Recurrent Implantation Failure

RECURRENT
IMPLANTATION
FAILURE
Dr Shivani Sachdev Gour
MD DNB MROCG (UK)

Knowledge & progress made in:
Simplifying diagnostic approach of the couple
Understanding folliculogenesis
Controlling hormones
Facilitating egg retrieval and embryo transfer
Culturing embryos up to blastocyst stage
Still a lot to learn from:
Endometrial receptivity
Embryo beyond morphology

EMBRYO QUALITY
5
Vestibulum nec
congue tempus
0203
01
While implantation is a
process with a well-
defined starting point,
it is a gradual process
which lasts for several
weeks with no
universal agreement
on when the process
is completed

Implantation Failure……
◂ May occur very early on during the attachment or migration stages (No
objective evidence e.g. –ve hCG)
◂ May also occur at a later stage (+ve hCG) but process becomes disrupted
◂ Definition: Refers to the failure of the embryo to reach a stage when an
intrauterine gestational sac is recognized by ultrasonography.
◂ Implantation failure can apply to patients undergoing ART and patients trying to
conceive without any fertility treatment.
◂ It is a separate entity from RPL
6

RIF
There is no accepted formal
definition for RIF
Recurrent implantation failure is only
applicable to patients undergoing ART
Orvieto et al - 3 failed IVF-ET cycles with good quality embryos transferred .
Zeyneloglu et al. - 3 unsuccessful IVF specifically with two embryos of high quality
Simon and Laufer - embryo & endometrium can both play an active role in RIF
Coughlan et al. suggest a more complete working definition taking into account maternal
age, number of embryos transferred, and number of cycles completed.
They define RIF as the failure of clinical pregnancy after 4 good quality embryo transfers,
with at least three fresh or frozen IVF cycles, and in women under the age of 40
◂ Reprod Biol Endocrinol 2018 Dec 5;16(1):121.Recurrent Implantation Failure-update Overview on Etiology, Diagnosis,
Treatment and Future Directions Bashiri,Halper, Orvieto
7

International Committee Monitoring
ART and WHO definition: the
detection of hCG in blood or urine
without subsequent clinical signs of
pregnancy .
Coulam et al: when 2 or more
increasing values of hCG, yet no
evidence of G sac detected on TVS 2
weeks later
BIOCHEMICAL PREGNANCY
Despite the fact that many
authors agree on a similar
general definition, the
parameters used to measure
the hCG level differ
substantially between > 5 to
> 25 mIU/ml
8

INCIDENCE
Due to variations in
definitions there is
scarce data for incidence
Biochemical pregnancy –
incidence - 8 to 33% in
the general population,
including those who
spontaneously conceived
In spontaneous
conception it is estimated
that 30% of pregnancies
are lost before
implantation and 10% are
clinical pregnancy losses
It is also important to note
that spontaneous
pregnancy is only
achieved in around 30% of
normal fertile couples on
the first try, and many
succeed on subsequent
efforts .
9
Moreover, it may be worth considering whether or not biochemical pregnancy is a pathological
process.

CAUSE: OOCYTE QUALITY
Cause of RIF is often suspected when there is a poor response to ovarian
stimulation[#].
Retrieval of a high proportion of immature oocytes; Reduced fertilization rate; low
embryo utilization rate.
When the above features are associated with low AFC, high FSH and low AMH
Cumulus cells are supposed to play a vital role in implantation. Cumulus cell gene expression appears to correlate with
oocyte quality, embryo competence & pregnancy outcome[$] Cumulus cells are a source of prostaglandins and express
angiogenic factors (VEGF) that may play a role in angiogenesis at the implantation site
◂ Coughlan C. Reproductive BioMed Online (2014) 28, 14– 38
◂ #Ferraretti, A.P. Hum. Reprod. 26, 1616–1624
◂ $ Assou, S. Mol. Hum. Reprod. 16, 531–538
10

MATERNAL AGE
Maternal age plays a
crucial role in the quality
of the embryos that are
used for IVF.
Pregnancy rates also
have been found to be
decreased as maternal
age increases
Salumets et al. found age
to be the major predictive
factor contributing to
pregnancy outcome in FET,
specifically with ICSI
Starting around age 39,
there was a significantly
higher rate of occurrence of
biochemical pregnancy.
Shapiro et al. found higher
rates of embryo-
endometrial asynchrony
with increasing maternal
age. 50% vs 68.1% of
transfers were
asynchronous in women
< 35 yr vs women
> 35 years old.
11

“
Nearly 57% of the couples of all ages in
United Kingdom remained childless even after
undergoing 6 complete IVF cycles
Female age is the main factor related to
delivering a child through ART
◂ Thus, patients older than 35 years of
age require multiple cycles to increase
the probability of live birth.
12

SPERM QUALITY
Widely accepted,
conventional semen
analysis does not
accurately reflect
sperm quality.
Sperm DNA damage is
associated with poor
embryo development
DNA fragmentation
may be associated
with an increased
risk of miscarriage
but association with
RIF not yet
established
13
Coughlan C. Reproductive BioMed Online (2014) 28, 14– 38

BMI
Increased BMI (> 25 kg/m2) has also been shown to
impact implantation rate .
In patients undergoing IVF, Class I, II, and III obese
patients (BMI > 30 kg/m2) had the highest chance of
implantation failure demonstrated by respective odds
ratios, 0.69 (0.53–0.90), 0.52 (0.36–0.74), and 0.58
(0.35–0.96), when compared with patients of normal
weight (BMI 18.5–24.99 kg/m2).
Reprod Biol Endocrinol 2018 Dec
5;16(1):121.Recurrent Implantation Failure-update
Overview on Etiology, Diagnosis, Treatment and
Future Directions Bashiri,Halper, Orvieto

BMI
◂ Though there have been no reported differences
across different BMI groups for biochemical
pregnancy specifically, the Class III Obesity
Patients (BMI > 40 kg/m2) had the highest overall
rates of miscarriage (including biochemical
pregnancy)
◂ In addition, overweight and obese women (BMI
> 25 kg/m2) undergoing IVF who had fewer
oocytes collected had higher risks of implantation
failure and miscarriage than women of healthy
weight with the same number of collected oocytes

SMOKING - MATERNAL
Smoking has been shown to lead to a significantly
increased risk of miscarriage (time unspecified) for
each pregnancy in comparison with non-smoking
patients undergoing ART
In women undergoing IVF, lower estradiol levels
found during ovarian stimulation.
Cigarette toxins might play a role in disrupting
C.luteum formation and implantation of the embryo
Maternal smoking was more commonly linked to
spontaneous miscarriage with normal fetal
karyotype than abnormal karyotype, suggesting that
the toxic effects of CO and nicotine
16

SMOKING - PATERNAL
Kunzle et al. found that male smokers had a
significantly decreased sperm count
(229.4 ± 251.5 × 106 cells
vs278.1 ± 264.2 × 106 cells, P = .0001),
higher percentage of abnormal morphology
(21.2 ± 14.6% normal forms vs. 23.7 ± 15.5% normal
forms, P = .0007)
decreased motility (105.6 ± 132.7 × 106 cells vs.
126.6 ± 136.8 × 106 cells, P = .0016)
and increased pH level measured by citrate
concentration (86.7 ± 57.3 v111.7 ± 303.1, P = .0072)
Reprod Biol Endocrinol 2018 Dec 5;16(1):121.Recurrent Implantation Failure-
update Overview on Etiology, Diagnosis, Treatment and Future Directions
Bashiri,Halper, Orvieto
17

STRESS
It has been shown that elevated levels of cortisol,
also known as “the stress hormone,” lead to a 2.7
times greater chance (95% CI = 1.2–6.2) of
miscarriage within the first 3 weeks after conception
in comparison with women with low cortisol levels.
Cortisol production in the body rises in response to
psychological, immunological, and other stressors,
suggesting that it serves as a marker signaling the
female body that it is not in its best state for
reproduction
18

STRESS
This suggests that preventing / decreasing maternal
stressors may have positive outcome on pregnancy.
In contrast, Pasch et al. found that psychological
stress such as clinical anxiety/ depression does not
have a significant affect on IVF outcome in women
undergoing a first time fertility treatment.
However, it is IVF failure that may lead to higher
rates of both anxiety and depression in the immediate
period after a negative IVF outcome.
There were higher rates of post-IVF depression in
women with IVF failure than in women who achieved
successful pregnancy (44% vs. 30% P < .001).
19

Congenital Uterine Anomalies
20
May affect endometrial receptivity manifesting as either infertility or RPL
Preliminary evidence that the septate uterus may also contribute to RIF
Ban-Frangez et al proved that septum large or small was associated with a 80%
miscarriage rate which reduced to 30% post removal
However, women with a bicornuate uterus usually have normal implantation, but
these patients have a higher risk of mid trimester pregnancy loss

Intra Uterine Abnormalities
21
The frequency of unrecognized intrauterine pathologies in patients with RIF varies
between 25% and 50%
Sub-mucous fibroids: Studies have concluded that removal favorably impacts the
pregnancy rates
Intra-mural fibroids: >4cm usually impact and may result in RIF. Removal conversely
does not impact pregnancy rates
Endometrial polyps: removal favorably impacts the pregnancy rates
Adhesions: Some studies found an association (8.5% women with RIF were found to
have RIF)
Shokier et al. J. Obstet. Gynaecol. Res. 30, 84–89
Shokier et al . Fertil. Steril. 94, 724–729.

Role of Endometrium
22
The endometrium itself can also be the source of implantation failure.
Thin ET: Etiologies include : Previous endometrial trauma, prolonged OCP, and impaired blood flow
Evaluating the blood flow in the uterine radial arteries is useful. With decrease in blood flow, ECGF , VEGF
production can be reduced, which deprives it of angiogenesis and growth factors
Miwa et al. conducted a TVS Doppler USG study found that UA RI was significantly higher in patients with
thin endometrium < 8 mm than with normal ET > 8 mm (0.852 (0.826–0.955) vs. 0.751 (0.549 –
0.840), P < .05)
ET has been determined to have an effect on implantation rates. Though an exact threshold has not been
unanimously agreed upon, about 8 mm is the lower limit for which ART can still usually be successful.
From 9 mm to 16 mm chance of pregnancy increases from 53 to 77% showing that a significant difference
does exist in implantation rates .

Endometrial Flora
◂ In some cases, it is not necessarily CE that leads to decreased IR, but rather the
constituents of bacterial flora present in the endometrium.
◂ While it was once thought that the endometrium was a sterile environment, it has now
been accepted that Lactobacillus colonize this region in addition to the vagina.
◂ In a recent study, Moreno et al. demonstrated that women
with Lactobacillus dominated endometrium undergoing IVF have been shown to
achieve higher rates of successful implantation (60.7% vs. 23.1%) and live birth (58.8%
vs. 6.75%) rates compared to those with non-Lactobacillus dominated endometrium
(Gardnerella, Streptococcus, and other organisms present).
23

Genetics
24
Chromosomal abnormalities including translocations, mosaicism, inversions, and deletions are
more frequent in RIF patients than the general population, and yet the prevalence is only about
2%.
The most common abnormality is translocation.
Voullaire et al. looked at the difference between women with aneuploidy in 1/2 chromosomes,
and women with complex abnormalities, defined as 3 or more chromosomes with aneuploidy.
Though this is a rare occurrence, it was shown to be significantly more likely to be in women who
had RIF, whereas aneuploidy in only 1/2 chromosomes was not considered to be a significant
cause of RIF. It is accepted that this complex abnormality is mitotically derived as it is observed
more commonly in the embryos than in the oocytes upon collection.

Genetics
Parental karyotyping is recommended in RIF only in specific
subgroups such as nulliparous women with h/o miscarriage, as it
would be very expensive to make it a universal test, and it would only
protect a small group of patients
2016 Koot et al. published a study which found an endometrial gene
signature made up of 303 genes which was found to be predictive of
RIF. RIF patients had down regulation of genes that were involved in
cell regulation, division, cytoskeleton, cilia formation confirming the
complexity of the approach to evaluation and treatment of RIF.
In addition, men with severe infertility are also recommended for
karyotyping .
25

uNK and pNK are they different?
Peripheral NK
<10% resemble uNK
90% are CD56dim and CD16+
Significant cytotoxic activity
Uterine NK
appear in midsecretory phase
80% are CD56bright and CD16-
Little cytotoxic activity
Express KIR, ILT-2, NK G2 and
HLA-C, HLA-E and HLA-G

NK Cells – uterine/ peripheral
NK cells were given their name because of their ability to kill leukemic
cell lines
P NK cell level and activity in these two groups were significantly higher than
those of the women who went on to achieve successful live births .
Sacks et al. found that women with RIF had significantly increased P NK cells by
concentration (0.23 × 109/L ± 0.11 vs. 0.20 × 109/L ± 0.13) and percentage (> 18%,
threshold value) of lymphocytes compared with controls. However, it is important
to note that the sensitivity of this test was only 11% suggesting multiple other
factors may be involved in RIF
P NK cells were relatively equal in women whose next pregnancy resulted in
both biochemical pregnancy & miscarriage
28

29
Uterine NK cells were measured via endometrial biopsy and levels greater than
> 250 CD56 cells per high power field 400× were found in 53% of idiopathic RIF
patients and only in 5% of controls.
Though cut off values still require standardization, analysis of NK cells might
eventually prove to be useful to women suffering from idiopathic RIF .
On the other hand, a recent meta-analysis by Seshadri et al. set out to
determine the role of both peripheral and uterine NK cells in infertility and
recurrent miscarriage and found some conflicting data regarding their role.
In addition NK cells levels did not seem to have an association with live birth
rate in those undergoing IVF (RR 0.57; 95% CI 0.06; 5.22; P = 0.62). Other
factors like Th1/Th2 ratio and TNF-α levels may be involved in immune
mechanisms also Hhcg; LIF; CAM; PLA2 etc
NK Cells – uterine/ peripheral

Association between uNK number or activity and RM/infertility
1. Tremendous inconsistency
2. Causative role for NK cells
in reproductive problems?
Clifford 1999
Quenby 1999
Quenby 2005
Tucerman 2007
Ledee-Bataille 2005
Michimata 2002
Shimada 2004
Matteo 2007

Association between pNK number or activity and RM/infertility
Kwak 1995
Aoki 1995
Ntrivalas 2001
Yamada 2003
Shakar 2003
Beer 1996
Matsubayashi 2001
Ntrivalas 2001
Emmer 2000
Souza 2002
Wang 2008
Vujisic 2004

Relevant citations on uNK and pNK (n=783)
Tang et al Hum Reprod 2011

“
Testing NK cell levels therefore cannot necessarily be
used to distinguish women with RIF from the general
population, but rather might be used in women with
already established RIF, to determine whether the
etiology of their implantation failure is related to their
immunological profile .
33

34
Automimmune Antibodies
Includes: ANA, ACAs, APLAs – may be involved in biochemical pregnancy loss.
Although the mechanism is still not well understood, there is also a strong
association between anti-β2 glycoprotein 1 and ANA and implantation failure.
β2 glycoprotein 1 is the cofactor for anticardiolipin.
Stern et al. found it present that 30% of patients with implantation failure tested
positive (aPI, aPE, aPS) vs 16% of fertile controls (P = .019) .
It is important to understand that this is a strong association, but there is no
evidence to suggest that these antibodies directly cause the implantation failure.

35
Antiphospholipid syndrome (APS) might be important to consider in relation
to RIF
Definition: One clinical and one Lab criteria must be met
Clinical criteria : vascular thrombosis or pregnancy morbiditiy (fetal death >
10 weeks, premature birth < 34 weeks, or 3/more consecutive miscarriages
< 10 weeks of gestation).
Laboratory criteria : LA/ ACL antibody in plasma >40GPL or MPL or > 99th
percentile,or Anti-β2 glycoprotein-I antibody in plasma >99th percentile
All measured twice and 12 weeks apart.
Studies have shown that these antibodies are present in RIF patients,
however, these specific clinical and laboratory criteria might not be met in
RIF patients.

36
A meta analysis conducted by Hornstein et al. demonstrated that data from
seven studies revealed no statistically significant association between presence
of anti-phospholipid antibodies and CPR & LBR in future IVF cycles, though
exact levels were not specified .
There is accumulating evidence of non-criteria clinical and laboratory
manifestations of APS, of which one criterion is two or more unexplained failed
IVF cycles. In addition, some studies have suggested that these women benefit
from standard APS treatment .
Due to presence of specific antibodies implicated in both APS and RIF, it is
important to consider if RIF should be added to the clinical criteria for
antiphospholipid syndrome.

37
Hereditary thrombophilia
There is some data suggesting that hereditary thrombophilias may be involved in
a subgroup of women with unexplained recurrent implantation failure.
Azem et al. found that there were higher rates of inherited thrombophilias such as
MTHFR deficiency
factor V leiden
prothrombin deficiency
antithrombin III deficiency
in women with RIF in comparison with controls (44% vs. 18.2%, P = .012) .
Though this needs to be confirmed by further studies, this could lead to the
evaluation of antithrombotic agents as another potential intervention for women
suffering from RIF.

8 case-control
3 cohort NO
RISK FOR ART FAILURE
n=6,092

Investigations
41
ResearchRecommended

OTHER INVESTIGATIONS: Specific to the case
42
oAnti-thyroid antibodies
o NK cell testing
o Antiphopholipid antibodies
o Thrombophilic disorders
oSperm DFI

Many women who have experienced RIF have also been determined
to have chronic endometritis (CE) from bacterial colonization, often
with minimal or no clinical signs of infection . Kushnir et al. found
that among a sample of infertile patients, 45% had CE, particularly
those with RIF .
Hysteroscopy
Hysteroscopy had a 40%
sensitivity for detection of CE,
visualizing mucosal edema,
endometrial hyperemia, presence
of micropolyps (all part of
diagnostic criteria for CE) [46, 47].
Histology
Bouet et al. confirmed a prevalence
of 14% of CE using histological
evaluation in RIF patients
Immunohistochemistry
Immunohistochemistry stain for
syndecan-1(CD 138), a plasma cell
marker, can be used to provide a
more accurate diagnosis
43
Culture
Though culture is the least reliable method of
detecting CE, it did allow for specific pathogens to be
detected for targeted therapy. Most common bacteria
GBS, E Coli, E Faecalis, or Mycoplasma.
Cicinelli et al. found that 66% of women were
diagnosed with CE via hysteroscopy, 57.5% with
histology, and 45% were also culture positive

Genetics
Parental karyotyping is recommended in RIF only in specific
subgroups such as nulliparous women with h/o miscarriage, as it
would be very expensive to make it a universal test, and it would only
protect a small group of patients
2016 Koot et al. published a study which found an endometrial gene
signature made up of 303 genes which was found to be predictive of
RIF. RIF patients had down regulation of genes that were involved in
cell regulation, division, cytoskeleton, cilia formation confirming the
complexity of the approach to evaluation and treatment of RIF [67].
In addition, men with severe infertility are also recommended for
karyotyping [64].
44

MANAGEMENT
STRATEGIES:
Therapeutic
Interventions
45

Embryo Factor
Ongoing debate/ Currently the IR per embryo is only about 15% .
◂ Guerif et al. - quality of the embryo in patients with RIF was important factor.
However, there were higher IR in the blastocyst group (25.4%) vs CS group (12.4%)
despite embryo quality
◂ Levitas et al. found that in patients with RIF with good ovarian response during IVF,
IR higher with blastocyst vs CS transfer (21.2%/6%). In addition, fewer embryos were
actually transferred per cycle in the blastocyst group (3.4 ± 0.7 vs. 1.9 ± 0.4)
◂ A 2016 Cochrane review determined that evidence of
blastocyst transfer over cleavage stage embryo transfer was
of low quality for live birth outcome, and only moderate quality
for clinical pregnancy outcome.
46

Fresh embryo vs Fozen embryo transfer
◂ RCT NEJM 2018
◂ No significant difference in outcome in LBR between women who underwent frozen vs
Fresh ET with CS embryos (48.7% vs. 50.2% RR, 0.97; 95% CI, 0.89 to 1.06; P = .5).
◂ These results may not be applicable to those undergoing blastocyst transfer due to
differences in the embryo-endometrial cross talk at the different stages of the embryo
development and endometrial preparation.
◂ In addition, there was no significant difference in biochemical pregnancy, IR, CPR, or
neonatal outcomes between the two groups.
◂ The only significant difference was that FET has lower rates of OHSS (.6% vs. 2%
RR, 0.32; 95% CI 0.14 to 0.74; P = .005) which has also been reported in other studies
[75].
47

ET Method
◂ Ultrasound guided transfer led to higher rates of clinical pregnancy
and live births. The ideal type of catheter used (rigid versus soft)
can be dependent on cervical shape.
◂ Additionally, in some cases removing cervical mucus via aspiration
can lead to more successful pregnancy outcome.

OI Protocol
49
meta-analysis 2017 - in the general IVF population – Lower PR with antagonists vs agonists (RR 0.89,
95% CI 0.82–0.96).However, antagonists had lower rates of OHSS (RR 0.63, 95% CI 0.50–0.81),
Barmat et al. found no significant differences in IR, and the only major difference found was the
convenience due to shorter timing of antag protocol.
Orvieto et al. recently suggested a new protocol for IVF in patients with RIF which includes using both
GnRH-agonists and antagonists with administration of GnRH agonist and hCG double trigger
It will be important to determine if a specific stimulation protocol for IVF in RIF patients will make a
significant difference in implantation and birth outcomes.
However, this could also differ in success rate depending on the etiology of patient’s implantation
failure as well as other important clinical parameters including maternal age.

Removal of hydrosalpinges
◂ Salpingectomy/
Disconnection:
The treatment of hydrosalpinges in
women with RIF should be either
salpingectomy or salpingostomy,
with proximal tubal occlusion
reserved for cases with severe/dense
tubo-ovarian adhesions when the
surgical morbidity in such cases is
significantly increased

Progesterone
51
As in RPL, progesterone type may play an important part in increasing the birth rate in RIF patients.
A very recent meta analysis and systematic review performed by Roepke et al. in 2018 concluded - no
specific treatment for idiopathic RPL, with the exception of progesterone administration starting from
ovulation
In addition, a RCT by Tournaye et al. found oral dydrogesterone to be non inferior to vaginal progesterone
for luteal support; No significant difference in CPR at 12 weeks gestation among the two groups. Oral
dydrogesterone has fewer side effects & easier for patient adherence
Thus, progesterone / orally administered dydrogesterone used in IVF protocols, may have a significant
role in improving PR and LBR among patients with RIF mainly when started in the luteal phase.
More studies are needed to support this.

ANATOMIC INTERVENTION
◂ Polyps, myomas, adhesions, and septa can all affect implantation, and the gold standard for
evaluation is hysteroscopy.
◂ The previously reported prevalence of undetected anomalies was between 20 and 45%, however,
Fatemi et al. found the prevalence in their study population to be only 11%, identifying polyps as the
most common pathology (41%)
◂ Cenksoy et al. demonstrated dramatically different findings, in that 44.9% of patients in their study
had abnormal hysteroscopic results. After corrected pathology, 51% of these women became
pregnant. The IR was significantly higher in those who had corrected polyps (P = .001), but not
those with corrected adhesions suggesting that different pathologies may not have the same PR&
IR after intervention.
◂ Demirol et al. found that CPR were significantly higher in those that had hysteroscopy and treatment
for polyps / adhesions in comparison with those who did not (30.4% vs. 21.6%, P < .05).
◂ Many of the patients with abnormal hysteroscopy findings had normal HSG results Hysteroscopy
might serve as a useful diagnostic tool in many RIF patients, as some literature suggests that with
this intervention there can be major changes in pregnancy outcome.

ENDOMETRIAL INJURY
53
Many studies suggest that injury to the endometrium prior to implantation in IVF patients causes
decidualization, an increase in local cytokines involved in wound healing such as LIF and IL-11, both
important in the implantation process
Barash et al. were the first to report on the topic, IR of the patients who underwent biopsy (injury) prior
to their IVF vs no injury cycle was 27.7% vs 14.2% IR (P = .00011). CPR (66.7% vs.
30.3%, P = 0.00009) LBR 48.9% vs 22.5% (P = 0.016)
Gibreel et al. found both a significantly higher BPR (29.6% vs. 11.7%) and CPR (25.9% vs. 9.8%) in
patients undergoing EB, than those undergoing a placebo procedure. Both groups of women were given
doxycycline after the procedure to prevent possible infection

Endometrial Injury
54
However, there is no agreement on what degree of injury, the number of injuries, or when in the
menstrual cycle this procedure must occur to work, if at all.
This is a widely used treatment, though there is insufficient evidence demonstrating a strict protocol for
how to perform this procedure, and therefore more data is needed
A 2015 Cochrane review calls for more trials suggesting that there is only moderate quality evidence
that endometrial injury done between day 7 of the previous cycle and day 7 of the embryo transfer cycle
can lead to increased clinical pregnancy and live birth rates in women with previous embryo transfer

ROLE OF PGT
55
Though initially it was hypothesized that PGT might be helpful in RIF recent studies such as - by Rubio et
al. concluded there was no significant difference in IR (36.6% vs, 21.4%), CPR (53.5% vs. 33.3%), or LBR
(47.% vs. 27.9%) between those evaluated and not evaluated with PGT
It is possible that the trophectoderm biopsy from these embryos is not representative
In addition, Greco et al. found that implanted mosaic embryos can actually develop into healthy newborns,
though this was shown in a small sample size
While PGS does help select best quality embryo for transfer, the more embryos that are transferred with
consistent rates of failed pregnancy, the less likely it is that the embryo is the problem in these cases
There may be additional mechanisms at play esp in those with advanced maternal age. It is recommended
that women with RIF should be karyotyped to determine if they may have balanced translocations. PGD is
recommended only in these cases, as these can lead to aneuploidy in their gametes

◂ Antithrombotic agents
◂ Heparin has been evaluated for use in RIF patients, though
there is not yet evidence to recommend its use for
improved pregnancy outcomes in these patients.
◂ A group of RIF patients treated with low molecular weight
heparin had almost identical implantation, clinical pregnancy,
and live birth rate outcomes when compared with controls [81].

Empirical therapies
◂ Aspirin

Antibiotics
◂ In patients who have had CE diagnosed via hysteroscopy and culture, antibiotic therapy has been shown to be an
effective intervention to cure most infections, leading to more successful implantation rates in future IVF cycles.
◂ Women infected with common gram positive bacteria, Enterococcus and Strep Agalactiae, were given Amoxicillin
and Clavulanate twice a day for 8 days, and gram negative bacteria such as Escheria Coli were given ciprofloxacin
twice a day for 10 days. Women with Mycoplasma and Ureaplasma were treated with 1g Josamycin twice a day
for 12 days with the addition of Minocycline in persistent cases.
◂ When infections were cured, the implantation rate was found to be higher in the next cycle at 37%, though not
statistically significant in comparison with a rate of 17% in those who had persistent infection even after three
antibiotic treatments.
◂ The CPR in those with CE who cleared their infection with antibiotics was 65.2% in comparison with 33% in those
with persistent infection (P = 0.039).
◂ The LBR in those who had cleared their CE with antibiotics was 60.8%, significantly higher than the 13.3% in
those who had not cleared the infection (P = 0.02)

Male Factor
60
particularly spermatozoal morphology also can play a part in RIF
IMSI : IR (19.2% vs. 7.8%, P = 0.042), CPR (43.1% vs. 10.5%, P = 0.02) and LBR (34.7% vs.
0%, P = 0.003) were reported to be significantly higher among cases with IMSI vs ICSI in a retrospective
study conducted by Shalom-Paz et al. in 2015 , other studies could not demonstrate any benefit of using
IMSI.
There is still a lack of specific microscopic criteria for the assessment of sperm morphology, and
therefore more studies are required to confirm the advantages of IMSI before a standardized clinical
protocol can be created for this particular procedure
A Cochrane review in 2013 called for further trials to be conducted since higher quality evidence needs
to be established in order to recommend this technique for clinical practice

Other Strategies
◂ Sildenafil: Proposed in the treatment of women with RIF associated with a thin
endometrium. Hypothesis behind the use of sildenafil is that it increases endometrial blood
flow. Use has not been confirmed in a RCT
◂ Endometrial perfusion with granulocyte colony stimulating factor: The novel approach
requires further investigation to confirm its usefulness
◂ Luteal support with GnRHa: it is unclear whether GnRHa has any significant benefit over
other commonly used forms of luteal support such as progesterone or HCG

◂ Peripheral blood mononuclear cells
◂ PBMCs consist of B lymphocytes, T lymphocytes, and monocytes.
◂ These cells produce many cytokines that have been known to improve endometrial
receptivity during implantation.
◂ PBMC injection via IUI catheter before ET greatly improved the outcome of implantation
in those who previously suffered from RIF.
◂ Yu et al. confirmed that IR was significantly higher (23.66% vs. 11.43%) .
◂ Li et al. found that only patients with 4 or more previous implantation failures could
benefit. There was a significant increase in IR (22% vs. 4.88%, P = 0.014), CPR (39.58%
vs. 14.29%, P = 0.038), and LBR (33.33% vs. 9.58%, P = 0.038) after their next FET

TACROLIMUS
◂ Tacrolimus is currently approved for immunological allograft transplant rejection.
◂ It has been used by Nakagawa et al. as a plausible treatment for RIF patients with
an elevated Th1/Th2 ratio. However, due to the delicate balance of cytokine levels
that must be maintained, dosing must be specifically adjusted in order to maintain
certain levels of Th1 cytokines essential to the process of implantation. IR 45.7%
vs 0% successful implantations (P < 0.0001).
◂ This indicates that this immunological imbalance might play a significant role in
some patients with recurrent implantation failure.

o RCOG – 2011
“This remains a research field and testing for uNK cells should not be
offered routinely in the investigation of recurrent miscarriage.”
o ASRM – 2012
“Treatments with no proven benefit include leukocyte immunization
and IVIG therapy”

Treatment Risks….
Heparin Corticoids IVIGs
• thrombocytopenia
• bleeding
• fluid retention
• HTA
• mood swings
• weight gain
• risk of infections
• high blood sugar
• cleft palate
• headache
• dermatitis
• pulmonary edema
• anaphylactic react.
• hepatitis
• acute renal failure
• venous thrombosis
• aseptic meningitis
• risk of diabetic newborn

67
Lifestyle modifications
In November 2017 The ESHRE released a new set of guidelines for RPL patients.
Recommendations for RPL patients include smoking cessation, acheiving a healthy range BMI and
reducing stress levels
lifestyle interventions such as assistance in quitting smoking, healthier diet and regular exercise, and
emphasis on taking care of mental health may positively impact those suffering from RIF.
These modifications require less invasive medical assistance and seem like an optimal first step in
trying to change future implantation outcome in IVF treatment in couples struggling to get pregnant and
have a successful delivery outcome.
In addition, other behavioral changes may also be relevant to improve outcomes in these patients.

◂ Encouraging the patients to engage in activities that create enjoyment & positive
environment
◂ This intervention is relatively simple, can be done in the comfort of the patient’s
familial and social circle, and on the patient’s own time, tailored as per perosnal
interests
◂ Eg include spending 3 days meeting with friends each week, eating out in a nice
restaurant once a week, making specific time for creative activity, or watching a
comedy film a few times a week.
◂ This concept might be a great starting point for future studies in RIF treatment,
and even now might be a great first step in protocol for evaluating and treating
patients suffering from RIF.

69
Conclusion
RIF is a complex problem with a wide variety of etiologies / mechanisms/ treatment options.
Recommendations vary depending on the source of their problem. Perhaps the best and yet most
complex answer is personalized medicine, a personal approach to each patient depending on her
unique set of characteristics.
It would help to establish a set of standardized tests to use, in order to do a preliminary evaluation on
each patient, which would then hopefully direct the approach of treatment for each individual couple.
This can be implemented when we have well designed studies that will help us to establish new
protocols.

Recurrent Implantation Failure

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