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Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2018) 1e12

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Obstetrics and Gynaecology
journal homepage: www.elsevier.com/locate/bpobgyn

6
1 What to do when good-quality embryos
2
3 Q 15 repeatedly fail to implant
4
5 QQ
141 C. Coughlan a, b, *
6 a
Q2 Consultant Reproductive Medicine & Surgery, United Arab Emirates
7 b
IVI Gynaecology & Fertility Clinic, Dubai, United Arab Emirates
Q3
8
9
10
a b s t r a c t
11
Keywords:
12
Implantation Recurrent implantation failure (RIF) is very distressing for couples
13 In vitro fertilization and frustrating for their clinicians who seek to find a solution. RIF
14 Failure is defined as the failure to achieve a clinical pregnancy following
15 the transfer of at least four good-quality embryos in a minimum of
16 three fresh or frozen cycles in a woman of age below 40 years. An
17 agreed local protocol regarding how couples with RIF should be
18 further investigated and managed should be in place. Ovarian
19 function should be assessed by measuring antral follicle count,
20 FSH, and AMH. Chromosomal testing of the couple is advised to
exclude genetic abnormalities that may lead to RIF. Various uterine
21
pathologies including fibroids, endometrial polyps, congenital
22
anomalies, and intrauterine adhesions should be excluded by ul-
23 trasonography and hysteroscopy. Hydrosalpinges are a recognized
24 cause of implantation failure and should be excluded by hystero-
25 salpingogram, and if necessary, laparoscopy should be performed
26 to confirm or refute the diagnosis. Consideration should be given
27 to preimplantation genetic screening (PGS) and the adoption of a
28 “freeze-all” protocol. Treatment offered should be evidence based,
29 aimed at improving embryo quality or endometrial receptivity.
30 Gamete donation or surrogacy may be necessary if there is no
31 realistic chance of success with further IVF attempts.
© 2018 Published by Elsevier Ltd.
32
33
34
35
36
37
38
39
40 * Reproductive Medicine & Surgery, Dubai, United Arab Emirates. Q 16

41 E-mail address: caroljcoughlan@eircom.net.

42 https://doi.org/10.1016/j.bpobgyn.2018.07.004
43 1521-6934/© 2018 Published by Elsevier Ltd.

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2 C. Coughlan / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2018) 1e12

1 Q4 Introduction
2
3 Implantation is a process whereby the embryo attaches itself to the luminal surface of the endo-
4 metrium followed by migration and invasion into the deep layer of the endometrium where it embeds.
5 Traditionally, implantation has been considered as a process involving only the embryo and the
6 endometrium, but studies show that cumulus cell competency may also contribute to the process [1].
7 In clinical practice, implantation is often considered to be successful when there is ultrasonographic
8 evidence of an intrauterine gestational sac. Implantation failure may occur very early during the
9 attachment or migration stages, with the result that there is no objective evidence of a pregnancy, i.e., a
10 negative urine or blood pregnancy test result (human chorionic gonadotrophin (hCG)). It may also
11 occur later following successful migration of the embryo through the luminal surface of the endo-
12 metrium, when hCG produced by the embryo may be detected in the blood or urine, but the process
13 becomes disrupted before the formation of an intrauterine gestational sac. In this situation, it is
14 clinically referred to as a biochemical pregnancy. In assisted conception treatment, implantation is
15 considered to be successful when an embryo has produced an intrauterine gestational sac, detectable
16 by ultrasonography, usually approximately 3 weeks after oocyte retrieval or approximately 5 weeks of
17 gestation. Implantation failure refers to the failure of the embryo to reach a stage when an intrauterine
18 gestational sac is recognized by ultrasonography. From the clinical point of view, it is worthy to note
19 that the term “implantation failure” refers to two different types of situation: those in whom there has
20 never been evidence of implantation (no detectable hCG production) and those who have evidence of
21 implantation (detectable hCG production) but did not proceed beyond the formation of a gestational
22 sac visible on ultrasonography. In a clinical setting, one has to decide when does it become unusual for
23 all replaced embryos to fail to implant? Recurrent implantation failure (RIF) is a recognized clinical
24 entity, but to date, there is no universally agreed definition. When defining this challenging condition, a
25 number of factors have to be considered as follows:
26 Embryo quality: One important variable is clearly the quality of the embryo. Hence, in arriving at a
27 clinically useful definition of RIF, some investigators specified that good-quality embryos had been
28 replaced [2]. A good-quality embryo was defined as having the correct number of cells corresponding
29 to the day of its development, and day 5 embryos (blastocysts) were graded according to expansion and
30 quality of the inner cell mass and trophectoderm [3]. Other criteria included blastomeres of equal size
31 and regular in distribution, even distribution of cytoplasm without granularity, and less than 10%
32 fragmentation [3].
33 How many embryos? Some previous investigators proposed that RIF should be referred to as
34 failure to achieve a clinical pregnancy after a total of 10 or more embryos had been transferred to the
35 uterus [4]. This might have been appropriate when the implantation rate was rather lower than the
36 rate that most in vitro fertilization (IVF) centers can currently achieve, partly because the culture
37 environments and the quality of culture media used are at present improved. The implantation
38 potential of a blastocyst is well recognized to be greater than that of the day 2 or 3 embryo, mainly
39 because of natural selection of better quality embryos for further development. The increasing use
40 of blastocyst transfer has further improved implantation rates. It seems appropriate, given the
41 improved implantation rate achieved currently, to base the definition on the transfer of four or more
42 embryos.
43 Frozen or fresh cycle? Some investigators believed that frozen embryo transfer cycles be
44 excluded from the definition of RIF [5], almost certainly based on earlier data that indicated the
45 implantation rate of frozen embryos was inferior to that of fresh embryos. However, there is good
46 evidence that the implantation rate of frozen embryos is similar to that of fresh embryos [6,7].
47 Hence, the number of embryos transferred should include both fresh and frozen cycles in
48 considering the diagnosis of RIF.
49 Embryos or cycles? Should the diagnosis of RIF be based entirely on the number of embryos
50 transferred or should it be based on the number of embryo transfer cycles? Many investigators prefer
51 to base it on the failure to achieve a clinical pregnancy after three transfer cycles [5], whereas others
52 proposed to use the number of embryos transferred [4]. There are pros and cons for each approach. The
53 definition based on the number of embryos transferred is more scientific and logical, but the definition
54 based on the number of transfer cycles is more pragmatic and easily understood by patients.

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1 Maternal age: Finally, given that embryo quality is closely related to maternal age [8], the definition
2 should incorporate an age limit of 40 years, although, strictly speaking, biological age is a more relevant
3 consideration.
4 Embryo vs. uterine factors: Although RIF may be due to either embryo or uterine factors, RIF
5 requires that good-quality embryos be replaced. It emphasizes on cases of failure primarily due to
6 uterine factors. However, embryo factors should not be necessarily excluded.
7 RIF vs. recurrent IVF failure: RIF is not the same as recurrent IVF failure. The latter condition merely
8 refers to the failure to achieve a pregnancy after several IVF attempts, a common cause being poor
9 response to ovarian stimulation [9]. Suboptimal embryo quality, advanced maternal age, and uterine
10 factors are also relatively common causes for recurrent IVF failure. The term recurrent implantation
11 failure is a subgroup of recurrent IVF failure and should not be used to replace the latter.
12 Proposed definition. Based on the above considerations, it is proposed that RIF be defined as the
13 failure to achieve a clinical pregnancy after transfer of at least four good-quality embryos in a minimum
14 of three fresh or frozen cycles in a woman of age below 40 years [10]. However, an internationally
15 agreed consensus on the definition should be reached following further discussion, analogous to that
16 of polycystic ovarian syndrome (Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop
17 Group, 2004).
18 The embryo and endometrium are both critical to the process of implantation. Many factors can
19 affect the implantation potential of an embryo, including sperm and oocyte quality in addition to
20 iatrogenic factors such as laboratory conditions and embryo transfer technique. In addition, many
21 conditions of the uterine cavity may influence the ability of the embryo to implant. Despite the transfer
22 of good-quality embryos in this particular case, the emphasis should not be placed on uterine factors
23 alone as the sole cause of implantation failure. Current methods of embryo assessment are by no means
24 perfect.
25
26
27 Management of a couple with recurrent implantation failure
28
29 A multidisciplinary approach should be adopted in the management of a couple who have
30 experienced repeated cycle failures despite the transfer of good-quality embryos. It should involve not
31 only an experienced fertility specialist but also a senior embryologist and where appropriate a
32 reproductive surgeon or a counselor.
33 Patients need to be reassured that their treatment is under the supervision of an experienced
34 clinician. The couple should be offered ample time for their questions to be addressed and a clear
35 treatment plan agreed. The appointment should include a thorough review of the diagnosis of the
36 underlying cause of infertility, the investigation results, the treatment protocol, the response to
37 ovarian stimulation, the quality of the oocyte and embryos, and possible explanation regarding why
38 they have not achieved a successful pregnancy. The couple should have been explained that any
39 treatment plan recommended would be discussed and confirmed in a multidisciplinary team meeting
40 and the final decision confirmed in writing. Second, there ought to be an agreed local protocol
41 regarding how couples with repeated failed IVF cycles should be further investigated and managed.
42 The protocol ought to be updated regularly to consider the findings of recent studies and should
43 contain sufficient details to ensure that patients and staff clearly understand the plan of action, and
44 the rationale behind any decisions made. Appropriate counseling of the couple is of utmost impor-
45 tance before proceeding with further treatment. It is beneficial to instigate appropriate investigations
46 and review previous unsuccessful IVF treatment cycles with a view to modify or change the treatment
47 protocol if indicated. Couples who experience repeatedly failed cycles despite the transfer of good-
48 quality embryos may benefit from chromosomal testing to exclude chromosomal abnormalities,
49 which may predispose to RIF.
50
51 Lifestyle changes
52
53 In addition to a review of investigations and treatment, clinicians should discuss and educate
54 patients regarding lifestyle changes, and these could improve the likelihood of treatment success.

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4 C. Coughlan / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2018) 1e12

1 Smoking: Women who smoke should be advised to stop. Overall, the literature strongly supports an
2 association between cigarette smoking and infertility. There is evidence that smoking is associated
3 with an increased gonadotrophin requirement for ovarian stimulation, fewer oocytes retrieved, higher
4 numbers of cancelled cycles, lower implantation rates, and more cycles with failed fertilization in
5 smokers than in nonsmokers [11]. Male partners should also be advised to abstain from smoking, as
6 there is good evidence that semen parameters are 22% poorer in smokers than in nonsmokers [12].
7 Body mass index (BMI): Couples should be informed of the adverse effect of obesity on fertility
8 treatment outcome and be encouraged to improve their general health [13].
9 Underweight women (BMI < 19 kg/m2) should be encouraged to gain weight and obese women
10 (BMI
30 kg/m2) should be advised to lose weight before further attempts at IVF treatment. Women
11 should be provided with assistance to lose weight, including psychological support, dietary advice,
12 exercise classes, and, where appropriate, weight-reducing agents or bariatric surgery. Obesity also has
13 an adverse effect on male fertility and long-term health.
14 Alcohol Consumption: Women who are trying to become pregnant should be advised to reduce
15 alcohol consumption to one or two units once or twice per week and avoid episodes of intoxication to
16 reduce the risk of harming a developing fetus. Men should be informed that excessive alcohol intake is
17 detrimental to semen quality [14].
18
19
Ovarian stimulation protocol
20
21
Ovarian response to gonadotrophin stimulation should be reviewed. If the response is deemed
22
satisfactory, it is not necessary to change the stimulation protocol. In a small proportion of women who
23
are deemed to have suboptimal response to ovarian stimulation, the dose of gonadotrophin may be
24
increased. There is no established evidence that an antagonist protocol is better than an agonist
25
protocol, or vice versa [15]. There is some evidence to suggest that “poor responders” to ovarian
26
stimulation and women above the age of 35 years may benefit from the addition of luteinizing hor-
27
mone (LH) to cycles [16]. In women with endometriosis and adenomyosis, the use of an ultra-long
28
protocol involving the administration of gonadotrophin-releasing hormone (GnRH) agonists for a
29
few months before IVF or intracytoplasmic sperm injection (ICSI) may increase the pregnancy rate [17].
30
Currently, standard IVF protocols utilize hCG as a surrogate for the LH surge. In contrast to hCG, the
31
GnRH agonist induces a surge of both follicle-stimulating hormone (FSH) and LH resembling the
32
natural mid-cycle surge. For patients where a significant number of immature oocytes were retrieved
33
in previous cycles, some studies have suggested that the GnRH agonist trigger results in the retrieval of
34
more mature oocytes but does result in luteal phase insufficiency. Studies, although retrospective,
35
suggest an advantage to using a GnRH agonist in combination with hCG as a double trigger in IVF cycles
36
to increase the number of mature oocytes [18,19].
37
38
39 Sperm DNA fragmentation
40
41 There is insufficient evidence to recommend the routine use of sperm DNA integrity tests in both
42 the evaluation and treatment of the infertile couple and for patients undergoing IVF/ICSI [20]. However,
43 sperm DNA fragmentation testing may be useful for a subgroup of patients with repeated IVF failures
44 without an apparent cause in which “unrepairable” sperm DNA damage may be the limiting factor
45 responsible for their fertility problem [20]. When suboptimal-quality sperm is considered to be a
46 contributory cause of IVF failure, supported by an increased amount of sperm DNA fragmentation,
47 several treatment options may be considered. First, oral antioxidant treatment has been shown to
48 reduce the incidence of sperm DNA fragmentation [22]. Second, on the basis of the observation that
49 sperm DNA damage is lower in the seminiferous tubules than in the cauda epididymis and ejaculated
50 sperm, it has been proposed that men with high levels of DNA damage in ejaculated sperm have sperm
51 removed surgically from the testis for ICSI [23]. The use of testicular sperm in couples with repeated
52 IVF failures associated with high sperm DNA fragmentation in semen has been reported to result in a
53 significant increase in pregnancy rates and reduction of miscarriage rate, but further studies are
54 required to confirm the benefit [24,25].

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1 Improving embryo quality and selection

2
3 Blastocyst Transfer: Several studies have suggested that extending embryo culture to Day 5/6 to
4 transfer the embryo at the blastocyst stage increases the implantation rate [26]. In women with a
5 history of IVF failures, blastocyst transfer ought to be considered if not performed in previous
6 treatment cycles.
7 Assisted Hatching (AH): Hatching of the blastocyst plays an integral role in the implantation
8 process. Failure to hatch (due to intrinsic abnormalities in either the blastocyst or zona pellucida
9 (ZP)) is a possible cause of implantation failure. AH involves the artificial thinning or breaching of
10 the ZP and has been proposed as one technique to improve implantation and pregnancy rates
11 following IVF [27]. The American Society for Reproductive Medicine published recommendations
12 regarding AH and concluded that there is evidence that AH slightly improves clinical pregnancy
13 rates (CPRs) in patients with poor prognosis, including those with more than two previous
14 unsuccessful IVF cycles, in cases of poor-quality embryo, and, particularly, patients of advanced
15 maternal age [27].
16 Preimplantation genetic screening (PGS): The hypothesis of PGS suggests that elimination of
17 aneuploidy embryos before transfer will improve implantation rates, increase pregnancy and live
18 birth rates, and reduce miscarriages [28]. Chromosomal aneuploidies are the main reason for
19 pregnancy loss and implantation failure [29,30]. The improved outcome with PGS is based on the
20 assumption that with chromosomal aneuploidies being the main reason for IVF failure, elimination
21 of aneuploid embryos before embryo transfer will improve IVF outcomes. In 2011, Mastenbroek et al.
22 published a review and meta-analysis of all the randomized controlled trials (RCTs) that compared
23 aneuploidy testing versus standard IVF published up to that date [31]. They reported no beneficial
24 effect of PGS on the live birth rate, and PGS was shown to have an adverse effect on the chance of
25 conceiving in patients of advanced maternal age [31]. The negative findings were attributed to the
26 strategy adopted at that time to conduct chromosomal analyses, namely, cleavage-stage biopsy and
27 9-chromosome fluorescence in situ hybridization (FISH) analysis. FISH analysis is very limited as
28 only nine out of the 24 chromosomes composing the human karyotype were analyzed; this means
29 that all the aneuploidies, which at that stage of embryo development can affect any chromosome,
30 were ignored [32]. The limited testing method in addition to the single-cell analysis led to high
31 technical variability, overestimation of mosaicism, and an undiagnosed embryo rate as high as 10%
32 [33e36]. Third, cleavage-stage biopsy affects embryo viability and its implantation potential [37].
33 The current embryo biopsy technique for PGS, day 5 multiple-cell trophectoderm biopsy, and the
34 current testing methods of next-generation sequencing and 24 chromosome screening have resulted
35 in significantly improved implantation rates as compared to the initial day 3 single blastomere
36 biopsy and the initial genetic testing method FISH. The group of patients who have been suggested
37 throughout the years to potentially benefit from PGS include subfertile women of advanced
38 maternal age (usually defined as
35 years old), with a history of recurrent pregnancy loss (RPL:
39 usually at least three previous miscarriages) or with RIF (three or more failed embryo transfers), and
40 severe male factor [38]. However, the role of PGS is still controversial [39]. Data about PGS efficacy
41 calculated on a per intention-to-treat basis, as well as an analysis of its cost-effectiveness, are still
42 missing [40]. Although real mosaicism and methodological aspects can affect the reliability of the
43 diagnosis due to false-positive errors, trophectoderm biopsy is a safe and extensively validated
44 approach with a low biological and technical margin of error [40]. The prevalence of mosaic diploid/
45 aneuploid blastocysts is estimated to be between 0% and 16%, which is tolerable; second, all the
46 comprehensive chromosome screening (CCS) technologies adapted to or designed to conduct PGS
47 are highly concordant; and third, a clinically recognizable error rate per blastocyst of only 0.21% is
48 reported [40]. In conclusion, there is a sufficient body of evidence to support the clinical application
49 of CCS-based PGS on trophectoderm biopsies for couples who have experienced repeatedly failed
50 IVF cycles despite the transfer of what are described as good-quality embryos, but further large
51 randomized studies are required to conclusively confirm [41]. The limiting factor is the need for a
52 high standard laboratory to conduct blastocyst culture, biopsy, and vitrification without affecting
53 embryo viability [40].
54

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1 Embryo transfer
2
3 Embryo implantation has been found to be dependent on embryo quality, endometrial receptivity,
4 and transfer efficiency [42]. In women with previous failed IVF cycles, the details of previous embryo
5 transfers should be reviewed, paying particular attention to any technical difficulties encountered. If
6 there had been difficulty with previous embryo transfers, identified as a procedure taking longer than
7 usual, causing significant pain, requiring change of catheter, cervical dilatation, or use of a tenaculum,
8 the pregnancy rate would be expected to be low [43]. Difficult embryo transfer may be due to cervical
9 stenosis, acute anteversion/retroversion, or acute anteflexion/retroflexion of the uterus. Several
10 techniques may be considered in women with a history of difficult embryo transfer. First, the transfer
11 should be performed under ultrasound guidance [44]. Second, a trial transfer should be discussed
12 and considered. Third, filling the bladder in women with acute anteversion or anteflexion is a simple
13 measure that may sometimes be useful but will not be helpful in cases of acute retroversion or
14 retroflexion where an empty bladder is preferable. The application of a tenaculum to the anterior lip of
15 the cervix and applying traction gently downward may help to straighten an acutely flexed uterus but
16 may compromise pregnancy rates by inducing uterine contractions [43]. The use of a rigid catheter may
17 help to negotiate the cervix if previously difficulty was encountered with the use of a soft catheter.
18 Alternative methods to transcervical embryo transfer include transmyometrial and tubal transfers but
19 should be reserved for cases that are extremely difficult or impossible. There is insufficient evidence to
20 show that bed rest after transfer improves outcome.
21
22 Endometrial receptivity
23
24 Embryo implantation is a complex process requiring a receptive endometrium. Supraphysiological
25 hormone levels during the follicular phase of controlled ovarian stimulation may result in reduced
26 endometrial receptivity; this may in turn have an adverse effect on implantation and pregnancy rates
27 in IVF/ICSI cycles [45,46]. Many studies have suggested a freeze-all policy in which all embryos are
28 electively cryopreserved for transfer in a subsequent frozen-thaw cycle in the hope of providing a more
29 physiological environment for embryo transfer and improving implantation and pregnancy rates
30 [7,47,48]. A recent prospective cohort study identified a statistically significant improvement in
31 ongoing pregnancy and implantation rates following a freeze-all policy for patients with RIF [49].
32
33 Molecular assessment of endometrial receptivity
34
35 The endometrial receptivity assay (ERA) is a new technique that uses a customized array to identify
36 markers of endometrial receptivity [39]. It is based on the analysis of the expression of 238 genes
37 thought to be involved in endometrial implantation [39]. This test is performed in the hope of
38 determining a personalized “window of implantation” and is performed by obtaining an endometrial
39 biopsy sample on day LH þ7 in a natural cycle or on the sixth day of progesterone administration
40 during a hormone replacement therapy (HRT) cycle. Results are expressed as prereceptive, receptive, or
41 postreceptive. According to the result, the timing of the embryo transfer can be adjusted, thus facili-
42 tating a “personalized” embryo transfer. The ERA test requires large randomized studies to validate its
43 Q 5 use before introduction into routine clinical practice.
44
45 Endometrial scratch
46
47 Historical observations made in the guinea pigs provided the first evidence that injury to the
48 progestational endometrium resulted in decidualization and subsequent improved uterine receptivity
49 [50]. Subsequently, several studies examined the impact of endometrial injury in the luteal phase
50 preceding an IVF treatment cycle in women with RIF and suggested that superficial endometrial injury
51 (scratch) may improve implantation rates in this subgroup of women [51,52]. The Royal College of
52 Obstetricians and Gynaecologists published a scientific impact paper on the endometrial scratch
53 procedure in 2016, concluding that the available evidence at that time pointed toward a potential
54 benefit of endometrial biopsy in women with RIF when performed in the cycle preceding the IVF

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1 treatment cycle [53]. However, due to heterogeneity in the study populations and in the method used
2 to induce local endometrial injury, further large prospective randomized studies were recommended
3 to confirm or refute the clinical value of local endometrial trauma in women with RIF [53].
4
5
6 Hysteroscopy
7
8 A recent multicenter RCT found that outpatient hysteroscopy before IVF in women with a normal
9 ultrasound of the uterine cavity and a history of unsuccessful IVF treatment cycles does not improve
10 the live birth rate [54]. However, where ultrasound suggests the presence of endometrial pathology,
11 hysteroscopy is a valuable investigative and treatment modality. It may be performed as an outpatient
12 procedure, wherein small lesions may be removed at the same time, but more significant pathology
13 may need to be dealt with later under general anesthesia.
14
15 Intracavity lesion
16
17 Submucous fibroid: A meta-analysis showed that submucous fibroids significantly reduced the
18 implantation rate, CPR, and live birth rate and significantly increased the miscarriage rate [55].
19 The presence of a submucous fibroid in women with a previous failed IVF cycle, regardless of the size,
20 should be removed, as it has been shown in the meta-analysis that removal of submucous fibroids
21 improves CPRs [55].
22 Endometrial polyps: Similarly, endometrial polyps in women with RIF ought to be removed. It has
23 been shown that the removal of endometrial polyps in women undergoing intrauterine insemination
24 (IUI) treatment resulted in doubling of the CPR [56].
25 Uterine Septum: In women with previously failed IVF cycles, uterine septa should be removed,
26 regardless of the size. The various techniques used to remove uterine septa have been reviewed [57].
27 Intrauterine adhesions: It is accepted that intrauterine adhesions would interfere with the
28 implantation process and adversely affect the implantation rate, thereby necessitating removal if
29 present in women with RIF [58]. Nevertheless, there are yet no established literature data to confirm
30 that removal of intrauterine adhesions improves the implantation rate. Furthermore, intrauterine
31 adhesions often recur after surgical removal, and there is a high rate of complication (10% or more) in
32 cases of severe intrauterine adhesions resulting in partial or complete obliteration of the cavity.
33 The procedure should be carried out by an experienced reproductive surgeon under ultrasound or
34 laparoscopic guidance to minimize complications [58].
35
36 Myometrial pathology
37
38 Intramural fibroid: Although women with RIF should have submucous fibroids removed, the
39 possible contribution of intramural fibroids, which are not distorting the uterine cavity, to RIF is far
40 from being clear. There is no consensus on whether or not intramural fibroids in women with RIF
41 should be removed [59]. Many clinicians would recommend removal of intramural fibroids if they are
42 more than 4 cm in diameter. There is a lower threshold to remove an intramural fibroid if it is situated
43 Q 6 in the anterior lower uterine segment, as it may pose problems in delivery of the fetus, especially if
44 cesarean section is required. The pros and cons of myomectomy should be carefully explained in each
45 case. Couples should be aware of the possible complications of myomectomy including the likelihood
46 of blood transfusion, a small risk (1%) of hysterectomy, a relatively high risk of adhesion formation over
47 the uterine scar, and a small but serious risk of scar rupture during the ensuing pregnancy. On the other
48 hand, the couples should also understand that intramural fibroids may cause not only implantation
49 failure but also a number of other problems including miscarriage (in both first and second trimesters),
50 red degeneration, preterm delivery, placental abruption, fetal growth restriction, malpresentation,
51 difficulty with delivery, and intrapartum and postpartum hemorrhage. The final decision must be
52 individualized, and the involvement of a reproductive surgeon in the decision-making process is
53 recommended. Adenomyosis: The role played by adenomyosis in reproductive failure is receiving
54 increasing attention [17]. Unlike intramural fibroids, adenomyosis is not as amenable to surgical

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8 C. Coughlan / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2018) 1e12

1 treatment, but Tremellen and Russell, (2011) reported on cases of RIF associated with adenomyosis, all
2 successfully treated with an ultra-long pituitary downregulation protocol [17].
3
4
5 Hydrosalpinges
6
7 Currently, there is good evidence that the removal of hydrosalpinges improves the implantation and
8 live birth rates in women who undergo IVF [60]. There are conflicting reports on whether or not
9 salpingectomy compromises ovarian response to stimulation during subsequent IVF treatment. It is
10 prudent, when carrying out salpingectomy, to diathermize and incise as close to the Fallopian tube as
11 possible and as far away from the ovary as possible, to avoid disruption to the ovarian blood supply. If
12 salpingectomy is anticipated to be technically difficult due to adhesions, potentially incurring the risk
13 of adversely affecting ovarian blood supply, proximal tubal occlusion can be achieved laparoscopically
14 by tubal clipping and thereby preserving ovarian reserve.
15 Salpingectomy is not the only surgical treatment option for women with hydrosalpinges contem-
16 plating IVF treatment. Salpingostomy may be a possible alternative, as it not only “removes” the
17 hydrosalpinges but also creates the possibility of natural conception. It seems logical, therefore, to
18 recommend that women with hydrosalpinges and minimally damaged fallopian tubes be considered
19 for salpingostomy as opposed to salpingectomy, whereas tubes that are severely damaged (especially
20 for those with intraluminal adhesions) ought to be removed (salpingectomy). The drawback of
21 salpingostomy is the possible reoccurrence of hydrosalpinges, which then necessitates a further
22 QQ78 procedure to remove the tube, further delaying treatment and incurring extra cost.
23
24 Clinical trials
25
26 Despite the absence of good scientific evidence for a benefit from immunotherapy, immunomod-
27 ulators (intralipid, heparin, aspirin, and immunotherapy) are increasingly offered to women under-
28 going IVF, particularly if they have previously experienced unsuccessful IVF cycles. The potential risks
29 and costs of these therapies outweigh any benefits [61e65]. Couples who experience unsuccessful IVF
30 cycles are desperate to seek a treatment that will lead to a successful outcome. Many of them would
31 have searched the Internet looking for a “new” treatment on the horizon. They may not be able to judge
32 for themselves the scientific credibility of such claims they come across on the Internet. They often seek
33 the advice of their specialist to confirm if certain “new” treatments are worth trying. Clinicians should
34 be able to judge if certain treatments are proven to be of value. If not, treatment should not be initiated
35 or the treatment should be offered only as part of a clinical trial. In this situation, prior ethics approval
36 for the trial should have been obtained and national research governance guidelines followed. Written
37 consent from each patient should be obtained.
38
39 Gamete donation and surrogacy
40
41 Couples with recurrent IVF failures need guidance on the appropriateness of proceeding with
42 further IVF attempts. If implantation fails to occur despite repeated treatment attempts or if the
43 prognosis of further IVF treatment is considered poor, alternative treatment options ought to be
44 explored. If the likely source of the problem lies with the embryo, gamete donation should be advised.
45 On the other hand, if the problem lies with the uterus, for example, multiple fibroids or Asherman
46 syndrome, which has failed to respond to surgical treatment, surrogacy should be discussed as an
47 option for the couple.
48
49 Conclusion
50
51 Couples who experience RIF despite the transfer of good-quality embryos should be offered
52 appropriate investigations to rule out an underlying cause. The main treatment strategy in couples
53 with implantation failure is to improve the quality of the embryo transferred and the receptivity of the
54 endometrium.

Please cite this article in press as: Coughlan C, What to do when good-quality embryos repeatedly fail to
implant, Best Practice & Research Clinical Obstetrics and Gynaecology (2018), https://doi.org/10.1016/
j.bpobgyn.2018.07.004
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C. Coughlan / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2018) 1e12 9

1
2 Practice points
3
4  A multidisciplinary approach should be adopted in the management of recurrent implanta-
5 tion failures. Genetic testing of the couple should be considered where treatment cycles
6 repeatedly fail despite the transfer of good-quality embryos.
7  Hysteroscopy should be considered before a further treatment cycle if ultrasound is
8 suggestive of uterine pathology.
 Appropriate investigations should be carried out to exclude hydrosalpinx as it has been
9
shown to reduce implantation rates, increase miscarriage rates, and reduce live birth rates.
10
Removal of hydrosalpinges has been shown to improve the outcome of IVF cycles.
11  Submucosal fibroids have been shown to reduce implantation, pregnancy, and live birth
12 rates; the removal of submucosal fibroids improves implantation rates.
13  Endometrial polyps should be removed: polypectomy has been shown to improve outcome
14 in women who undergo intrauterine insemination.
15  The use of ultra-long protocol may improve treatment outcome in women with endometri-
16 osis and adenomyosis.
17  Consider removal of intramural fibroids measuring more than 5 cm.
18  Intrauterine adhesions are a recognized cause of thin endometrium, which does not respond
to ovarian steroid stimulation; if present, intrauterine adhesions should be removed.
19
 Preimplantation genetic screening and elective “freeze-all” cycle should be considered when
20 IVF cycles repeatedly fail despite the transfer of good-quality embryos.
21  Empirical therapies should, whenever possible, be considered only in the setting of carefully
22 conducted clinical trials.
23
24
25
26
27
28 Research agenda
29
30  The benefit of a “freeze-all” and segmentation cycle approach requires further studies in
31 recurrent implantation failure.
32  Possible benefit of bed rest after embryo transfer.
 Use of testicular sperm in couples with RIF and high DNA fragmentation.
33
 Use of novel stimulation regimens and “double trigger” for patients with RIF.
34
35
36
37 Conflicts of interest
38
39 The author has no conflict of interest.
40
41 Uncited reference
42
43 [21], [66].
Q 13
44
45
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54

Please cite this article in press as: Coughlan C, What to do when good-quality embryos repeatedly fail to
implant, Best Practice & Research Clinical Obstetrics and Gynaecology (2018), https://doi.org/10.1016/
j.bpobgyn.2018.07.004