trying for a number of years, and those who have had failures with more advanced reproductive technologies. References 1. Watson A, Vandekerckhove P, Lilford R, Vail A, Brosens I, Hughes E. A meta-analysis of the therapeutic role of oil soluble contrast media at hysterosalpingography: a surprising result? Fertil Steril 1994;61:470 –7. 2. Wichmann L, Isola J, Tuohimaa P. Prognostic variables in predicting pregnancy. A prospective follow up study of 907 couples with an infertility problem. Hum Reprod 1994;9:1102– 8. 3. Lenton EA, Weston GA, Cooke ID. Long-term follow-up of the apparently normal couple with a complaint of infertility. Fertil Steril 1977; 28:913–9. 4. Templeton AA, Penney GC. The incidence, characteristics, and prognosis of patients whose infertility is unexplained. Fertil Steril 1982;37:175– 82.
175