recurrent pregnancy loss - uterine factors based on fertility sterility journal - evidence based Dr.Anu.M - Mch Resident - Department of Reproductive Medicine and Surgery

1. UTERINE FACTORS IN RECURRENT
PREGNANCY LOSSES
Dr. Anu.M
I year Mch Resident
Department of Reproductive
Medicine and Surgery, SRIHER

2. VOLUME 115, ISSUE 35, P538-545, MARCH 01, 2021

3. 2013
RPL is a distinct disorder
defined by two or more
failed clinical pregnancies
Pregnancy is defined as a
clinical pregnancy
documented by
ultrasonography or
histopathological
examination

4. A diagnosis of Recurrent
Pregnancy Loss (RPL) could
be considered after the
loss of 2 or more
pregnancies.
All pregnancy losses (PLs)
from the time of
conception until 24 weeks
of gestation
Confirmed at least by
either serum or urine b-
hCG, including non-
visualized pregnancy losses
Ectopic
Molar pregnancies
Implantation failure

5. Recurrent “Early” Pregnancy
Loss (REPL) is the loss of 2 or
more pregnancies before 10
weeks of gestational age
Primary RPL is described as
RPL without a previous
ongoing pregnancy (viable
pregnancy) beyond 24
weeks’ gestation
Secondary RPL is defined as
an episode of RPL after one
or more previous
pregnancies progressing
beyond 24 weeks’ gestation

6. Recurrent miscarriage
is defined as the loss of
three or more
consecutive
pregnancies
All pregnancy losses
from the time of
conception until 24
weeks of gestation

7. There is no general consensus
for defining recurrent pregnancy
loss (RPL) and its management
Youssef A, Vermeulen N, Lashley E, Goddijn M, van der Hoorn MLP. Comparison and appraisal of (inter)national
recurrent pregnancy loss guidelines. Reprod Biomed Online 2019;39:497–503.

8. It is appropriate to start investigating infertile women—
particularly if they are young—after two miscarriages
(ESHRE 2018)

10. PREVALENCE
RPL occurs in 1%–3% of couples who try to conceive(ESHRE 2018)
Anatomical uterine anomalies –
15% to 42% cases of RPL
Congenital uterine
anomalies - 7%–28%
Acquired uterine
anomalies- 6%–15%

11. To determine which of the abovementioned entities are
likely to impair pregnancy development and which are just
innocent bystanders unrelated to RPL, clinicians must
perform a thorough uterine assessment in concordance
with the international guidelines

12. The sensitivity of 2D ultrasounds is low (60%–80%) for detecting uterine malformations

13. Sonohysterogram, hysterosalpingogram, and/or hysteroscopy
2012
SHG allows the delineation of the internal contours of the uterine cavity as well as the
surface of the uterus

14. Smit JG, Overdijkink S, Mol BW, Kasius JC, Torrance HL, Eijkemans MJ, et al. The impact of diagnostic criteria on the reproducibility of the hysteroscopic diagnosis of the septate uterus: a
randomized controlled trial. Hum Reprod 2015;30:1323–30.
Hysteroscopy only offers mediocre accuracy for distinguishing septate from arcuate uteri with poor
interobserver agreement on final diagnosis.
Hence,hysteroscopy per se is insufficient as a single tool for appropriately diagnosing uterine malformations and deciding
on the appropriate treatment, notably, the need for resection—metroplasty—of septate uteri
Combining both hysteroscopy and laparoscopy remains the gold standard for diagnosing uterine malformations
because it offers a simultaneous internal and external view of the uterus. Yet this dual approach is invasive

15. Pelvic MRI may be helpful in
complicated cases associated
with complex anatomical
defects like rudimentary
cavities but is not routinely
necessary
Class U3 and U5 malformations

16. Venetis CA, Papadopoulos SP, Campo R, Gordts S, Tarlatzis BC, Grimbizis GF. Clinical implications of
congenital uterine anomalies: a meta-analysis of comparative studies. Reprod Biomed Online 2014;
Higher prevalence of miscarriage in women with congenital uterine malformations compared to controls
The septate uterus is the congenital malformation most commonly associated with RPL, being found in
6%–16% of cases
Septate uteri result from partial or complete failure of resorption of the medial septum between the two
Mullerian ducts during fetal life.
Other congenital disorders, in particular, unicornuate, arcuate, and bicornuate uteri, are reported in only
0.5%–2% of cases of RPL
Women with septate uterus (RR 2.65) and bicornuate uterus (RR 2.32) had an increased probability of
first-trimester PL, compared to their controls
Women with arcuate uterus (RR 2.27), septate uterus (RR 2.95) and bicornuate uterus (RR 2.90) had an
increased probability of second-trimester PL, compared to their controls
CONGENITAL MALFORMATIONS AND RPL

17. The American Fertility Society classification of Mullerian Agenesis-1988

21. The coronal—frontal view—of the uterus is ideal for diagnosing congenital uterine anomalies

22. September 1, 2016

25. The lack of a universally accepted standard definition of septate uterus may add
variability in diagnostic classifications and affect the actual incidence of surgical
metroplasties
Ludwin A, Ludwin I. Comparison of the ESHRE-ESGE and ASRM classifications of Mullerian duct anomalies in
everyday practice. Hum Reprod 2014;30:569–80.

26. PATHOPHYSIOLOGY BY WHICH SEPTATE UTERUS INTERFERES
WITH EARLY PREGNANCY DEVELOPMENT
Inadequate implantation of the embryo on a poorly vascularized septum
The septum could alter the pre- and postovulatory changes of the
endometrium under the influence of estradiol and progesterone
Uterine contractibility
Disruption of the physiology of endometrial factors such as, notably, vascular
endothelial growth factor
Rikken J, Leeuwis-Fedorovich NE, Letteboer S, Emanuel MH,Limpens J, van der Veen F, et al. The
pathophysiology of the septate uterus: a systematic review.Br J Obstet Gynecol 2019;126:1192–9.

27. MANAGEMENT OF CONGENITAL MALFORMATIONS
Hysteroscopic metroplasty is the most commonly preferred approach for resecting the uterine
septum
A 15 French gauge (FR) hysteroscope with a 5 FR operative channel allows the use of
instruments (including bipolar and monopolar electrodes and cold scissors).
Alternatively, a 15–26 FR resectoscope (hysteroscope with cauterization loop) equipped with
bipolar or monopolar cautery or laser can be used with comparable results
This procedure has been determined to be safe and effective, although this determination was
based on nonrandomized and mainly retrospective trials only
Rikken JF, Kowalik CR, Emanuel MH, Mol BW, Van der Veen F, van Wely M,et al. Septum resection for women of reproductive age with a septate uterus. Cochrane Database Syst Rev
2017;1:CD008576.

28. COMPLICATIONS OF HYSTEROSCOPIC METROPLASTY
Uterine perforation
Postoperative
intrauterine adhesions
Cervical laceration
Increased rate of CS
due to dystocic
obstetrical
presentations
Uterine rupture during
subsequent
pregnancies reported
Sentilhes L, Sergent F, Berthier A, Catala L, Descamps P, Marpeau L. [Uterine rupture following operative hysteroscopy]. Gynecol Obstet Fertil 2006;34:1064–70.
Abdominal ultrasound guidance during surgery, the use of barrier gels, and postoperative hysteroscopies are options
aimed at reducing postoperative complications

29. The ASRM and French guidelines recommend septum resection in case of septate uteri associated with RPL

31. ACQUIRED UTERINE ANOMALIES AND RPL

32. LEIOMYOMAS
0.5-1.3% of RPL Infertility due to implantation failure
3 cell populations –
well-differentiated,
intermediate-
differentiated and
fibroid stem cells
Faster growth with
higher proportion of
fibroid stem cells –
impact on fertility
Altered uterine
contractility
Disturbances in
endometrial cytokine
expression
Abnormal
vascularization
Chronic
endometrial
inflammation
Mechanical stretch of
endometrium/
myometrium alter varying
gene expressions
HOXA-10 levels have been reported
to be reduced not only in the tissue
around the leiomyomas themselves
but also in the endometrium
elsewhere in the endometrial cavity
How fibroids adversely affect pregnancy development?
Payson M, Malik M, Siti-Nur Morris S, Segars JH, Chason R, Catherino WH.Activating transcription factor 3 gene expression suggests that tissue stress plays a role in
leiomyoma development. Fertil Steril 2009;92:748–55.
Rackow BW, Jorgensen E, Taylor HS. Endometrial polyps affect uterine receptivity. Fertil Steril 2011;95:2690–2

34. Fertility and Sterility 2011 952204-2208.e3DOI: (10.1016/j.fertnstert.2011.03.079)-The FIGO classification of causes of abnormal uterine bleeding in the reproductive years

39. Intramural leiomyomas have a questionable impact on fertility and early pregnancy development, which may due to differences
related to their size
The size of intramural myomas can augment the risk of RPL, especially when myomas are >4 cm, a point of view that remains
controversial according with certain researchers

42. Fertility outcomes are decreased in women with submucosal fibroids, and removal seems to
confer benefit
Subserosal fibroids do not affect fertility outcomes, and removal does not confer benefit.
Intramural fibroids appear to decrease fertility, but the results of therapy are unclear.
More high-quality studies need to be directed toward the value of myomectomy for intramural
fibroids, focusing on issues such as size, number, and proximity to the endometrium

43. The presence of multiple fibroids is a significant
predictor of miscarriage and RPL
Benson CB, Chow JS, Chang-Lee W, Hill JA 3rd, Doubilet PM. Outcome of pregnancies in women with uterine leiomyomas identified by
sonography in the first trimester. J Clin Ultrasound 2001;29:261–4.

44. DIAGNOSIS OF LEIOMYOMAS
Donnez J, Dolmans MM. Uterine fibroid management: from the present to the future. Hum Reprod Update 2016;22:665–86.
The first-line tool for diagnosing uterine fibroids is ultrasound

45. DIAGNOSIS OF LEIOMYOMAS
Donnez J, Dolmans MM. Uterine fibroid management: from the present to the future. Hum Reprod Update 2016;22:665–86.
Hysteroscopy is the gold standard for diagnosing intrauterine anomalies,
fibroids protruding into the endometrial cavity (FIGO 0–2), and
endometrial polyps

46. DIAGNOSIS OF LEIOMYOMAS
Donnez J, Dolmans MM. Uterine fibroid management: from the present to the future. Hum Reprod Update 2016;22:665–86.
Sonohysterography can also delineate submucosal myomas, and in the case of totally
or partially intramural myomas (FIGO 3–5), it can indicate the proximity of intramural
myomas to the endometrial cavity with high accuracy

47. DIAGNOSIS OF LEIOMYOMAS
Donnez J, Dolmans MM. Uterine fibroid management: from the present to the future. Hum Reprod Update 2016;22:665–86.
Magnetic resonance imaging can at times provides extra information, particularly on
the number of myomas, size, and relationship with the serosal surface.
Magnetic resonance imaging can
be used as a second diagnostic
test when ultrasounds are not
sufficiently informative
The distance between myomas
and the subserosal surface has
to be measured before
performing operative
hysteroscopy to reduce the risk
of uterine perforation during
surgery.

48. MANAGEMENT OF LEIOMYOMAS
Most studies on the effects of myomectomy on RPL were small case report series
without controls, which were subject to various methodologic limitations
Myomectomy improves the chances of pregnancies in case of submucosal
myomas, but the data are insufficient to support a true decrease of pregnancy
losses and even less for the possible cure of RPL
No clear benefit of surgery has been demonstrated for intramural myomas with
no impact on the uterine cavity
Pritts EA, Parker WH, Olive DL. Fibroids and infertility: an updated systematic review of the evidence. Fertil Steril 2009;91:1215–23.

49. Hysteroscopic resection of submucosal myomas is performed routinely on outpatient bases for
type 0 and 1 myomas <2 cm in diameter
Larger myomas - schedule a two-step procedure
‘‘Classic’’ 22–26 FR resectoscope with a U-shaped cutting loop is commonly used
Hysteroscopic tissue removal system without energy through the progressive slicing and
morcellation of the myoma has shown good results
Vitale SG, Sapia F, Rapisarda AMC, Valenti G, Santangelo F, Rossetti D, et al. Hysteroscopic morcellation of submucous myomas: a systematic review.
Biomed Res Int 2017;2017:6848250.

50. The risk of complications increases for myomas having a diameter >3 cm
Intrauterine hyaluronic-based barrier gels and postoperative diagnostic hysteroscopy at 4–6
weeks decrease the risk of adhesions after myomectomies
Donnez J, Dolmans MM. Uterine fibroid management: from the present to the future. Hum Reprod Update 2016;22:665–86.

51. Other types and multiple myomas need an abdominal approach to the myomectomy
Abdominal myomectomies carry a higher morbidity, increased risk of complications
Abdominal approaches often mandate future cesarean sections and a postsurgical delay before
attempting to conceive because of the potential risk of uterine rupture(1%)
More likely to generate pelvic adhesions that could cause subsequent infertility issues
Randomized controlled trials have provided clinical evidence supporting the safety and efficacy
of barrier gels for the reduction of postsurgical adhesions after myomectomies
The risk-benefit ratio has to be taken into
account, and all options have to be discussed
with the patient before surgery.
Mettler L, Hucke J, Bojahr B, Tinneberg HR, Leyland N, Avelar R. A safety and efficacy study of a resorbable hydrogel for reduction of post-operative adhesions following myomectomy. Hum
Reprod 2008;23:1093–100.

52. Minimally invasive abdominal myomectomies reduce the risk of adhesions and improve
postoperative recovery and cosmetic results
But they are not possible in all cases especially when multiple fibroids are present and/or their
size is >10 cm
The possible benefit of robotic surgery has not been yet demonstrated for such procedures and
still needs to be investigated
Thubert T, Foulot H, Vinchant M, Santulli P, Marzouk P, Borghese B, et al. Surgical treatment: myomectomy and hysterectomy; endoscopy: a major advancement. Best Pract Res Clin Obstet
Gynaecol 2016;34:104–21.

54. Despite the lack of consensus, surgery for submucosal fibroids is conducted by most
practitioners to improve fertility outcome—notably, in case of RPL
Myomectomy through hysteroscopy is a safe and effective method for removing submucosal
myomas <3 cms
This should be prompted to optimize fertility outcomes in patients of reproductive age with
RPL and submucosal fibroids (FIGO 0–2), while waiting for definitive data
Huchon C, Deffieux X, Beucher G, Capmas P, Carcopino X, Costedoat- Chalumeau N, et al. Pregnancy loss: French clinical practice guidelines. Eur J Obstet Gynecol
Reprod Biol 2016;201:18–26.

55. ENDOMETRIAL POLYPS
1.6-6% of RPL
Localized endothelial
tumors that include
endometrial glands,
stroma, blood vessels and
typically fibrous tissue
Morphology varies – size,
sessile or pedunculated,
single or multiple
When followed for a year,
spontaneous resolution in
27% of cases, specifically
seen in smaller polyps
(<1cm) (Lieng et al., 2009)

56. HOW ENDOMETRIAL POLYPS ADVERSELY IMPACT FERTILITY?
Mechanical interference
Release of molecules –
increased glycodelin,
aromatase, inflammatory
markers
Reduced HOXA-10 and -
11 messenger RNA
Decreased concentration
of mid-secretory
endometrial implantation
factors like IGFBP-1, TNFα
and osteopontin
Ben-Nagi J, Miell J, Yazbek J, Holland T, Jurkovic D. The effect of hysteroscopic polypectomy on the concentrations of endometrial
implantation factors in uterine flushings. Reprod Biomed Online 2009;19:737–44.

57. DIAGNOSIS OF ENDOMETRIAL POLYP
Ultrasound is an efficient
means for diagnosing
endometrial polyps -
sensitivity of 54% and
specificity of 80%
Office Hysteroscopy had
94% sensitivity, 95%
specificity, 62% PPV, 99%
NPV for detection of
endometrial polyps.
Sonohysterography or office
hysteroscopy has found
20%–30% cases of
endometrial abnormalities
that had been missed on
ultrasound
Shiva M, Ahmadi F, Arabipoor A, Oromiehchi M, Chehrazi M. Accuracy of two-dimensional transvaginal sonography and office hysteroscopy for detection of uterine abnormalities in patients with
repeated implantation failures or recurrent pregnancy loss. Int J Fertil Steril 2018;11:287–92.

58. MANAGEMENT OF ENDOMETRIAL POLYPS
Although there are no adequate studies showing benefit for polypectomy in RPL, hysteroscopic removal
can be considered for larger polyps (>1 cm) in women with RPL without any other known cause
(Lieng et al., 2010, Salim et al., 2011, Jaslow, 2014)

60. Yet case report studies indicate that hysteroscopic polypectomy improves fertility outcome
after intrauterine insemination and/or ART - endometrial polypectomies ought to be
recommended in patients seeking to conceive
Surgical removal of polyps is performed mainly using a 15–26 FR resectoscope or 5 FR
hysteroscope with an operative channel (bipolar electrodes, scissors) under general anesthesia
or during ‘‘see-and-treat’’ approaches using office hysteroscopy
This procedure—very safe—has a low rate of complications
Chiofalo B, Palmara V, Vilos GA, Pacheco LA, Lasmar RB, Shawki O, et al.Reproductive outcomes of infertile women
undergoing ‘‘see and treat’’ office hysteroscopy: a retrospective observational study. Minim Invasive Ther Allied Technol
2019:1–7.

62. No universally accepted recommendations have
been accepted to guide polyp management

63. INTRAUTERINE ADHESIONS/ASHERMAN SYNDROME
Fibrotic tissue developing from
the opposing walls of uterine
cavity or cervix
Alter the quality of
endometrial mucosa
Uterine curettage
Infection
Intrauterine surgery
Postobstetrical complications-Retained
fragments of placenta
Hysteroscopic surgery for polypectomy,
myomectomy and lysis of adhesions(10-30%)

65. INTRAUTERINE ADHESIONS/ASHERMAN SYNDROME
1.3 – 9.6% cases of RPL
IUAs are frequently encountered, in one in five(20%) women after miscarriage
The extent of IUAs was reported as mild, moderate and severe respectively in 58.1, 28.2 and 13.7% of
cases
Relative to women with one miscarriage, women with two or three or more miscarriages showed an
increased risk of IUAs by a pooled OR of 1.41 and 2.1, respectively
Recurrent miscarriages and D&C procedures were identified as risk factors for adhesion formation.

66. There were no studies assessing IUAs as a cause—or a
consequence—of RPL
Intrauterine adhesions (IUA) are frequently detected in
women with RPL, but the relationship and impact of IUAs on
long-term reproductive outcomes remain undetermined

67. However, the presence of moderate to severe IUAs may greatly
affect fertility and predisposes to pregnancy and obstetrical
complications
Intrauterine adhesions may lead to pregnancy loss due to
insufficient endometrium development for supporting the
fetoplacental growth
Yu D, Wong YM, Cheong Y, Xia E, Li TC. Asherman syndrome—one century later. Fertil Steril 2008;89:759–79.

68. Office hysteroscopy is the gold standard for IUAs diagnosis
Conversely, ultrasound is a poor tool for detecting IUAs when used without SHG
Pabuccu R, Atay V, Orhon E, Urman B, Ergun A. Hysteroscopic treatment of intrauterine adhesions is safe and effective in the restoration of normal menstruation
and fertility. Fertil Steril 1997;68:1141–3.

69. No consensus exists about the proper management of IUAs - Similar
pregnancy outcomes were reported after conservative, medical, or
surgical treatment of IUAs
There is no consensus regarding the surgical method, instruments, or
use physical barriers—intrauterine device, Foley catheters, and so on—
for preventing recurrence
Mild avascular adhesions can be treated during the course of office
hysteroscopy, whereas lysis of severe adhesions requires general
anesthesia
Hysteroscopic adhesiolysis is best performed with cold scissors or
bipolar/monopolar energy which is effective in the case of mild to
moderate IUAs
The initial severity of the adhesions appears to strongly correlate with
reproductive outcome, severe adhesions having the highest rate of
recurrence
Pabuccu R, Atay V, Orhon E, Urman B, Ergun A. Hysteroscopic treatment of intrauterine adhesions is safe and effective in the restoration of normal menstruation
and fertility. Fertil Steril 1997;68:1141–3.

70. These precautions include, notably, practicing second-look office hysteroscopy for identifying and easily
removing newly formed IUAs approximately 4 weeks after surgery
This practice should be recommended for all women undergoing hysteroscopic surgery with a risk of IUA
recurrence (resection for myomas, polyps, or IUAs)
However, treatment of mild and moderate adhesions has a positive impact on subsequent
fertility

71. Uterine anatomical factors—congenital and acquired—are involved in RPLs. Given the relatively
easy access to hysteroscopy, MRI, and high-resolution ultrasound techniques, we should
perform complete uterine assessment in all women who present with a history of RPL
Even if the tools for assessing the uterus are present, much work remains to be done to better
understand the clinical process of RPL and identify the molecular mechanism underlying it.
Data on surgical indications in case of congenital and acquired uterine anomalies are still
conflicting
In spite of this, we believe that resection of uterine septa, IUAs, submucosal myomas, and
endometrial polyps is indicated in women with RPL.
CONCLUSION

74. Clinico-hysteroscopic
scoring system of IUA
MILD (good prognosis) 0-4
MODERATE(fair prognosis) 5-10
SEVERE(poor prognosis) 11-22
Nasr A et al, Gynecol Obstet Invest 2000;