Hysteroscopic resection of the septum improves the

pregnancy rate of women with unexplained infertility:

a prospective controlled trial
Antonio Mollo, M.D.,
a
Pasquale De Franciscis, M.D.,
b
Nicola Colacurci, M.D.,
b
Luigi Cobellis, M.D.,
b
Antonio Perino, M.D.,
c
Renato Venezia, M.D.,
c
Carlo Alviggi, M.D.,
a
and Giuseppe De Placido, M.D.
a
a
Department of Obstetrics, Gynecology, Urology, and Reproductive Medicine, Federico II University of Naples;
b
Department of
Gynecology, Obstetrics, and Reproductive Sciences, Second University of Naples; and
c
Department of Obstetrics and
Gynecology, University of Palermo, Palermo, Italy
Objective: To assess fecundity of infertile women after surgical correction of uterine septum.
Design: Prospective controlled trial.
Setting: Three academic infertility clinics.
Patient(s): Forty-four women affected by septate uterus and otherwise unexplained infertility represented the
study group (group A), and 132 women with unexplained infertility were enrolled as control subjects (group B).
Intervention(s): Hysteroscopic metroplasty was performed in group A, and group Bwas managed expectantly. All
women were followed-up for 1 year without any other intervention.
Main Outcome Measure(s): Fecundity rate was calculated as the number of pregnancies per 100 person-months
Result(s): Pregnancy rate (38.6% vs. 20.4%) and live birth rate (34.1% and 18.9%) were signicantly higher in
group A than in group B. The survival analysis showed that the probability of a pregnancy in the twelve-months
follow up was signicantly higher in patients who had undergone metroplasty than in women with unexplained
infertility. The corresponding fecundity (10-week pregnancy) rates were 4.27 and 1.92 person-months in women
who had undergone metroplasty and in women with unexplained infertility, respectively.
Conclusion(s): Hysteroscopic resection of the septumimproves fecundity of women with septate uterus and other-
wise unexplained infertility. Patients with septate uterus and no other cause of sterility have a signicantly higher
probability of conceiving after removal of the septum than patients affected by idiopathic sterility. (Fertil Steril

2009;91:262831. 2009 by American Society for Reproductive Medicine.)

Key Words: Hysteroscopic metroplasty, septate uterus, primary infertility, fecundity
Septate uterus is a congenital anomaly characterized by per-
sistence of the partition resulting from the fusion of the two
mullerian ducts. This anomaly has been commonly associ-
ated with a poor reproductive outcome, such as abortion
and preterm delivery (1, 2). Hysteroscopic metroplasty is
a simple and safe approach for the removal of the septum
(3). There is a large body of evidence that this operation
improves live birth rate in patients affected by recurrent abor-
tion; in contrast, the role of the metroplasty in patients af-
fected by primary infertility is still debated (4, 5).
Although retrospective and performed in small series of
unselected patients, many studies have described an increase
of the fecundity rate after hysteroscopic metroplasty. This
evidence is consistent with data emerging from a prospective
observational study conducted in a large and homogeneous
population of infertile women with septate uterus and
otherwise unexplained infertility (6). All these trials were
based on self-control design examining reproductive per-
formance before and after surgery.
Because removal of the septum is strongly recommended
to avoid abortion (7, 8) the issue of a prospective controlled
trial, comparing treated and untreated women, remains unre-
solved. Nevertheless, it could be hypothesized that if septate
uterus is a cause of sterility, its removal would increase the
fecundity rate. Based on this consideration, postoperative
reproductive outcome of women with septate uterus and oth-
erwise unexplained infertility would be signicantly better
compared with patients affected by the sole unexplained in-
fertility. The present study was designed to assess whether
women affected by septate uterus and no other causes of
infertility were more likely to become pregnant in the year af-
ter metroplasty than a similar group of infertile women with-
out uterine malformation.
MATERIAL AND METHODS
Patient Selection
Participants were recruited between November 1, 1997, and
October 31, 2003, from a population of infertile women
aged between 18 and 35 years referring to the outpatient
infertility clinics of our institutions. Institutional Review
Received January 18, 2008; revised and accepted April 7, 2008; published
online June 19, 2008.
A.M. has nothing to disclose. P.D.F. has nothing to disclose. N.C. has
nothing to disclose. L.C. has nothing to disclose. A.P. has nothing to dis-
close. R.V. has nothing to disclose. C.A. has nothing to disclose. G.D.P.
has nothing to disclose.
Reprint requests: Antonio Mollo, M.D., Department of Obstetrics, Gyne-
cology, Urology, and Reproductive Medicine, Federico II University of
Naples, Via Pansini 5, 80131 Naples, Italy (FAX: 39-081-7463747;
E-mail: antmollo@unina.it).
Fertility and Sterility

Vol. 91, No. 6, June 2009 0015-0282/09/$36.00

Copyright 2009 American Society for Reproductive Medicine, Published by Elsevier Inc. doi:10.1016/j.fertnstert.2008.04.011
2628
Board approval was obtained from the Ethics Committees of
our institutions. Only normogonadotrophic normoovulatory
women, with body mass indexes (BMIs) ranging between
18 and 28 kg/m
2
, were considered. Patients affected by sep-
tate uterus and otherwise unexplained infertility represented
the study group (group A). For each patient included in the
study group, the rst three consecutive women whose condi-
tion was diagnosed as unexplained infertility were enrolled as
control subjects (group B).
All of the women underwent diagnostic work-up to detect
endocrine, chronic inammatory, infectious, anatomic, and
chromosomal alterations. A semen analysis was obtained
from the partner. Endocrinometabolic assessment included
tests for diabetes, dysthyroidism, hypopituitarism, hyperpro-
lactinaemia, luteal insufciency, and hyperandrogenism.
Transvaginal ultrasound scan was performed to evaluate pel-
vic anatomy and ovarian structure. Serum levels of rheuma-
toid factor, C-reactive protein, antibodies against nucleus,
mitochondria, smooth muscle cells, phospholipids, and cardi-
olipin (IgM and IgG) were assessed. Cervical swabs to diag-
nose Chlamydia trachomatis, Mycoplasma hominis, and
Ureaplasma urealyticum infections were performed. Chla-
mydia antibody testing (IgM and IgG) was also done. Tubal
patency was screened by means of hysterosalpingography.
Hysteroscopy was performed to detect either mullerian mal-
formations or organic pathologies. Karyotype was studied to
detect chromosomal aberrations. After this work-up, all pa-
tients without any detectable pathology underwent diagnostic
laparoscopy. The Rotterdam criteria (9) were adopted for
diagnosing polycystic ovary syndrome. Endometriosis was
classied according to the revised American Fertility Society
criteria (10).
After this work-up, 44 patients with septate uterus and no
other cause of infertility were included in the study group
(group A), and 134 subjects affected by unexplained infertil-
ity served as the control group (group B).
Methods
In group A surgery was scheduled in early proliferative phase
without pharmacologic preparation at the time of diagnostic
laparoscopy. All of the surgeons involved in the study were
experienced hysteroscopists with similar skill levels. The
procedure was performed with a 26-Fr resectoscope tted
with a monopolar 90

-angle knife electrode and with

a 0-degree telescope (Karl Storz, Tuttlingen, Germany).
The electrical generator was set at 6080 W pure cut current.
The uterine cavity was distended with a urologic solution
(sorbitol 2.7 p/v, mannitol 5.4 p/v) at a constant inow
pressure of 6090 mm Hg. Fluid balance was recorded by
measuring the infused and drained uid from the hystero-
scope. After insertion of the resectoscope, tubal ostia were
visualized and the septum was incised across the apex from
the lower margin, gradually reducing it with progressive up-
wards horizontal midline incisions until visualization of the
muscular bers. The procedure was considered to be com-
plete when a normal cavity was obtained and the endoscope
could be moved freely from one tubal ostium to the other.
Postoperative follow-up consisted of an ultrasonographic
and hysteroscopic examination performed 1 month after sur-
gery. With the presence of a normal-shaped cavity, patients
were asked to have unprotected sexual intercourse for the
next 12 months. Control subjects (group B) were managed
expectantly in the 12 months following the control visit
scheduled 1 month after the laparoscopy.
The results are reported as mean SD. Data were analyzed
with SPSS version 12.0 (SPSS, Chicago, IL). Chi-squared
statistics were used to compare discontinuous data. The cu-
mulative pregnancy rate for 12 months of follow-up was cal-
culated by using Kaplan Maier survival analysis. The starting
point of the life table calculation was the date of the control
visit for both groups, and the end point was the date preg-
nancy began (worked out by early ultrasound examination
at 10 weeks of amenorrhea) or 12 months if not pregnant.
The comparison of pregnancy probability between groups
was evaluated by using log rank test. The fecundity rate is
the number of pregnancies per 100 person-months. In partic-
ular, fecundity rate was calculated as follows: number of
pregnancies/months of observation for every patients.
P<.05 was considered to be statistically signicant.
RESULTS
In the present study, the reproductive outcome of 176 patients
affected by unexplained infertility was assessed. Forty-four
of these women had a uterine septum (group A), and the re-
maining 132 served as the control group (group B). The
two groups were similar for age, duration of infertility, and
BMI (Table 1). Postoperative diagnostic hysteroscopy
showed a normal-shaped cavity in all patients. Reproductive
outcome is shown in Table 2. Only one patient in the study
group and three patients in the control group were lost during
the follow-up. After the 12-month follow-up period, 17 preg-
nancies (38.6%) in group A and 27 (20.4%) in group B were
achieved (P.016). Two abortions and three preterm deliver-
ies in patients who had undergone metroplasty, and two abor-
tions and only one preterm delivery in the control subjects,
were registered. Live birth rate was signicantly higher in
group A than in in group B (34.1% and 18.9%, respectively;
c
2
: P<.05). The survival analysis showed that the probability
of a pregnancy during the 12-month follow up signicantly
differed between the two groups (log rank: P<.05; Fig. 1).
The corresponding fecundity (10-week pregnancy) rates
were 4.27 and 1.92 person-months in the women who had un-
dergone metroplasty and the women with unexplained infer-
tility, respectively (Table 2).
DISCUSSION
Uterine septum is the most common uterine malformation
and is associated with the worst reproductive outcome; surgi-
cal correction of the anomaly signicantly improves the preg-
nancy outcome (1113). On the other hand, the issue whether
the septate uterus is a cause of infertility is controversial.
Fertility and Sterility

2629
Thepresent data demonstrate that sterilepatients withseptate
uterus and no other cause of sterility have a signicantly higher
probability of conceiving after removal of the septum than
patients affected by idiopathic sterility. The two study groups
were homogeneous, and a bias in the diagnosis of idiopathic in-
fertility is unlikely, because the study population was restricted
to infertile women in whom a standard work-up including lap-
aroscopy revealed no factors that could explain infertility.
Data from the literature analyzing the impact of uterine
septum on the reproductive potential of women with primary
infertility is questionable. Several self-control studies (13
19) reported an increased pregnancy rate after metroplasty
in unselected groups of infertile patients, ranging from 21%
to 71%. Unfortunately, heterogeneity and low numbers of pa-
tients, retrospective design of some of them, and the absence
of a control group make the interpretation of the results dif-
cult. Data from assisted reproductive technologies (ART)
have also provided contrasting information on this issue. In
a retrospective analysis of untreated sterile patients present-
ing with septate uterus and undergoing ART for other reasons
(tubal factor, male factor, endometriosis), Marcus et al. (20)
found implantation and pregnancy rates similar to those of
the general sterile population undergoing ART, suggesting
that metroplasty would not be useful in patients without
any prior reproductive failure. In contrast, Lavergne et al.
(21) found signicantly lower implantation and pregnancy
rates after ART in sterile women with untreated uterine mal-
formation compared with the general sterile population.
Moreover, dividing the patients into groups according to
the treatment received, the difference was annulled when
patients underwent metroplasty.
More recently, Pabuccu and Gomel (6) published the rst
prospective observational study to assess the spontaneous
fecundity of a selected series of infertile women after metro-
plasty. A pregnancy rate of 41% was reported in patients with
septate uterus presenting no other reason for infertility after
surgical treatment of the malformation. Those authors sug-
gest that such a percentage, even though lower than those
reported in the literature concerning women with recurrent
abortion, supports the idea of the existence of a subtle
factor able to impair implantation in these patients. Unfor-
tunately, this study also was performed according to a self-
control design.
Although prospective randomized trials would be required
to denitively assess the relationship between septate uterus
and infertility, deontologic issues render such study design
unrealizable. Because this malformation is a cause of abor-
tion, it would not be ethical to randomize affected women
to a no treatment group. As a consequence, the only way
to perform a longitudinal prospective-controlled trial is to
identify an adequately selected control population. The pres-
ent study is the rst prospective trial designed to have women
with unexplained sterility treated surgically for uterine mal-
formation as the study population, and patients with
TABLE 1
Patient characteristics.
Group A Group B
Patients, n 44 132
Type, n
Va 8
Vb 36
Age, yrs 29.7 3.2 30.7 3.7
Duration of infertility, yrs 2.4 0.8 2.6 0.7
Body mass index, kg/m
2
22.9 2.5 23.4 2.7
Mollo. Metroplasty in unexplained infertility. Fertil Steril 2009.
TABLE 2
Reproductive outcome.
Group A Group B
P
value
Patients, n 44 132
Pregnancies, n (%) 17 (38.6) 27 (20.4) <.05
Abortions, n (%) 2 (11.8) 2 (7.4) NS
Pretermdeliveries,
n (%)
3 (17.6) 1 (3.7) NS
Term deliveries,
n (%)
12 (70.6) 24 (88.9) NS
Live birth rate, % 34.1 18.9 <.05
Fecundity rate 4.27 1.92
Mollo. Metroplasty in unexplained infertility. Fertil Steril 2009.
FIGURE 1
Cumulative probability of a pregnancy in the 12
months after the control visit scheduled 1 month
after the metroplasy in study group A (red line) and 1
month after the diagnostic laparoscopy in control
group B (black line).
Mollo. Metroplasty in unexplained infertility. Fertil Steril 2009.
2630
Mollo et al. Metroplasty in unexplained infertility Vol. 91, No. 6, June 2009
unexplained sterility with no uterine malformation as the
control group. This design was based on the idea that if sep-
tate uterus is a cause of infertility, an increase in fecundity
rate after its removal would be expected. This hypothesis
seems to be supported by the present data. More specically,
both cumulative probability to become pregnant and fecun-
dity rate were signicantly higher in the study group.
The results of this study enforce the idea that uterine septum
could affect implantation and early pregnancy processes, and
they are consistent with experimental and histologic ndings.
Septumstructure seems to be different than that of normal my-
ometrium and is probably the cause of the altered maturation
process of the covering endometrium that can lead to implan-
tation failure. As a matter of fact, some authors have observed
an altered proportion between muscular and broelastic con-
nective tissue and an abnormal vascularization (22). Fedele
et al. (23) found maturation defects of the endometrium cov-
ering the septum with reduced number of glandular ostia and
altered maturation of the cilia. In these patients, the resection
of the septum could lead to a restoration of the normal uterine
contractility and endometrial maturation, which in turn may
result in a improved reproductive performance.
In recent years, technologic improvements in endoscopic
technology have led to the introduction of minihysteroscopes
not exceeding 5 mm in diameter, tted with bipolar elec-
trodes working in saline solution, which allow a simple and
safe treatment of many intrauterine pathologies, reducing
the risk of severe complications (24). We have recently
shown (25) that a minihysteroscope with bipolar electrode
for the incision of uterine septum is as effective as resecto-
scope with unipolar electrode in terms of reproductive out-
come and is associated with a shorter operating time and
a lower complication rate.
At the present time it is widely acknowledged that the
diagnosis of septate uterus demands surgical treatment
when associated with adverse reproductive outcome, but
the role of metroplasty in infertile women with a septate
uterus and otherwise unexplained infertility is still debated
(6). The ndings of the present study, together with availabil-
ity of minisurgical techniques, strongly encourage the treat-
ment of uterine septa diagnosed during the sterility work-up
of women whose primary infertility remains otherwise
unexplained.
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