How Long To Wait After Uterine Septum Removal
Abstract
STUDY QUESTION
Does septum resection ameliorate reproductive outcomes in women with a septate uterus?
SUMMARY ANSWER
Hysteroscopic septum resection does not improve reproductive outcomes in women with a septate uterus.
WHAT IS KNOWN ALREADY
A septate uterus is a congenital uterine bibelot. Women with a septate uterus are at increased risk of subfertility, pregnancy loss and preterm nativity. Hysteroscopic resection of a septum may better the take chances of a live birth in affected women, only this has never been evaluated in randomized clinical trials. We assessed whether septum resection improves reproductive outcomes in women with a septate uterus, wanting to go pregnant.
Written report DESIGN, SIZE, Duration
We performed an international, multicentre, open-label, randomized controlled trial in 10 centres in The netherlands, UK, United states and Iran between Oct 2010 and September 2022.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Women with a septate uterus and a history of subfertility, pregnancy loss or preterm birth were randomly allocated to septum resection or expectant management. The main outcome was conception leading to live nascence within 12 months after randomization, defined as the nativity of a living foetus beyond 24 weeks of gestational historic period. We analysed the data on an intention-to-treat basis and calculated relative risks with 95% CI.
MAIN RESULTS AND THE ROLE OF CHANCE
Nosotros randomly assigned 80 women with a septate uterus to septum resection (n = twoscore) or expectant management (n = xl). We excluded ane woman who underwent septum resection from the intention-to-treat assay, because she withdrew informed consent for the study shortly afterwards randomization. Alive birth occurred in 12 of 39 women allocated to septum resection (31%) and in 14 of 40 women allocated to expectant direction (35%) (relative risk (RR) 0.88 (95% CI 0.47 to 1.65)). There was one uterine perforation which occurred during surgery (1/39 = 2.6%).
LIMITATIONS, REASONS FOR CAUTION
Although this was a major international trial, the sample size was still limited and recruitment took a long menstruation. Since surgical techniques did not fundamentally change over time, we consider the latter of limited clinical significance.
WIDER IMPLICATIONS OF THE FINDINGS
The trial generated high-level evidence in add-on to show from a recently published large cohort study. Both studies unequivocally do not reveal whatsoever improvements in reproductive outcomes, thereby questioning whatever rationale behind surgery.
Written report FUNDING/COMPETING Interest(Due south)
In that location was no study funding. G.H.East. reports a patent on a surgical endoscopic cutting device and process for the removal of tissue from a trunk cavity licensed to Medtronic, outside the scope of the submitted work. H.A.five.V. reports personal fees from Medtronic, outside the submitted piece of work. B.W.J.M. reports grants from NHMRC, personal fees from ObsEva, personal fees from Merck Merck KGaA, personal fees from Guerbet, personal fees from iGenomix, outside the submitted work. K.K. reports several research and educational grants from Guerbet, Merck and Ferring (location VUMC) outside the scope of the submitted work. The remaining authors have naught to declare.
TRIAL REGISTRATION NUMBER
Dutch trial registry: NTR 1676
TRIAL REGISTRATION DATE
18 February 2009
Date OF FIRST PATIENT'S ENROLMENT
20 October 2010
Introduction
The septate uterus is a congenital uterine anomaly. It is infrequently detected, with an estimated prevalence of around 0.2–ii.3% in women of reproductive age ( Saravelos et al., 2008; Chan et al., 2022b). Women with a septate uterus are at increased risk for subfertility, pregnancy loss and preterm nascency ( Chan et al., 2022a). Hysteroscopic septum resection is currently standard practice to restore normal uterine anatomy, with the aim of improving reproductive outcomes.
At nowadays, the American Lodge of Reproductive Medicine (ASRM) guideline for management of the septate uterus recommends hysteroscopic resection (ASRM, 2022). In dissimilarity, guidance on recurrent pregnancy loss associated with a septate uterus from the European Society of Human Reproduction and Embryology (ESHRE), the National Institute for Wellness and Intendance Excellence (NICE) and the Royal College of Obstetricians and Gynaecologists (RCOG) do not support the apply of the procedure, until acceptable studies would have demonstrated its effectiveness (RCOG, 2022; NICE, 2022; ESHRE, 2022).
Recently, a large cohort study including 257 women with a septate uterus, showed that surgery did non improve chance of conception, nor did information technology announced to prevent pregnancy loss or preterm nascency. Surgical complications occurred in seven women (4.half dozen%) ( Rikken et al., 2022).
To provide a college level of prove, we here performed a randomized controlled trial comparison hysteroscopic septum resection with expectant direction in women with a septate uterus.
Materials and methods
Pattern
This written report was designed as an international, multicentre, open up-label, randomized controlled trial carried out in centres with expertise in hysteroscopic septum resection. These centres were three tertiary-care and four secondary-intendance hospitals collaborating in the Dutch Consortium for Women's Health Research, and iii 3rd-care hospitals in the USA, UK and Iran, respectively.
Ethical approval
The TRUST (The Randomised Uterine Septum Trial) trial was registered within kingdom of the netherlands Trial Register, number NTR1676. The trial protocol and all subsequent amendments were approved past the Medical Ethical Committee of the Academic Medical Center (IDS NL24082.018.08 MEC Academic Medical Center, Amsterdam), Kingdom of the netherlands on 28 October 2008 (MEC 08/245), and by the boards of directors of all participating hospitals.
All adverse and serious adverse events suspected of having a causal relationship to surgery were recorded. A serious adverse event was defined every bit death or illness necessitating intensive care unit (ICU) treatment. All serious adverse events had to be reported to the ethics commission of the Academic Medical Centre, Amsterdam. The study protocol has been published previously ( Rikken et al., 2022).
Eligible women were provided with trial data verbally and in writing past consultant gynaecologists or dedicated research employees at the outpatient clinics. All women provided written informed consent. Women could withdraw from the trial at any fourth dimension.
Study population
Women of reproductive age with a septate uterus, wanting to become meaning and with a history of subfertility, pregnancy loss or preterm birth were eligible. Women with a contraindication to surgery were not eligible. Initially, afterwards ethical study approving merely women with recurrent pregnancy loss were included. During the course of the trial, the eligibility criteria were extended to include women with a history of subfertility (2011), 1 pregnancy loss or preterm birth (2015). This broadening of inclusions was based on a systematic review published in 2022 that showed that women with a septate uterus had reduced clinical pregnancy rates and increased rates of pregnancy loss and preterm birth when compared with women with normal uteri ( Chan et al., 2022a,b). A septate uterus was diagnosed by the treating consultant according to the leading classification systems at that time of recruitment (AFS, 1988; Grimbizis et al., 2022; ASRM, 2022). The presence of a uterine septum had to be ascertained by hysterosalpingography, 3-dimensional pelvic ultrasound, MRI, saline or gel infusion sonohysterography or hysteroscopy combined with laparoscopy ( Faivre et al., 2022; Ludwin et al., 2022; Siam and Soliman, 2022; Graupera et al., 2022).
Definitions
The following listing of definitions was used. Subfertility: the inability to excogitate for a minimal menstruation of 12 months of trying to conceive ( Zegers-Hochschild et al., 2022); Pregnancy loss: the spontaneous demise of a pregnancy before 24 weeks of gestation, including non-visualized or biochemical pregnancies, confirmed by either serum or urine b-HCG; Recurrent pregnancy loss: two or more than, not necessarily sequent, pregnancy losses (ESHRE, 2022); Preterm birth: birth before a gestational age of 37 complete weeks ( Blencowe et al., 2022); Clinical pregnancy: the presence of a foetal heartbeat at or across 6 weeks of pregnancy; Ongoing pregnancy: a viable intrauterine pregnancy of at to the lowest degree 12 weeks duration, confirmed on an ultrasound scan ( Braakhekke et al., 2022).
Randomization and blinding
Women were randomly allocated (i:1) to hysteroscopic septum resection or expectant management, by use of a central countersign protected net-based randomization program. The randomization listing behind the plan was prepared past an independent statistician with a variable cake size with randomly selected block sizes that varied between two, 4 and vi. There was no stratification. Neither the recruiters nor the trial project group could access the randomization sequence. Considering of the nature of the interventions, blinding women or doctors was impossible.
Procedures
Women allocated to hysteroscopic septum resection had their surgical procedure performed nether full general or loco-regional anaesthesia. The choice of instrumentation was left to the participating surgeon, which could include monopolar or bipolar resectoscopes with needle and/or loop electrosurgical electrodes, bipolar vaporization electrodes (Versapoint®) or conventional mechanical pair of scissors. To monitor the depth of the myometrial resection and to preclude uterine perforation during surgery, laparoscopic or ultrasound monitoring was advised (Zhang et al., 2022). To assess the results of the septum resection, a diagnostic control hysteroscopy 6–viii weeks postoperatively was performed in an outpatient setting.
Women allocated to expectant direction did non receive any specific intervention and were advised to go on trying to conceive naturally or with assisted reproductive technologies in example of subfertility. In women with recurrent pregnancy loss and co-existing antiphospholipid syndrome, low dose aspirin or low molecular weight heparin were allowed. Women could opt for hysteroscopic septum resection if the commencement pregnancy after randomization resulted in a pregnancy loss or if pregnancy did not occur after 1 twelvemonth of follow-upward.
Outcomes
The primary upshot measure was formulation leading to alive nascency inside 12 months after randomization. Live nascency was divers as the birth of a living foetus across 24 weeks of gestational historic period. Secondary outcomes included clinical pregnancy, pregnancy loss, ongoing pregnancy and preterm nativity, with conception leading to these outcomes within 12 months afterward randomization. In women with an ongoing pregnancy, pregnancy outcomes such as multiple pregnancy, ectopic pregnancy, placental abruption, uterine rupture and way of delivery were assessed. Data on specific complications during and following hysteroscopic septum resection, similar uterine perforation, fluid overload and endometritis, were collected. We followed women for at least 1 yr, and followed those who conceived inside that period for the grade of that pregnancy. If women had a pregnancy loss within ane year, we followed them until the next conception leading to live nascency if within 12 months after randomization, or otherwise until 12 months subsequently randomization.
Sample size
For the sample size adding, nosotros estimated live nascence rate to be 35% in women with a septate uterus without surgery and nosotros expected an increase to 70% with surgery, based on retrospective studies ( Homer et al., 2000; Chan et al., 2022a). Using a two-sided test, an alpha-error of 5% and a beta-fault of 20%, 62 women were needed to demonstrate this difference. Anticipating lost-to-follow-upwardly and protocol violations, an additional 10% was needed. Thus, a minimum of 68 women needed to be randomized. Considering of the minor sample size, we did not plan an acting assay.
Statistical analysis
We analysed the data on intention-to-treat footing. We calculated relative risks and 95% CIs for all pregnancy outcomes. To business relationship for time to conception leading to alive birth, nosotros constructed Kaplan–Meier curves using the log-rank test to compare the treatment arms and calculated the respective hazard rates with 95% CI. Additionally, we performed a per-protocol assay limited to women who were treated co-ordinate to their allocated study arm, regardless of outset having a pregnancy loss or not having go pregnant. We used SPSS® (IBM 2022, United states of america) software for all statistical analyses (version 25).
Results
Between 20 October 2010 and 3 September 2022, 80 women were randomly assigned and allocated to septum resection (n = twoscore) or expectant management (n = xl) (Fig. 1).
Figure ane.
Trial profile. *One woman withdrew informed consent immediately afterwards beingness randomized as she did not prefer a septum resection. **Ii women appeared to accept no septate uterus at time of surgery and hence septum resection was cancelled. ***Ane woman had a septum resection afterwards 1 month, iii women subsequently 4 months and one woman after 9 months of follow-up.
Figure one.
Trial profile. *One adult female withdrew informed consent immediately later on existence randomized as she did not prefer a septum resection. **Two women appeared to accept no septate uterus at fourth dimension of surgery and hence septum resection was cancelled. ***One adult female had a septum resection after i month, three women later on iv months and i adult female afterward 9 months of follow-up.
Baseline characteristics were similar between the ii treatment arms (Tabular array I). Surgical details of women allocated to septum resection are shown in Table II. One uterine perforation occurred immediately afterward introduction of the hysteroscope, after which the surgeon stopped the process without any further interventions needed. The septum was removed iv weeks later without further complications. Serious adverse events (death or illness necessitating ICU handling) were not reported. Seven women did not take monitoring via laparoscopy or ultrasound during surgery, which we documented as a protocol departure. In that location were 27 women (69%) who had a control hysteroscopy at 6 weeks follow-up. Two women had a residual septum, including the woman with the uterine perforation. Both women underwent a second process.
Table I
Baseline characteristics.
| Septum resection (north = 39) | Expectant direction (due north = 40) | |
|---|---|---|
| Age (years) * | 31.0 (29–32) | 31.seven (30–33) |
| Parity | ||
| 0 | 31 (fourscore) | 32 (fourscore) |
| 1 | half-dozen (fifteen) | 7 (18) |
| >1 | 2 (five) | 1 (2) |
| BMI (kg/mii) * | 25 (24–27) | 25 (23–26) |
| Smoker | ||
| Yes | 3 (viii) | 5 (13) |
| No | 36 (92) | 35 (87) |
| Inclusion criteria ** | ||
| Pregnancy loss | 23 (59) | 27 (67) |
| Subfertility | 15 (39) | 13 (33) |
| Preterm nativity | ii (five) | 4 (10) |
| Diagnosis | ||
| Fractional septum | 35 (92) | 36 (90) |
| Complete septum | iii (8) | 4 (10) |
| Unknown | ane | |
| Diagnostic procedure *** | ||
| Sis/GIS | 4 (ten) | four (ten) |
| 3D ultrasound | 11 (28) | xv (38) |
| MRI | 6 (fifteen) | 7 (18) |
| Hysteroscopy + laparoscopy | 21 (54) | 17 (43) |
| HSG | 9 (23) | iii (7.5) |
| Septum resection (n = 39) | Expectant management (n = xl) | |
|---|---|---|
| Historic period (years) * | 31.0 (29–32) | 31.7 (30–33) |
| Parity | ||
| 0 | 31 (80) | 32 (lxxx) |
| 1 | half-dozen (15) | 7 (eighteen) |
| >1 | 2 (5) | 1 (two) |
| BMI (kg/chiliad2) * | 25 (24–27) | 25 (23–26) |
| Smoker | ||
| Yes | iii (8) | 5 (13) |
| No | 36 (92) | 35 (87) |
| Inclusion criteria ** | ||
| Pregnancy loss | 23 (59) | 27 (67) |
| Subfertility | xv (39) | 13 (33) |
| Preterm birth | 2 (5) | 4 (ten) |
| Diagnosis | ||
| Partial septum | 35 (92) | 36 (xc) |
| Complete septum | 3 (viii) | 4 (x) |
| Unknown | 1 | |
| Diagnostic procedure *** | ||
| Sister/GIS | four (ten) | 4 (x) |
| 3D ultrasound | 11 (28) | 15 (38) |
| MRI | vi (xv) | 7 (xviii) |
| Hysteroscopy + laparoscopy | 21 (54) | 17 (43) |
| HSG | nine (23) | 3 (seven.v) |
Data are in hateful (standard departure) or n (%).
* BMI, torso mass index; GIS, gel infusion sonohysterography; HSG, hysterosalpingography; MRI, magnetic resonance imaging; SIS, saline infusion sonohysterography.
** Women could have more than one inclusion criterium.
*** Combinations of diagnostic procedures could have been used.
Table I
Baseline characteristics.
| Septum resection (north = 39) | Expectant direction (northward = 40) | |
|---|---|---|
| Age (years) * | 31.0 (29–32) | 31.seven (30–33) |
| Parity | ||
| 0 | 31 (80) | 32 (80) |
| one | 6 (15) | vii (eighteen) |
| >1 | 2 (5) | ane (ii) |
| BMI (kg/m2) * | 25 (24–27) | 25 (23–26) |
| Smoker | ||
| Yes | 3 (8) | v (xiii) |
| No | 36 (92) | 35 (87) |
| Inclusion criteria ** | ||
| Pregnancy loss | 23 (59) | 27 (67) |
| Subfertility | 15 (39) | xiii (33) |
| Preterm birth | 2 (five) | four (10) |
| Diagnosis | ||
| Partial septum | 35 (92) | 36 (90) |
| Complete septum | iii (8) | 4 (10) |
| Unknown | 1 | |
| Diagnostic process *** | ||
| Sis/GIS | 4 (10) | four (10) |
| 3D ultrasound | xi (28) | 15 (38) |
| MRI | 6 (15) | 7 (18) |
| Hysteroscopy + laparoscopy | 21 (54) | 17 (43) |
| HSG | 9 (23) | 3 (seven.5) |
| Septum resection (n = 39) | Expectant direction (n = forty) | |
|---|---|---|
| Historic period (years) * | 31.0 (29–32) | 31.vii (thirty–33) |
| Parity | ||
| 0 | 31 (eighty) | 32 (80) |
| 1 | vi (15) | seven (18) |
| >ane | 2 (5) | 1 (2) |
| BMI (kg/mii) * | 25 (24–27) | 25 (23–26) |
| Smoker | ||
| Yeah | 3 (eight) | v (13) |
| No | 36 (92) | 35 (87) |
| Inclusion criteria ** | ||
| Pregnancy loss | 23 (59) | 27 (67) |
| Subfertility | fifteen (39) | 13 (33) |
| Preterm birth | 2 (5) | four (10) |
| Diagnosis | ||
| Partial septum | 35 (92) | 36 (90) |
| Complete septum | 3 (8) | 4 (10) |
| Unknown | ane | |
| Diagnostic procedure *** | ||
| SIS/GIS | iv (10) | 4 (10) |
| 3D ultrasound | 11 (28) | 15 (38) |
| MRI | half dozen (15) | 7 (18) |
| Hysteroscopy + laparoscopy | 21 (54) | 17 (43) |
| HSG | 9 (23) | 3 (7.5) |
Information are in mean (standard deviation) or due north (%).
* BMI, body mass index; GIS, gel infusion sonohysterography; HSG, hysterosalpingography; MRI, magnetic resonance imaging; SIS, saline infusion sonohysterography.
** Women could have more than one inclusion criterium.
*** Combinations of diagnostic procedures could have been used.
Table 2
Surgical details for women allocated to uterine septum resection.
| Septum resection (due north = 39) | |
|---|---|
| Free energy modality | |
| Resectoscope (needle- or loop electrode) | 25 (64) |
| Vaporization electrode (Versapoint®) | 7 (eighteen) |
| Mechanical—pair of scissors | five (13) |
| No resection | 2 (5) |
| Concomitant imaging | |
| Laparoscopy | 28 (72) |
| Ultrasound | iv (x) |
| None | 7 (18) |
| Successful (complete resection) * | |
| Yes | 36 (92) |
| Uterine perforation | |
| Yep | one (2.6) |
| Command hysteroscopy** | |
| Yes | 27 (69) |
| Repeat procedure (incomplete resection) | |
| Yes | 2 (5.1) |
| Septum resection (northward = 39) | |
|---|---|
| Energy modality | |
| Resectoscope (needle- or loop electrode) | 25 (64) |
| Vaporization electrode (Versapoint®) | vii (18) |
| Mechanical—scissors | v (13) |
| No resection | 2 (5) |
| Concomitant imaging | |
| Laparoscopy | 28 (72) |
| Ultrasound | 4 (x) |
| None | 7 (18) |
| Successful (complete resection) * | |
| Aye | 36 (92) |
| Uterine perforation | |
| Aye | i (two.vi) |
| Control hysteroscopy** | |
| Yes | 27 (69) |
| Echo procedure (incomplete resection) | |
| Aye | two (5.1) |
Data are in n (%).
* Successful was divers every bit removal of the septum without complications as assessed at the terminate of the procedure.
**Hysteroscopy at 6 weeks of follow-up to assess the anatomy of the uterus.
Table Ii
Surgical details for women allocated to uterine septum resection.
| Septum resection (due north = 39) | |
|---|---|
| Energy modality | |
| Resectoscope (needle- or loop electrode) | 25 (64) |
| Vaporization electrode (Versapoint®) | 7 (18) |
| Mechanical—scissors | 5 (thirteen) |
| No resection | 2 (v) |
| Concomitant imaging | |
| Laparoscopy | 28 (72) |
| Ultrasound | 4 (ten) |
| None | seven (18) |
| Successful (complete resection) * | |
| Yep | 36 (92) |
| Uterine perforation | |
| Yes | 1 (ii.six) |
| Control hysteroscopy** | |
| Yes | 27 (69) |
| Repeat procedure (incomplete resection) | |
| Yep | 2 (5.ane) |
| Septum resection (n = 39) | |
|---|---|
| Energy modality | |
| Resectoscope (needle- or loop electrode) | 25 (64) |
| Vaporization electrode (Versapoint®) | 7 (eighteen) |
| Mechanical—scissors | five (13) |
| No resection | 2 (5) |
| Concomitant imaging | |
| Laparoscopy | 28 (72) |
| Ultrasound | 4 (10) |
| None | 7 (eighteen) |
| Successful (complete resection) * | |
| Yes | 36 (92) |
| Uterine perforation | |
| Yes | ane (two.half-dozen) |
| Control hysteroscopy** | |
| Yes | 27 (69) |
| Echo procedure (incomplete resection) | |
| Yes | 2 (5.1) |
Data are in n (%).
* Successful was defined as removal of the septum without complications as assessed at the end of the process.
**Hysteroscopy at six weeks of follow-up to assess the anatomy of the uterus.
Reproductive outcomes
Reproductive outcomes are summarized in Table III. In the intention-to-treat analysis, 12 of 39 women who were allocated to septum resection (31%) had a live nascence, compared to xiv of 40 women who were allocated to expectant management (35%); this corresponds to a RR 0.88 (95% CI 0.47–1.7) and an accented risk departure of minus 4.2% (95% CI −24.9% to xvi.5%). There was as well no evidence of a difference in clinical pregnancy, ongoing pregnancy, pregnancy loss or preterm nascence rates. The hateful time to conception leading to live birth was 9.viii months (95% CI 8.6 to 11) following randomization for septum resection and 9.ii months (95% CI vii.8 to 11) later randomization for expectant direction (log rank: P = 0.64). The corresponding hazard ratio (60 minutes) was 0.83 (95% CI 0.39 to 1.9) (Fig. 2).
Figure 2.
Kaplan–Meier analysis of cumulative live nativity charge per unit in women who underwent septum resection and women who had expectant management.
Effigy 2.
Kaplan–Meier analysis of cumulative live birth rate in women who underwent septum resection and women who had expectant management.
Table III
Reproductive outcomes—intention-to-treat analysis.
| Septum resection (northward = 39) | Expectant direction (due north = xl) | RR (95% CI) | |
|---|---|---|---|
| Primary outcome | |||
| Live nascency | 12 (31%) | 14 (35%) | 0.88 (0.47–i.seven) |
| Secondary outcomes | |||
| Ongoing pregnancy * | 13 (33%) | 14 (35%) | 0.95 (0.52–1.8) |
| Clinical pregnancy | 22 (56%) | 19 (48%) | i.2 (0.77–i.two) |
| Pregnancy loss ** | 11 (28%) | 5 (13%) | 2.3 (0.86–5.9) |
| Preterm birth | v (13%) | four (ten%) | one.3 (0.37–4.4) |
| Septum resection (n = 39) | Expectant management (northward = twoscore) | RR (95% CI) | |
|---|---|---|---|
| Master outcome | |||
| Live birth | 12 (31%) | 14 (35%) | 0.88 (0.47–1.seven) |
| Secondary outcomes | |||
| Ongoing pregnancy * | 13 (33%) | xiv (35%) | 0.95 (0.52–ane.8) |
| Clinical pregnancy | 22 (56%) | xix (48%) | one.two (0.77–one.2) |
| Pregnancy loss ** | xi (28%) | five (13%) | 2.iii (0.86–v.9) |
| Preterm nativity | v (thirteen%) | 4 (10%) | i.3 (0.37–4.4) |
Information are in n (%).
RR, relative risk.
* One woman who underwent septum resection had an ongoing pregnancy that ended in a belatedly pregnancy loss at 17 weeks.
** One woman had a biochemical pregnancy that ended in a pregnancy loss at 5 weeks.
Table III
Reproductive outcomes—intention-to-care for analysis.
| Septum resection (north = 39) | Expectant management (north = 40) | RR (95% CI) | |
|---|---|---|---|
| Primary upshot | |||
| Live birth | 12 (31%) | 14 (35%) | 0.88 (0.47–1.7) |
| Secondary outcomes | |||
| Ongoing pregnancy * | xiii (33%) | fourteen (35%) | 0.95 (0.52–1.8) |
| Clinical pregnancy | 22 (56%) | 19 (48%) | ane.2 (0.77–i.2) |
| Pregnancy loss ** | 11 (28%) | v (13%) | 2.3 (0.86–v.9) |
| Preterm birth | 5 (xiii%) | 4 (10%) | one.3 (0.37–4.4) |
| Septum resection (n = 39) | Expectant direction (north = 40) | RR (95% CI) | |
|---|---|---|---|
| Primary outcome | |||
| Alive birth | 12 (31%) | 14 (35%) | 0.88 (0.47–1.7) |
| Secondary outcomes | |||
| Ongoing pregnancy * | 13 (33%) | fourteen (35%) | 0.95 (0.52–ane.eight) |
| Clinical pregnancy | 22 (56%) | 19 (48%) | one.ii (0.77–1.ii) |
| Pregnancy loss ** | 11 (28%) | 5 (13%) | 2.3 (0.86–5.ix) |
| Preterm birth | 5 (13%) | 4 (10%) | 1.3 (0.37–iv.4) |
Information are in n (%).
RR, relative risk.
* One woman who underwent septum resection had an ongoing pregnancy that ended in a tardily pregnancy loss at 17 weeks.
** One woman had a biochemical pregnancy that ended in a pregnancy loss at 5 weeks.
In women with an ongoing pregnancy, breech presentation at the time of delivery occurred in two women were allocated to septum resection and in vi women who were allocated to expectant management (Table IV). Of thirteen women who allocated to septum resection, ix (69%) had a caesarean section while 5 of 14 women who allocated to expectant direction (36%) had a caesarean section (RR one.9 (95% CI 0.88 to 5.0)). The reasons for a caesarean section in women who were allocated to septum resection were elective reasons (northward = 3), non-progressive labour (n = 1), foetal distress (n = 1), placenta praevia (north = 1) or unknown (n = 4), and the reasons in women who were allocated to expectant management were breech presentation (due north = iii) or foetal distress (n = ii). 2 women in the septum resection arm had twin pregnancies (xv%) versus none in the expectant management arm. There were no cases of ectopic pregnancy, uterine rupture, placental abruption, postpartum haemorrhage or intra-uterine foetal expiry.
Table IV
Pregnancy outcomes for women with an ongoing pregnancy—intention-to-treat.
| Septum resection (n = 13) | Expectant direction (n = 14) | RR (95% CI) | |
|---|---|---|---|
| Presentation at term | |||
| Cephalic | 11 (85%) | 7 (54%) | 1.6 (0.87–two.viii) |
| Breech | 2 (xv%) | 6 (46%) | |
| Unknown | 0 | 1 | |
| Mode of commitment | |||
| Caesarean department | nine (69%) | 5 (36%) | ane.9 (0.88–v.0) |
| Spontaneous | 4 (31%) | nine (64%) |
| Septum resection (north = 13) | Expectant management (northward = fourteen) | RR (95% CI) | |
|---|---|---|---|
| Presentation at term | |||
| Cephalic | 11 (85%) | 7 (54%) | i.half-dozen (0.87–ii.viii) |
| Breech | two (15%) | 6 (46%) | |
| Unknown | 0 | ane | |
| Way of delivery | |||
| Caesarean department | 9 (69%) | v (36%) | 1.9 (0.88–five.0) |
| Spontaneous | four (31%) | 9 (64%) |
Data are in n (%).
RR, relative risk.
Table Iv
Pregnancy outcomes for women with an ongoing pregnancy—intention-to-treat.
| Septum resection (n = 13) | Expectant management (northward = fourteen) | RR (95% CI) | |
|---|---|---|---|
| Presentation at term | |||
| Cephalic | xi (85%) | 7 (54%) | 1.vi (0.87–two.8) |
| Breech | ii (15%) | 6 (46%) | |
| Unknown | 0 | ane | |
| Fashion of delivery | |||
| Caesarean department | ix (69%) | v (36%) | ane.ix (0.88–5.0) |
| Spontaneous | iv (31%) | ix (64%) |
| Septum resection (north = xiii) | Expectant direction (north = 14) | RR (95% CI) | |
|---|---|---|---|
| Presentation at term | |||
| Cephalic | 11 (85%) | 7 (54%) | 1.vi (0.87–2.eight) |
| Breech | 2 (15%) | 6 (46%) | |
| Unknown | 0 | 1 | |
| Mode of delivery | |||
| Caesarean section | 9 (69%) | 5 (36%) | 1.9 (0.88–5.0) |
| Spontaneous | 4 (31%) | ix (64%) |
Data are in n (%).
RR, relative risk.
Per-protocol analysis
In line with the intention-to-treat analysis, the per-protocol analysis showed no evidence of a difference in live nativity, ongoing pregnancy, clinical pregnancy, pregnancy loss or preterm nascency, RR 0.92 (95% CI 0.55 to 1.5), RR 0.99 (95% CI 0.53 to 1.nine), RR 1.ane (95% CI 0.74 to 1.7), RR 1.83 (95% CI 0.lxx to 4.8) and RR one.2 (95% CI 0.34 to 3.ix), for septum resection versus expectant management respectively) (Table V).
Table V
Reproductive outcomes—per-protocol analysis.
| Septum resection (n = 36) | Expectant direction (north = 33) | RR (95% CI) | |
|---|---|---|---|
| Primary event | |||
| Live nascence | 12 (33%) | 12 (36%) | 0.92 (0.55–ane.5) |
| Secondary outcomes | |||
| Ongoing pregnancy * | xiii (36%) | 12 (36%) | 0.99 (0.53–1.9) |
| Clinical pregnancy | 21 (58%) | 17 (52%) | one.1 (0.74–one.7) |
| Pregnancy loss | 10 (28%) | v (15%) | 1.eight (0.70–4.8) |
| Preterm nascence | 5 (14%) | four (12%) | one.2 (0.34–3.9) |
| Septum resection (n = 36) | Expectant management (due north = 33) | RR (95% CI) | |
|---|---|---|---|
| Master effect | |||
| Live nascence | 12 (33%) | 12 (36%) | 0.92 (0.55–1.5) |
| Secondary outcomes | |||
| Ongoing pregnancy * | 13 (36%) | 12 (36%) | 0.99 (0.53–1.9) |
| Clinical pregnancy | 21 (58%) | 17 (52%) | 1.i (0.74–ane.seven) |
| Pregnancy loss | 10 (28%) | 5 (fifteen%) | 1.8 (0.lxx–iv.8) |
| Preterm birth | 5 (14%) | four (12%) | 1.ii (0.34–3.9) |
Data are in n (%).
RR, relative chance.
* Ane woman who underwent septum resection had an ongoing pregnancy that ended in a tardily pregnancy loss at 17 weeks.
Table V
Reproductive outcomes—per-protocol assay.
| Septum resection (n = 36) | Expectant management (n = 33) | RR (95% CI) | |
|---|---|---|---|
| Primary effect | |||
| Live nativity | 12 (33%) | 12 (36%) | 0.92 (0.55–ane.5) |
| Secondary outcomes | |||
| Ongoing pregnancy * | xiii (36%) | 12 (36%) | 0.99 (0.53–ane.ix) |
| Clinical pregnancy | 21 (58%) | 17 (52%) | 1.1 (0.74–1.7) |
| Pregnancy loss | 10 (28%) | 5 (15%) | one.8 (0.lxx–4.eight) |
| Preterm birth | five (fourteen%) | iv (12%) | 1.2 (0.34–3.9) |
| Septum resection (n = 36) | Expectant management (n = 33) | RR (95% CI) | |
|---|---|---|---|
| Principal outcome | |||
| Live nativity | 12 (33%) | 12 (36%) | 0.92 (0.55–1.5) |
| Secondary outcomes | |||
| Ongoing pregnancy * | xiii (36%) | 12 (36%) | 0.99 (0.53–1.9) |
| Clinical pregnancy | 21 (58%) | 17 (52%) | 1.1 (0.74–ane.vii) |
| Pregnancy loss | 10 (28%) | 5 (15%) | one.8 (0.lxx–4.8) |
| Preterm birth | 5 (14%) | four (12%) | 1.2 (0.34–iii.ix) |
Data are in n (%).
RR, relative adventure.
* 1 woman who underwent septum resection had an ongoing pregnancy that concluded in a late pregnancy loss at 17 weeks.
Discussion
In this international, multicentre, open-characterization, randomized controlled trial in women with a septate uterus, septum resection did not improve alive birth rates compared with expectant management. At that place was also no evidence of a difference in other reproductive outcomes, like ongoing pregnancy, pregnancy loss and preterm nativity rates. One complexity of handling, a perforation of the uterus, was sustained during septum resection.
Our study has a number of strengths. Nosotros performed a pragmatic written report, in which we included women who had been diagnosed by their treating gynaecologist in 10 centres in iv countries worldwide, based on the leading classification at that fourth dimension. This reflects daily practices and ensures a high generalizability of the study results. Whilst an accepted nomenclature of uterine anomalies remains elusive ( Grimbizis et al., 2022; ASRM, 2022; Ludwin et al., 2022), it seems unlikely that subtle changes in the definition of a uterine septum, would impact substantially upon our findings. In improver, there was a high compliance, i.due east. only a few women were lost to follow-up (4 women, five%).
A limitation of our study is that with our sample size of 68 women, nosotros were able to detect an comeback in live birth from 35% to 70% with surgery, which we expected based on the existing literature at the beginning of the written report ( Homer et al., 2000). To observe a smaller comeback of ten% in live births, for example from 35% to 45%, new studies would need to recruit at least 752 women. Whatever try to ostend or refute the results of this trial would thus need a worldwide, dedicated and adequately resourced collaboration. Such an enterprise is unlikely to be feasible, especially if one considers that the only other randomized controlled trial comparing septum resection with expectant management carried out in the United kingdom of great britain and northern ireland was forced to end considering of poor recruitment; six patients in a recruitment period of 3 years (airplane pilot randomized controlled trial of hysteroscopic septum resection, ISRCTN28960271).
Our findings are in line with our recently published international multicentre cohort report of 257 women with a septate uterus, which showed no differences in live nascence rates between women who underwent septum resection and women following expectant management, adjusted for possible confounders (53% vs 72%, respectively, HR 0.71, 95% CI 0.49 to i.02) ( Rikken et al., 2022).
Our study was not powered to evaluate any differential consequence of septum resection in women with pregnancy loss compared with those presenting with subfertility, or according to the number of pregnancy losses, nor was it powered to evaluate any possible differential effect of the size of the uterine septum. Complete septa are less common than incomplete septa and represented under ten% of our trial population. Of the seven women with a complete septate uterus, live birth occurred in two of 3 women (66.7%) who underwent septum resection, and 3 of 4 women (75%) who had expectant management.
The findings of this randomized controlled trial show that hysteroscopic septum resection does non improve live birth rates or other reproductive outcomes in women with a septate uterus. The surgical procedure, past definition, has the propensity for harm, with one peri-operative uterine perforation occurring in a woman undergoing septum resection in this trial. Thus, in light of the lack of any evidence of effectiveness and the potential for harm, we recommend against septum resection as a routine process in clinical practice. Women with a septate uterus need to exist informed about the data of this written report. After counselling, according to the principles of shared decision-making, an informed decision can then exist made.
Data availability
Request for information collected for the study can be made to the co-corresponding authors and will be considered on an individual footing. Additional, study-related documents are immediately available and tin can be requested from the co-corresponding authors.
Acknowledgements
Nosotros thank all women who participated in this trial, all participating institutions and their staff and research employees for their contribution to this study, and all recruiting staff and research employees in all hospitals in the Netherlands who referred their patients to one of the participating centres.
Authors' roles
C.R.M., B.W.J.M. and Chiliad.Thou. designed the study. C.R.K. and J.F.West.R. coordinated the trial. J.F.W.R. collected the data. Thou.H.East., One thousand.Y.B., T.S., F.W.J., A.One thousand.Thou.G.J.M. and H.A.v.5. managed the trial in the hospitals in the Netherlands, and commented on the newspaper. R.P. is responsible for the trial in Iran, T.J.C. in the UK and Thousand.D.South. in the U.s., and all commented on the typhoon paper. J.F.Due west.R. and Chiliad.v.Westward. performed the statistical analyses. J.F.Westward.R., M.five.W., M.G. and F.v.d.5. drafted the paper. All authors interpreted the data, critically revised the article and approved the final version.
Funding
There was no funder of this report. The corresponding author had full admission to all the information in the study and had last responsibility for the decision to submit for publication.
Conflict of involvement
H.A.v.5. reports personal fees from Medtronic, outside the submitted work. B.Due west.J.M. reports grants from NHMRC, personal fees from ObsEva, personal fees from Merck Merck KGaA, personal fees from Guerbet and personal fees from iGenomix, outside the submitted work. Thousand.K. works at the Section of Reproductive Medicine of the Amsterdam UMC (Location AMC and location VUMC). Location VUMC has received several research and educational grants from Guerbet, Merck and Ferring, outside the scope of the submitted piece of work. Yard.H.E. reports a patent on a surgical endoscopic cutting device and procedure for the removal of tissue from a trunk cavity licensed to Medtronic, outside the context of the submitted work. The remaining authors have nil to declare.
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