Can clinicians improve
implantation?
Omur Taskin,M.D
Dept. Obstet&Gynecol, Div. Reprod. Endocr.
Akdeniz University School of Medicine

Implantation is a complicated process that
requires the orchestration of a series of
events involving both the embryo and the
endometrium

implantation rates remain around 2535%(European IVF-Monitoring
Program,2005).
Problems?
High rates of implantation failure
 early pregnancy loss in IVF
 increase the transfer of multiple embryos.

Embryo transfer technique
cervical manipulation may result in an increase of
contractions of the uterus, which has been
observed to severe IVF outcome, possibly by
expelling embryos from the uterine cavity
Fanchin et al.,1998
stiff vs soft embryo transfer catheters

In a recent meta-analysis of seven randomized
controlled trails (RCT) comparing stiff and soft
embryo transfer catheters, significantly
increased pregnancy rates were observed with
the latter (odds ratio(OR) 1.34, 95% confidence
intervals(CI)1,18-1,54)
(Buckett,2006)

Traditionally, embryo transfer after IVF has
been performed ‘blindly’, with the aim of
placing the embryos 1 cm below the
fundus of the uterus (Schoolcraft, 2001)
Deposition of embryos



In a prospective investigation significantly better results were
obtained when the catheter tip was positioned close to the middle of
the endometrial cavity (Oliveira et al.,2004)
However, another randomized study revealed significantly higher
implantaion rates when embryos were deposited 1,5 or 2 cm from
the fundus, compared with 1 cm (Coroleu et al.,2002)
suggesting that for every additional 1 mm that embryos are
deposited away from the fundus, the odds of clinical pregnancy
increased by 11% (Pope et al.,2004)
Role of USG


The blind nature of traditional ‘clinical touch’ embryo
transfer had led to the suggestion of a role for ultrasound
in improving IVF outcomes.
A meta-analysis of four RCT comparing ultrasoundguided embryo transfer versus clinical touch showed a
significant higher pregnancy rate and implantation rate
after ultrasound-guided transfer (1,38 , 95% CI 1,201,60) (Buckett,2003)
BV colonization

During embryo transfer, it is likely that bacteria from the
cervix may be introduced into the uterine cavity. Bacterial
vaginosis is characterized by an overgrowth of anaerobic
organisms; the prevalence among women undergoing
IVF is approximately 25% (Liversedge et al.,1999).
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Careful evaluation of the uterus
Avoiding the initiation of uterine
contractility
Removing the cervical mucus
Proper placement of the embryos
Minimizing embryo expulsion
Adjuvant pharmaceutical therapies
Aspirin
Randomized controlled trials investigating
the use of aspirin
as an empirical therapy in non-selected IVF populations.
Low-dose aspirin for in vitro
fertilization: a systematic review and
meta-analysis
T.A.Gelbaya et al., human reproduction, 2007

Clinical pregnancy (CP) rate per embryo transfer (ET) was not found to be significantly
different between patients who received low-dose aspirin and those who received placebo
or no treatment (RR 1.09 95% CI 0.92-1.29). None of the other outcomes, including CP per
cycle, spontaneous abortion or ectopic pregnancy per CP and LB rate per cycle or ET was
found to differ significantly between the compared groups. On the basis of up-to-date
evidence, low-dose aspirin has no substantial positive effect on likelihood of pregnancy
and, therefore, it should not be routinely recommended for women undergoing IVF/ICSI.

A large body of evidence shows that APL antibodies, occasionally
found in low-risk obstetric populations (Lockwood et al.,1989; Stern et
al., 1998) , are commonly found in women with reproductive
dysfunction such as recurrent pregnancy loss (RPL) (Cowchock et al.,
1986 ;Matzner et al., 1994; Yetman and Kutteh, 1996) and idiopathic
infertility (Gleicher et al., 19891994; Birdsall et al., 1996)

Nevertheless, there is much controversy with regard to the
association between APL antibodies and IVF outcome. Unlike the
studies showing benefits after the use of heparin and aspirin in
women with RPL (Kutteh, 1996; Rai et al., 1997; Tulppala et al., 1997) , there is no
consensus regarding its use in IVF patients.
Characteristics of controlled trials on low-dose aspirin and
IVF outcome included in the systematic review
Forest plot of the effect of aspirin versus placebo or no
treatment on clinical pregnancy rate per embryo transfer.
Review: aspirin versus nothing in IVF.
Comparison: aspirin versus placebo or no treatment.
Outcome: clinical pregnancy/embryo transfer.
Forest plot of the effect of aspirin versus placebo or no
treatment on miscarriage rate per clinical pregnancy.
Review: aspirin versus nothing in IVF.
Comparison: aspirin versus placebo or no treatment.
Outcome: miscarriage/clinical pregnancy.
Forest plot of the effect of aspirin versus placebo or no treatment on cycle
cancellation rate.
Review: aspirin versus nothing in IVF.
Comparison: aspirin versus placebo or no treatment.
Outcome: no. of cycles cancelled/cycles.
Main results of the two RCTs comparing aspirin versus placebo in
poor responders (Lok et al., 2004)
or oocytes recipients (Weckstein et al., 1997)
Nitric oxide donors
Effect of vaginal sildenafil on the outcome of in vitro
fertilization(IVF) after multiple IVF failures attributed to poor
endometrial development
Geoffrey S. et al.,fertility sterility,2002

Patients: A cohort of 105 infertile women aged <40
years, with normal ovarian reserve and at least two
consecutive prior IVF failures attributed to
inadequate endometrial development

Interventions: patients underwent IVF using a long
GnRH-a protocol with the addition of sildenafil
vaginal suppositories (25 mg, 4 times per day) for 310 days

Although subgroups of women may be identified who benefit from NO
donor therapy, at present the available data demand caution in its use,
which at present the available data demand caution in its use, which at
present should be restricted to well-designed studies.
Aromatase inhibitors
Ascorbic acid

Ascorbic acid appears to be involved in normal folliculogenesis
(Luck et al.,1995), ovulation (Igarashi,1977) and luteal formation and
regression (Luck and Zhao,1993).

An imbalance of oxidative stress and antioxidant defence has been
implicated in the pathogenesis of several diseases, including
recurrent abortion, unexplained infertility and defective embryo
development.

However, a RCT investigating the effect of 1,5 or 10 mg of ascorbic
acid versus a placebo during the luteal phase in 620 women
undergoing IVF showed no difference in implantation rates
(Griesinger et al.,2002).
Prolonged progesterone

An important regulator of endometrium receptivity is the corpus luteum, the
primary function of which is the production of progesterone.

The optimal duration of progesterone administration remains to be clarified.
Many centers continue with progesterone supplementation throughout the
first trimester of pregnancy. However, the rationale for this approach is
unclear. Proponents point to the uterine relaxing properties of progesterone,
elegantly demonstrated by a reported negative correlation between uterine
contractility frequency and progesterone concentrations (Fanchin et
al.,1998)

Secondly, progesterone has been shown to have potentially beneficial
immunomodulatory properties. Studies in mice demonstrated that
progesterone administration abrogated the abortigenic effects of stress
exposure by decreasing the frequency of Th1 cytokines (Blois et al., 2004).
Previous studies suggested that succesful pregnancy is more likely when
Th2 rather than Th1 cytokines are predominant (Wegmann et al., 1993)

Although supplementation of progesterone is widely used to improve
implantation rates, the application of luteal oestradiol
supplementation remains controversial.

A meta-analysis of three RCT (Smitz et al., 1993; Lewin et al.,1994;
Farhi et al.,2000) using a long GnRH agonist protocol, reported no
difference in pregnancy rates when oestrogen was added to
progesterone in the luteal phase (Pritts and Atwood,2002).

In contrast, a recent RCT of 166 women undergoing ICSI reported
significantly higher pregnancy and implantation rates after oestradiol
supplementation (Lukaszuk et al.,2005).
Glucocorticoids

Uterine receptivity is controlled by locally acting growth factors,
cytokines and uterine natural killer (uNK) cells (Dey et al., 2004). It
has been shown that uNK cells may have an important role in early
implantation, since they accumulate around arteries supplying the
implantation site (Croy et al.,2002).

A defect in the integrity of the number of uNK cells has also been
implicated in implaniation failure. Ledee-Batailie et al. reported
higher numbers of NK cells in endomelrial biopsies from women with
implantation failure versus fertile controls (Ledee-Bataille et
al.,2005).

An RCT of 206 patients, investigating the use of glucocorticoids from
oocyte retrieval onwards, reported no differences in embryo
implantation or pregnancy rates (Moffitt et al., 1995). These results
are in line with another RCT addressing the effect of adjuvant
glucocorticoids (Mottia et al.,2005).
Peri-implantation glucocorticoid administration
for assisted reproductive technology cycles
Boomsma C. et al., cochrane dtabase syst rev, 2007
Objectives:

To investigate whether the administration of glucocorticoids
around the time of implantation improves clinical outcomes in
subfertile women undergoing IVF or ICSI, compared to no
glucocorticoid administration.


Thirteen studies (1759 couples) were included.
Overall, there is no clear evidence that administration of
peri-implantation glucocorticoids in ART cycles
significantly improves clinical outcome. The use of
glucocortcoids in women undergoing IVF (rather than
ICSI) was associated with an improvement in pregnancy
rates of borderline statistical significance.
Treatment of repeated unexplained in vitro
fertilization failure with intravenous
immunoglobulin: a randomized, placebo-controlled
Canadian trial
Mary D. S. et al.,fertility and sterility, 2000
Fifty-one couples with a history of repeated
unexplained IVF failure who were
preparing for another fresh IVF cycle or
replacement of cryopreserved embryos.

Conclusion(s): In this randomized clinical
trial, IVIG did not improve the live-birth
rate in couples with repeated unexplained
IVF failure, stringently defined by known
determinants of IVF outcome.
Insulin sensitizing drugs

A meta-analysis of eight RCT investigating metformin in women with
PCOS demonstrated no significant differences in pregnancy rates,
although the risk of ovarian hyperstimulation syndrome (OHSS) was
significantly reduced by metformin (Costeilo et al., 2006).

One recent RCT of 101 women with PCOS undergoing IVF, included
in this meta-analysis, demonstrated lower rates of miscarriage and
OHSS in the group receiving metformin (Tang et al., 2006).
GnRH agonist
Ovarian stimulation
regimens
Assisted hatching on assisted conception (IVF & ICSI)

Objectives: to determine whether assisted hatching (ah) of embryos
facilitates live births and clinical pregnancy and whether it impacts on
negative outcomes (such as multiple pregnancy and miscarriage)

Results: twenty-three randomised controlled trials consisting of 2668
women reported on 849 pregnancy outcomes

Conclusions: despite significantly improved odds of clinical pregnancy,
there is insufficient evidence to determine any effect of AH on live birth
rates. The increased multiple pregnancy rate is of concern although it
likely that with a policy of single embryo transfer this may be lowered.
Currently, there is insufficient evidence to recommend assisted
hatching.
Seif MM, Edi-Osagie EC. et al., cochrane database syst rev, 2005
Hyaluronic acid can successfully replace as the
sole macromolecule in a human embryo transfer
medium
Alex S. et al., fertility and sterility, 2003
Favorable influence of local injury to the endometrium in
intracytoplamic sperm injection patients with high-order
implantation failure
Local injury to the endometrium prior to controlled ovarian stimulation
may considerably improve implantation rates and pregnancy outcomes in
intracytoplasmic sperm injection patients with high-order implantation
failure (>=4 IVF trials and >=12 transferred embryos).
Fertility and Sterility,2007
Preimplantation genetic diagnosis and human implantation- A review
By selecting chromosomally normal embryos for replacement,
PGD for aneuploidy can increase implantation rates, reduce
spontaneous abortion rates, and avoid aneuploid conceptions.
When eight chromosomes are analysed, a significant increase
in implantation is achieved. PGD is also found to significantly
reduce the incidence of spontaneous abortion and
chromosomally abnormal conceptions
S. Munne et al., The Institute for Reproductive Medicine and Science of Saint Barnabas, 2003
The effect of serum concentration of leukamia inhibitory factor
on
in vitro fertilization treatment outcome
To evaluate the association of peripheral leukaemia inhibitory factor (LIF) levels on
implantation and miscarriage rates after in vitro fertilization (IVF) treatment.
The systemic levels of LIF concentration have no association with implantation rate or
miscarriage rate in women undergoing IVF treatment. Measuring serum LIF
concentration prior to embryo transfer in IVF treatment has no predictive value of
implantation rate or miscarriage rate.
Meen-yau T. et al., reprod immunol., 2007
The effect of intercourse on pregnancy rates during
assisted human reproduction

intercourse during an IVF cycle has the potential to improve pregnancy rates since
exposure to semen is reported to promote embryo development and implantation in
animals. Conversely, coitus-induced uterine contractions or introduction of infection
may have a detrimental effect.

A multicentre prospective randomized control trial was conducted to determine if
intercourse during the peri-transfer period of an IVF cycle has any influence on
pregnancy success. Participants undergoing thawed embryo transfer (Australian
centre) or fresh embryo transfers (Spanish centres) were randomized either to
abstain or to engage in vaginal intercourse around the time of embryo transfer

There was no significant difference between the intercourse and abstain groups in
relation to the pregnancy rate (23.6 and 21.2% respectively), but the proportion of
transferred embryos that were viable at 6-8 weeks was significantly higher in women
exposed to semen compared to those who abstained (11.01 versus 7.69 viable
embryos per 100 transferred embryos, P = 0.036, odds ratio 1.48, 95% confidence
interval 1.01-2.19).

Hence exposure to semen around the time of embryo transfer increases the
likelihood of successful early embryo implantation and development.
Tremellen et al, Hum Reprod. 2000 Dec;15(12):2653-8
Ways in which a
clinician could try
to improve
implantation rate.