Repeated implantation failure:
clinical approach
Alex Simon, M.D., and Neri Laufer, M.D.
In Vitro Fertilization Unit, Department of Obstetrics and Gynecology, Ein Kerem, Hebrew University, Hadassah Medical Center, Jerusalem,
Israel
Successful embryo implantation depends on a well-functioning endometrium as well as a normal healthy embryo. This process might be hampered if
either of these variables is defective. Repeated implantation failure (RIF) is diagnosed when good-quality embryos repeatedly fail to implant after transfer
in several IVF treatment cycles. The causes of RIF originate with either the mother or the embryo. The authors discuss factors that are associated with RIF
and address various treatment options. (Fertil Steril
Ò
2012;97:1039–43. Ó2012 by American Society for Reproductive Medicine.)
Key Words: Repeated implantation failure, recurrent implantation failure, RIF, IVF, implantation
R
epeated implantation failure
(RIF) is determined when trans-
ferred embryos fail to implant
after several IVF treatment attempts.
However, there are no formal criteria
defining the number of failed cycles
or the total number of embryos trans-
ferred in these IVF attempts. Accord-
ingly, different centers practicing IVF
may use different definitions for RIF
(1). Considering the current success
rate of IVF treatment and the mean
number of embryos transferred in each
cycle, we recommend defining RIF as
failure of implantation in at least three
consecutive IVF attempts, in which
one to two embryos of high-grade qual-
ity are transferred in each cycle.
Successful implantation is a com-
plex process involving two main
players: the mother as a host and the
embryo. Problems originating from
the host environment, such as abnor-
mal uterine anatomy, nonreceptive en-
dometrium, and the medical condition
of the mother (such as thrombophilia
and abnormal immunologic response)
can adversely affect the cross-talk be-
tween the embryo and the endome-
trium that is so crucial for successful
implantation (2–5). Similarly, this
endometrial–embryo interaction may be
hampered if the embryo is disordered.
Embryo abnormality can originate from
either paternal sperm factors or from
the oocyte and its ability to be fertilized
normally and cleave. Accordingly, the
investigation and treatment of patients
with RIF should focus on both male
and female risk factors that, once
identified, should be managed and
treated appropriately (Fig. 1).
FEMALE FACTORS AND RIF
Anatomic Causes
After several consecutive IVF failures
and in agreement with the definition
of RIF, patients should undergo hys-
teroscopy to assess the uterine cavity.
Three-dimensional ultrasonography
and hysterosalpingography are com-
plementary tools to be performed as
needed. Once an abnormality associ-
ated with implantation failure is recog-
nized, treatment options should be
considered, including uterine septec-
tomy, removal of intrauterine adhe-
sions, endometrial polypectomy or
myomectomy, particularly the submu-
cous type, and excision of hydrosalpinx
(5–7).
Endometrium
A functioning and receptive endome-
trium is crucial for embryo implantation.
During the menstrual cycle, the endome-
trium undergoes both morphologic and
biologic changes, during which it be-
comes prepared for interaction with the
embryo, leading to successful implanta-
tion. Once all biological changes are ad-
equate, the embryo can attach, invade
the endometrium, and finally implant.
Ultrasound examinationof the thickness
and appearance of the endometrium is
an easily performed means of assessing
morphologic changes occurring in the
endometrium during the follicular
phase, and is thus used as a measure to
predict successful implantation. Indeed,
several studies have reported a strong
association between endometrial thick-
ness and successful implantation (8, 9).
Noyes et al. (9) reported a significantly
higher pregnancy rate of 48.6% in
patients with endometrial thickness of
>9 mm, as compared with 16% in
those with <9 mm. Nevertheless,
others failed to confirm such an
association (10, 11). The minimal
adequate endometrial thickness for
successful implantation, as measured in
the late proliferative phase, varies
between studies, with a range of 6–8
mm. Thin, unresponsive endometrium
is hard to manage (12), and if all
Received February 1, 2012; revised March 8, 2012; accepted March 9, 2012; published online March 30,
2012.
A.S. has nothing to disclose. N.L. has nothing to disclose.
Reprint requests: Alex Simon, M.D., Hadassah Medical Center, Department of Obstetrics and Gynecol-
ogy, Ein Kerem, P.O. Box 12000, Jerusalem 91120, Israel (E-mail: simonal@hadassah.org.il).
Fertility and Sterility® Vol. 97, No. 5, May 2012 0015-0282/$36.00
Copyright ©2012 American Society for Reproductive Medicine, Published by Elsevier Inc.
doi:10.1016/j.fertnstert.2012.03.010
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