Is There A Place for Adjuvant Therapy in IVF?
03-05-2010
Source: Obstetrical & Gynecological Survey 2010; 65(4): 260-72
Segev, Yakir;Carp, Howard;Auslender, Ron;Dirnfeld, Martha
Reprint requests to: Martha Dirnfeld, MD, Division Fertility–IVF, Carmel Medical Center, 7
Michal St, Haifa 34362, Israel. E-mail: dirnfeld_martha@clalit.org.il.
Abstract
Objectives. To review studies of adjuvant therapies for in vitro fertilization (IVF), and to
establish the role of adjuvant therapy for women with repeated failure to conceive with IVF.
Design. Review of the literature. Articles were identified through a PubMed, Medline,
EMBASE, Cochrane library, and the national research Register literature search according to
preset criteria followed by a cross-reference of published data.
Main Outcome Measure(s). Clinical pregnancies and live births.
Result(s). Most adjuvant therapies for IVF are empirical, and prescribed without a clear
diagnosis of whether the failure to conceive is due to a maternal or fetal factor. Although
some randomized controlled trials are available, the results are conflicting.
Conclusion(s). No adjuvant therapy has been shown to be definitively advantageous. At
present the diagnosis of IVF failure is not specific enough to indicate a certain adjuvant
therapy. Hence, some unconfirmed therapies might be highly efficacious for subgroups with
particular characteristics. The use of endometrial biopsy with a pipelle is promising, but like
other therapies, requires additional testing. Chromosomal aberrations present a
confounding factor for maternal adjuvant therapies that are difficult to exclude.
Target Audience Obstetricians & Gynecologist, Family Physicians.
Learning Objectives After completion of this educational activity, the reader will be able to
interpret the proven scientifically significant studies of the various forms of adjuvant therapy
in IVF. Assess shortcomings in many of the different types of adjuvant therapy and interpret
potential dangers in some forms of adjuvant therapy.
Subfertility, usually defined as failure to conceive after 2 years of unprotected regular
intercourse, in the absence of known reproductive pathology, is a common problem
affecting as many as 1 in 6 couples. Main causes include sperm dysfunction, ovulatory
disorders, and mechanical factors such as tubal occlusion (1). In vitro fertilization (IVF) has
become a widely accepted clinical practice to assist reproduction. However, despite
improved technologies and better results in recent years, the majority of patients do not
have a successful pregnancy following a single IVF treatment.
The availability of assisted reproductive technology (ART) and delivery rates per oocyte
retrieval vary greatly between countries. Per aspiration, pregnancy rates ranges are 17% to
42% and delivery rates 8% to 34% (2,3).
Repeated treatments and failures have negative repercussions on quality of life, and each
failed cycle incurs substantial financial costs.
A number of adjuvant therapies have been used in conjunction with IVF to increase the
pregnancy rate for women with repeated IVF failures. Although mechanisms of actions have
been proposed, justification for the use of adjuvant therapies is usually empirical, and based
on physicians' personal views. Controlled randomized studies of adjuvant therapies in
women who have had repeated IVF failure are often difficult to perform, due to the great
variation between patients and the large sample size required.
The main factors found to influence the outcome of IVF and intracytoplasmic sperm injection
(ICSI) include maternal age, the number of oocytes retrieved, sperm quality, the number and
quality of the embryos transferred, the technique and ease of embryo transfer (ET), and
endometrial receptivity (4). The use of adjuvant therapy may improve the outcome of IVF,
and may be particularly beneficial for women with a history of repeated IVF failure. The aim
of this review is to establish the role of adjuvant therapy for poor responders and for women
with repeated failure to conceive with IVF.
Data collection and analysis
We performed a thorough literature search of articles cited in PubMed, Medline, EMBASE,
Cochrane library, and the national research Register from January 1982 to January 2009. The
quality of all trials was assessed in terms of level of evidence. Studies presented at meetings
or congresses, with only abstracts available, were excluded. In the final analysis we included
prospective randomized trials, prospective nonrandomized trials, studies with historical
controls, and retrospective studies. We included all studies comparing the specific adjuvant
therapy in question versus no treatment or placebo during IVF, or frozen-thawed embryo
transfer treatment. Due to its role as adjuvant therapy, most studies do not adhere to
specific protocols and indication for treatment. Therefore, owing to significant heterogeneity
among trials, each study and therapy was tried to be assessed in terms of indication and
pregnancy outcomes.
Fetal factors
Assisted Hatching
A number of studies have tried to assess the value of interventions aimed at improving the
embryo factor in implantation. Failure to hatch due to abnormalities in either the zona
pellucida or the blastocyst may be one of the factors that limit human reproductive
efficiency.
Assisted hatching (AH), in which artificial disruption of the zona pellucida is performed either
mechanically or chemically, is the procedure most commonly performed on the in vitro
embryo (5). AH has been clinically useful in a subgroup of patients with a poor prognosis,
including repeated failed IVF cycles, poor embryo quality, and older women (>37 years of
age). However, despite numerous studies, the role of AH is unclear. A recent review in the
Cochrane database (6) concluded that evidence to support the clinical use of AH in the
context of implantation failure is insufficient.
Preimplantation Genetic Screening
In vitro karyotyping of embryos of couples with implantation failure has shown that up to
66% may be chromosomally abnormal (7). Prolonged culture of aneuploid embryos has
shown that only 20.2% of aneuploidies and autosomal monosomies develop into blastocysts.
Most haploid embryos arrest before cavitation; triploid and tetraploid embryos have lower
rates of development to the blastocyst stage (8). Hence, preimplantation genetic screening
(PGS), which identifies specific chromosomes in an embryo, has been proposed as a
promising technique to exclude embryos with aneupoidy and therefore select better
embryos before their transfer (9). However, the effectiveness of PGS remains uncertain, due
to reports of low implantation and pregnancy rates following PGS (10,11).
PGS entails a number of drawbacks. Many zygotes do not survive the biopsy. With
fluorescent in situ hybridization or polymerase chain reaction techniques, only 5
chromosomes are usually assessed, 9 in leading centers. Only recently has screening of 24
chromosomes become available in a single blastomere using microarray chips. This is also
possible with comparative genomic hybridization microarrays. However, the arrays are
presently expensive, transfer in the same cycle time-consuming, and interpretation of results
difficult. PGS does not guarantee the birth of a healthy baby. All PGS tests are limited since
any single cell analyzed may differ genetically from the other cells in the embryo. This
condition is called mosaicism. It is currently hypothesized that in some cases of mosaicism
the embryo can “self correct”; thus, after PGS some embryos that may have developed into
normal fetuses are not selected for transfer.
A recent systematic review (12) of PGS in assisted reproduction (ART) concluded that there is
insufficient data to determine whether PGS is effective in treating implantation failure.
Maternal factors
A number of the treatment modalities used as adjuncts to ovulation induction claim to
increase the pregnancy rate. Medications include aspirin, glucocorticoids, growth hormone
(GH), dehydroepiandrosterone (DHEA), sildenafil, heparins and intravenous immunoglobulin
(IVIg), and antibiotics. Other methods include acupuncture, and endometrial biopsy using a
pipelle.
Aspirin
Aspirin as an adjuvant therapy for IVF has become of interest due to its anti-inflammatory,
vasodilatory, and platelet aggregation inhibition properties. Low-dose aspirin is shown to
prevent myocardial ischemia, decrease the incidence of preeclampsia and preterm labor,
and increase neonatal birth weight when initiated in the second trimester of pregnancy in
high-risk populations (13). Women with recurrent spontaneous abortion and
antiphospholipid (aPL) syndrome may also benefit from low-dose aspirin therapy (14). In a
number of large trials, aspirin use was without significant complications, except for a small
increased risk of gastrointestinal effects, and bleeding events (15).
Aspirin inhibits cyclooxgenase, the enzyme that catalyzes the synthesis from arachidonic acid
of prostaglandins, including PGI2 (prostacyclin, a vasodilator) and TXA2 (thromboxane A2, a
vasoconstrictor and promoter of platelet aggregation). Since aspirin inhibits TXA2 synthesis
more than PGI2 (16), its overall effect is vasodilation. Several trials have evaluated the
effectiveness of aspirin in increasing IVF success rate by improving either: ovarian blood
flow, folliculogenesis, and ovarian responsiveness; or uterine vascularity and receptiveness;
or both. However, the findings are mixed. In a randomized trial of 1380 consecutive women,
the live birth rate was 27% for those receiving 75 mg aspirin on alternate days from the day
of ET until 18 days after retrieval, and 23% for those who received no treatment (OR, 1.2;
95% CI, 1.0–1.6) (17). In an uncontrolled study, Sher et al (18) found IVF outcome in terms of
pregnancy rates, to significantly improve when aspirin, heparin, and IVIg therapy were
administered to women with repeat IVF failures and antiphospholipid antibodies, but not
when administered to those with negative antiphospholipid antibodies. In a randomized
controlled trial (RCT) Revelli et al (19) demonstrated that adjuvant therapy with aspirin and
steroids (prednisolone) does not improve uterine blood flow, implantation, or pregnancy
rates. Duvan et al (20) reported no significant differences in implantation or pregnancy rates.
Also Frattarelli et al (21) in the subgroup of poor responders found no differences in
pregnancy rates. Gelbaya et al concluded that aspirin does not significantly affect the clinical
pregnancy rate per ET (22).
A comparison of the studies claiming a benefit of low-dose aspirin (17) with those that did
not find a benefit (23,24) did not reveal any factors to explain the improved outcome with
aspirin. There were no differences in the time of initiation, duration of treatment, or dosage.
There were no sufficient data as to what specific subgroups of infertile patients, such as
oocyte recipients or poor responders were included in the different trials, therefore the
indication for use is not clear (21). Hence it is not possible to identify any subgroup for which
the use of aspirin is clearly beneficial. Consequently, aspirin cannot currently be
recommended for routine clinical use outside of the context of a clinical trial.
Glucocorticoids
The intra-uterine environment has recently become a focus for adjuvant therapies for IVF.
Uterine receptivity is controlled by locally acting growth factors and cytokines, as well as
other factors. Natural killer (NK) cells have also demonstrated an important role in early
implantation (25). Defects in the integrity of the cytokine network and excessive NK cell
activity have been implicated in implantation failure and recurrent miscarriage ( 25). The
potent anti-inflammatory and immunosuppressive properties of steroids suggest a role for
glucocorticoids in improving the intrauterine environment, thereby increasing embryo
implantation rates. Moreover, there is evidence that glucocorticoids may be effective in
improving the ovarian response (26).
A RCT of women with polycystic ovarian syndrome undergoing IVF demonstrated that
glucocorticoids may sensitize the ovary to gonadotrophins (26). A number of mechanisms
have been suggested by which the glucocorticoid dexamethasone may affect ovarian
function. Dexamethasone is a substrate for the enzyme 11-ß-hydroxysteroid dehydrogenase
type 1. Detection of this isoform in luteinized human granulosa cells and oocytes ( 27)
suggests that dexamethasone may directly influence follicular development. The regulation
of human 11-ß-hydroxysteroid dehydrogenase type 1 expression favors high preovulatory
follicular fluid cortisol concentration (28). Dexamethasone may act indirectly by increasing
serum GH, serum IGF-1 (29), and consequently follicular fluid IGF-1 concentrations. IGF-1
mRNA has not been detected in human preovulatory granulosa cells, and follicles appear to
derive IGF-1 from the circulation. Lower serum IGF-1 concentrations following pituitary
desensitization (30) may account for some of the suboptimal responses to gonadotrophin
stimulation. Dexamethasone co-treatment was reported to significantly increase serum IGF1 in pituitary-desensitized IVF cycles compared with placebo (30). Steroids also decrease the
number of NK cells (31).
Immunosuppression, leading to a favorable endometrial environment, is the rationale
behind the administration of high dose glucocorticoid from ET onward. Increased
implantation rates have been observed (32). Keay et al (33), in a double- blind, RCT of 290
cycles of normal responders (aged <41 years), administered dexamethasone in a long luteal
protocol until the day before oocyte retrieval. The cancellation rate was significantly lower in
the patients treated with steroids than in those who received placebo, 2.8 and 12.4%,
respectively, P = 0.001. Moreover, an increase implantation rate (16.3% vs. 11.6%) and
pregnancy rate (26.9% vs. 17.2%) per cycle was observed in the treatment group as
compared to placebo. The authors concluded that steroids may increase clinical pregnancy
rate and should be considered for inclusion in stimulation regimens to optimize ovarian
response.
The cause of infertility, type of ART, and intervention protocol varied considerably between
the trials. Most importantly, dosage and timing of the interventions were not uniform. A
recent review in the Cochrane database of peri-implantation glucocorticoid administration
for ART (34) did not find conclusive evidence that administration of glucocorticoids
significantly improves the clinical outcome in ART. Interestingly, the use of glucocorticoids in
women undergoing IVF (rather than ICSI) was associated with an improvement in pregnancy
rates of borderline statistical significance (34).
Gh
The demonstration in animal studies that GH may increase the intra-ovarian production of
IGF-I (35) led to the hypothesis that GH stimulates ovarian steroidogenesis and follicular
development, and enhances the ovarian response to follicle stimulating hormone (FSH) ( 36).
Synergistic activity with FSH, which amplifies the effect of IGF-1 on granulosa cells, is
believed to mediate the dependence of IGF-I on GH, both in vivo and in vitro (37). The
interaction between GH and IGF-I is particularly important due to the role of IGF-I in ovarian
function, as demonstrated in both animal models and in humans (38). The addition of IGF-I to
gonadotrophins in granulosa cell cultures increases gonadotrophin action on the ovary by
one of several mechanisms, including augmentation of the activity of aromatase, and the
production of 17 beta-estradiol, progesterone, and luteinising hormone receptor (38). IGF
stimulates follicular development, estrogen production, and oocyte maturation, this being
the theoretical basis for the introduction of GH or GH-releasing factor in IVF for poor
responders. Usually, 4 to 12 IU of GH is administered subcutaneously starting on the day of
ovarian stimulation with gonadotrophins (39).
Most studies used poor responders as the study group and we included all studies in which
the authors have clearly defined a poor response to controlled ovarian hyperstimulation in a
previous treatment cycle. The type of outcome measured was pregnancy rate, yet other
outcomes such as oocytes retrieved per couple were also included.
In a double-blind, placebo-controlled trial of 4 IU/d of GH as adjuvant therapy, cancellation
and pregnancy rates did not improve significantly (39). Increasing the GH dose to 12 IU/d in a
long luteal GnRH agonist regimen yielded similar results in a prospective study with historical
controls (40). Likewise, results were disappointing in a prospective, randomized, doubleblind, placebo- controlled study, in which Dor et al (41) administered 18 IU GH on alternative
days in a classic flare protocol with triptorelin and 300 IU/d of hMG to 14 poor responders.
However, a prospective study reported improved pregnancy rates (60%) and collection of
more oocytes in 10 patients treated with GH, compared with historical controls (7.5 and 3.5,
respectively, P < 0.001) (42). In a meta-analysis of trials assessing the effectiveness of GH
adjuvant therapy in women undergoing ovulation induction, the OR in poor responders for
pregnancy per cycle instituted was 2.55 (95% CI 0.64 ± 10.12) (43). Significant differences
were not observed in the number of follicles and oocytes, or in gonadotrophin dose.
Therefore, these published data do not support the use of GH as adjuvant therapy in poor
responders.
Dehydroepiandrosterone
DHEA and dehydroepiandrosterone sulfate (DHEA-S) are ubiquitous steroids of primarily
adrenocortical reticularis zone origin. These hormones circulate in high amounts during
reproductive life; however, concentrations decrease progressively with age (44), leading to
speculation that replacement of DHEA and DHEA-S in the elderly may have age-retardant
effects (44). DHEA is an essential substrate for steroidogenesis; hence, low levels of DHEA
may lead to reduced androstenedione, testosterone, and E2 synthesis (45). Furthermore,
well-controlled studies have demonstrated marked augmentation of serum IGF-I
concentrations with oral DHEA supplementation. Casson et al (46) reported a transient
increase in IGF-1 after 8 weeks of DHEA therapy in patients undergoing ovulation induction
with gonadotrophins. DHEA has been reported to amplify the hepatic and end-organ IGF-I
response to GH (47), which, in the milieu of the ovarian follicle, may potentiate
gonadotrophin action. Also, Casson et al (46) showed increased estradiol levels after DHEA in
patients with a poor response. Additional suppressive doses of DHEA improved outcomes in
clomiphene-resistant ovulatory subjects (48). Barad et al (49) assessed the role of DHEA
supplementation on pregnancy rates in women with diminished ovarian function. The
cumulative clinical pregnancy rates were significantly higher following 4 months of daily
treatment of 75 mg DHEA than in the same women without DHEA treatment. DHEA appears
to augment ovulation induction in poor responders, particularly in patients aged 35 to 40
years with normal FSH concentrations. This effect may have clinical potential. Not only
would it allow successful ovulation induction in patients with a previous poor response, but
it may allow dose reduction of gonadotrophins in patients with a normal response. Further
investigation is recommended.
Human polycystic ovaries have been described as a “stock-piling” of primary follicles,
secondary to an alteration at the transition from primordial to primary follicle. Possible
mechanisms for such are abnormal levels of growth factor, abnormally increased luteinzing
hormone levels, and increased ovarian androgens (50).
In summary, most studies deal with the DHEA supplementation to women with diminished
ovarian function or repeated IVF failures. In this population, there is reason to believe,
according to preliminary results, that DHEA may augment ovulation induction and
beneficially affect oocyte and embryo quality and therefore pregnancy rates.
Women using DHEA may experience possible androgenic effects, including acne, deepening
of the voice, and facial hair growth. These effects are minimal with a dose of 75 mg/d (51).
The long-term effects of DHEA supplementation remain unknown. As DHEA is a precursor of
sex steroids, its use could increase the risk of estrogen or androgen-dependent malignancies
(52).
Sildenafil
Sildenafil is a potent cGMP-specific phosphodiesterase type- 5 inhibitor. Its selective
inhibition of cGMP catabolism in cavernous smooth muscle tissue augments penile erection
(53–55). Sher and Fisch (56) showed vaginal sildenafil to improve uterine artery blood flow and
sonographic endometrial appearance in 4 patients with prior failed ART due to a poor
endometrial response.
The uterine artery pulsatility index, as measured in the cycle after pituitary down-regulation
with GnRH analogue, decreased after 7 days of sildenafil (indicating increased blood flow),
and returned to baseline following treatment with a placebo. The combination of sildenafil
and estradiol valerate improved blood flow and endometrial thickness in all patients. Three
of the 4 patients conceived (56). Sher and Fisch (57) subsequently conducted a trial of infertile
women aged <40 years, with normal ovarian reserve and at least 2 consecutive prior IVF
failures attributed to inadequate endometrial development. Patients underwent IVF using a
long GnRH-antagonist protocol with the addition of sildenafil vaginal suppositories for 3 to
10 days. Implantation and ongoing pregnancy rates were significantly higher in the 73 of the
105 patients who attained endometrial thickness of 9 mm. In contrast to these promising
studies, Check et al (58) found that the addition of sildenafil to an estrogen supplemented
regimen did not affect endometrial thickness or blood flow in women who had previously
failed to achieve an endometrial thickness greater than 8 mm in fresh IVF or frozen embryo
transfer cycles.
Few studies of the role of vasodilators as adjuvant therapy in IVF have been conducted since.
Sildenafil has not demonstrated a definitive role; further studies are necessary before
recommending routine use.
Heparin
Heparin is the treatment of choice for women with recurrent pregnancy loss due to aPL
antibodies. However, it is doubtful whether heparin alone or in combination with low-dose
aspirin improves the pregnancy rate in subfertile auto-antibody positive women with IVF
implantation failure. The evidence is scarce and the mechanisms whereby implantation
failure may be associated with aPL and Antinuclear antibodies require further investigation.
However, heparins are involved in activities other than anticoagulation, such as adhesion,
directly or indirectly (eg, via heparan sulfate proteoglycans or heparin-binding EGF) of the
blastocyst to the endometrial epithelium and subsequent invasion (59). aPL may be
responsible for the breakdown of the phospholipid adhesion molecules between different
elements of trophoblast (60). In addition, aPL significantly reduced hCG release and
trophoblast invasiveness (61), and inhibited trophoblast differentiation in vitro (62).
Based on the assumption that an altered immunological status may interfere with embryo
implantation at different stages, heparin has been administered to women undergoing IVF
(63). In Stern et al 's study (64) of 143 women who were seropositive for at least one aPL, no
significant difference in pregnancy or implantation rates was found between those treated
with heparin (5000 IU b.i.d.) and aspirin (100 mg daily) and those receiving placebo. The
authors concluded that heparin administration does not improve the outcomes of subfertile
women with aPL or with a history of repeated implantation failure. However, in a study of 83
women with a history of 3 or more previous IVF failures and at least one thrombophilic
defect, Qublan et al (65) found that 40 mg/d of the low molecular weight heparin,
enoxaparin, significantly increased implantation and pregnancy rates compared with placebo
(20.9% vs. 6.1% and 31% vs. 9.6%, respectively; P < 0.001 and P < 0.05, respectively). The live
birth rate was also significantly higher in those treated with enoxaparin compared with
placebo (23.8% vs. 2.8%, respectively; P < 0.05). The abortion rate was significantly higher in
the placebo-treated group than in the heparin-treated group (P < 0.05).
In summary, in subfertile women with no apparent cause, (other than possibly, inherited
thrombophilia), the use of heparin has shown contradictory results A practice bulletin issued
by the American Society of Reproductive Medicine (66) did not recommend aPL testing in
patients undergoing IVF, based on Horenstein et al systematic review (67). The American
Society of Reproductive Medicine bulletin did not recommend treatment in seropositive
patients (66). More randomized, placebo- controlled studies with larger sample sizes are
required before the routine use of anticoagulant therapy can be recommended for repeated
implantation failure.
Immunoglobulin
IVIg is a monomeric IgG preparation, produced from pooling the plasma of numerous blood
donors. Preparations therefore contain all the humoral IgG antibodies normally occurring in
the donor pool. The distribution of the IgG sub-classes corresponds to that of normal serum.
IVIg has been used for a variety of immunological disorders since 1980 (68).
Recurrent miscarriage and peri-implantation embryo failure in patients undergoing IVF and
ET have been attributed to inappropriate immune response, with an excess of
proinflammatory Th1 relative to Th2/3 type cytokines (69). Carp et al (70) have summarized
some of the possible modes of action of IVIg. IVIg may modulate the effect of cytokines. The
culturing of peripheral blood mononuclear cells in IVIg significantly inhibits production of the
proinflammatory cytokines interleukin-2, interleukin-10, tumor necrosis factor-α, and
Interferon-γ; and increases the proportion of cells producing anti-inflammatory cytokines.
IVIg reduces the number and the activity of peripheral blood NK cells. In addition, IVIg may
inhibit the action of pathological antibodies either by interaction of its Fc part with Fc
receptors or with Fab receptors, or by passively acting as antiidiotypic. IVIg modulates the
activation and effector functions of B and T lymphocytes, neutralizes pathogenic
autoantibodies, and interferes with antigen presentation. The anti-inflammatory effect of
IVIg may be due to interaction with the complement system. In laboratory animals, IVIg has
been shown to inhibit complement.
Coulam et al (71) showed that IVIg is useful in treating women with unexplained recurrent
failure to conceive with IVF/embryo transfer. The same team evaluated 32 women who had
previously failed IVF/ET, and whose circulating NK cells were elevated (72). Each woman
received IVIg 500 mg/kg before ET. If serum hCG concentrations were positive for
pregnancy, IVIg was continued until 28 weeks gestation. Pregnancy rates with and without
IVIg were 56% and 9%, respectively, (P < 0.0001). The live birth rate was 38% with, and 0%
without IVIg (P < 0.0001). Conversely, a case series (73), and placebo-controlled, randomized
trial (74) have shown no benefit of the use of IVIg in women with previous failed IVF cycles.
More recently, Elram et al (75) reported a 38.9% implantation rate in patients sharing HLA
antigens with their spouses. However, differences in patient selection criteria impede
comparison of these trials. In a study by Sher et al (76) 687 aPL- positive women, younger
than 40 years of age, with 3 consecutive IVF/ET failures, were administered heparin and
aspirin, either alone or in combination with IVIg. The addition IVIg significantly improved the
outcome.
Winger et al (77) recently showed, that treatment with the tumor necrosis factor-alpha
inhibitor adalimumab and IVIg improves pregnancy rates in young (<38 years) women with
infertility and T helper 1/T helper 2 cytokine elevation.
In a meta-analysis (78) of 3 randomized controlled trials of IVF- failure patients, IVIg
significantly increased the live birth rate per woman (P = 0.012). Properties and scheduling of
IVIg, and selection of patients with abnormal immune test results appear to be relevant
variables. The selection criteria used in the different trials of IVIg are heterogeneous.
Moreover, IVIg was used in addition to other immune modulators. Therefore, it is extremely
difficult to assess IVIg. Table 1 summarizes the characteristics of trials investigating IVIg and
IVF outcome and demonstrates the differences between the study groups and treatment
regimens. At present, IVIg is the only medication with grade I evidence of effect. However,
larger randomized controlled trials are still required. Presently, the cost of IVIg precludes its
wider use. Furthermore, since IVIg is produced from pooled blood, there is risk of
anaphylaxis, serum sickness, and possible prion transmission.
Antibiotics
The use of prophylactic antibiotics during IVF-ET is controversial. Iatrogenic infection from
the microorganisms that comprise the normal vaginal flora during transvaginal egg collection
is rare, despite the invasive nature of the procedure (80). However, ET has similarities to
hysterosalpingography; and salpingitis following hysterosalpingography is a well- recognized
complication (81). Sauer et al (82) reported severe pelvic infection complicating transcervical
ET in an agonadal woman who had not undergone prior transvaginal oocyte aspiration.
Bacterial contamination of the transfer catheter is shown to have a significant negative
impact on the outcome of the cycle (83–85). Egbase et al (84) demonstrated that
contamination of the ET catheter tip occurs during embryo transfer. Positive microbial
growth was observed from endocervical swabs and catheter tips in 70 and 49% of women,
respectively. The clinical pregnancy rates were 57.1% in patients without growth, and 29.6%
in those with positive microbial growth from catheter tips. The authors concluded that the
presence of normal cervical flora on the tip is associated with a lower clinical pregnancy rate.
Persistent cervical sterility cannot be achieved by routine use of vaginal antiseptics at the
time of oocyte retrieval or embryo transfer. Moreover, there is evidence that vaginal
antiseptics can have a negative impact on the quality of the oocytes collected and the
embryos available for transfer (86).
Peikrishvili et al (87) performed a randomized control trial of amoxycillin and clavulanic acid 1
gm/125 mg. The average number of oocytes retrieved, and embryos obtained and
transferred, were similar between those administered antibiotics from ovum pick-up for 6
days, and control patients who did not receive antibiotics. The implantation rate per transfer
was also similar for both groups (36.9% and 36.5%, respectively; P > 0.95). The pregnancy
loss rate was slightly higher in the group receiving antibiotics, but the difference was not
statistically significant (P = 0.15). Ceftriaxone and metronidazole administered at oocyte
recovery were shown to reduce bacteria on the transfer catheter, therefore increasing the
pregnancy rate (88). Several mechanisms can explain the reduction in the clinical pregnancy
rate in women with ET catheter contamination. Bacterial contamination may decrease the
embryo's capacity to implant due to effects on both the embryo itself and the endometrium
(89–91). The zona pellucida which has a barrier function against infection at cleavage, is lost
before implantation, exposing the embryo to the detrimental effects of the bacteria ( 92). In
the endometrium, any acute inflammatory response generates cytokines, macrophages,
prostaglandins and leukotrienes, which can have a deleterious effect on implantation ( 93). In
addition, IVF patients with bacterial vaginosis and a decreased vaginal concentration of
hydrogen peroxide-producing lactobacilli may have decreased conception rates and
increased rates of early pregnancy loss (94). Indeed, the recovery of hydrogen peroxide
(H2O2)-producing lactobacilli from the catheter tip appears to be associated with an
increased live-birth rate. Hydrogen peroxide-producing lactobacilli help maintain a healthy
vaginal flora. Their recovery from the transfer catheter tip may reflect the dominance of
lactobacilli, and the absence of other cervical–vaginal pathogens (91).
In summary, the selection criteria for using antibiotics are unclear, and the only randomized
trial (87) showed a result which was not statistically significant. Better understanding of the
effects of the cervico-vaginal flora and catheter contamination on IVF outcome may enable
targeting of specific interventions to decrease the pro-inflammatory cytokine response and
to establish normal vaginal bacterial flora. However, until more is known about specific
pathogenesis and potential mechanisms, selective use of antibiotics for this population is not
recommended. Broad-spectrum antibiotics may alter the vaginal flora and decrease the
number of H2O2-producing lactobacilli, which may, in the long run, paradoxically decrease
the success rates of IVF. Meanwhile, the embryo- transfer practitioner should try to ensure
maximum catheter sterility to improve the clinical pregnancy rate.
Other methods
Acupuncture
Used in China for centuries to regulate the female reproductive system (95), acupuncture has
recently gained popularity in the western world. The World Health Organization stated the
need for clinical studies to validate acupuncture, improve its acceptability to modern
medicine, and expand its use as a simple, inexpensive, and effective therapeutic option ( 96).
Three potential mechanisms have been postulated. Acupuncture may mediate the release of
neurotransmitters (97), thus stimulating the secretion of gonadotrophin releasing hormone,
and subsequent ovulation, and fertility (98). Acupuncture may stimulate blood flow to the
uterus by inhibiting uterine sympathetic nerve activity (99). Acupuncture may also stimulate
the production of endogenous opioids, which may inhibit the central nervous system
outflow and the biological stress response (100). Treatment regimens, timing of
administration, and outcomes assessed differ considerably between studies. Acupuncture
has been used as an adjunct to IVF on the day of transvaginal ultrasound-guided oocyte
retrieval (101), during ovarian stimulation (102), at ET, and afterward (103). The indication for
use in most studies was subfertility, primary or secondary, in couples undergoing ART. Table
2 compares trials of acupuncture as an adjuvant therapy for IVF.
A number of systematic reviews and meta-analyses have been conducted on the
effectiveness of acupuncture as an adjuvant therapy. In a meta-analysis of RCTs comparing
needle acupuncture administered within 1 day of ET to sham acupuncture or to no adjuvant
treatment, acupuncture was associated with significant improvement in clinical pregnancies,
ongoing pregnancies, and live births (110). In a recent review, Ng et al (111) concluded that
acupuncture significantly increases the pregnancy rate, especially when administered on the
day of embryo transfer. Although more randomized studies are needed, acupuncture may
help restore ovulation in patients with polycystic ovary syndrome (111). In a review by ElToukhy et al (112) of RCTs that compared the effects of acupuncture with no treatment or
sham acupuncture in women undergoing IVF with ICSI, none of the 5 trials in which
acupuncture was performed around the time of transvaginal oocyte retrieval, nor the 8 trials
in which acupuncture was performed around the time of ET, showed a significant increase in
clinical pregnancy or live birth rates.
In an attempt to discern between the conflicting results, Cheong et al (113) conducted a
systematic review that comprised 13 randomized controlled trials of acupuncture. Outcome
criteria were live birth, clinical ongoing pregnancy rate, miscarriage rate, and side-effects of
treatment. Although acupuncture performed on the day of ET was associated with an
increase in the live birth rate, the placebo effect and small sample size cannot be excluded as
explanations.
Moreover, the underlying mechanisms whereby acupuncture improves the pregnancy rate
remain elusive. The timing of treatment, the methods used in the above RCTs differed, the
acupoints or combinations of acupoints that may be effective for increased success in IVF
cannot yet be determined. Future trials are needed to develop specific guidelines for the use
of acupuncture in IVF. In the absence of sufficiently powered RCTs, acupuncture is currently
not recommended as a routine procedure (113).
Endometrial Biopsy (Pipelle)
The association between “scratching” of the endometrium and enhancement of
implantation is based on animal studies that showed that local injury to the endometrium
induced decidualization and subsequently improved receptivity of the uterus ( 114). The
wound-healing effect caused by endometrial sampling is considered the mechanism for this
increased receptivity (115,116). The various cytokines and growth factors secreted in wound
healing may favorably affect uterine receptivity, thus improving blastocyst implantation and
pregnancy rates (117). Kalma et al showed that endometrial biopsies from women on days 11
to 13 and 21 to 24 of spontaneous cycles enhanced expression of genes encoding membrane
proteins (118). In a study of 45 women, Barash et al (119) found pregnancy and live birth rates
in the IVF cycle to double following endometrial biopsy. They concluded that local injury to
the endometrium increases the incidence of implantation. Li et al (120) reported that excision
of polyps or thickened endometrium 2 weeks before ET significantly increases the incidence
of successful pregnancies following IVF (120). Zhou et al (121) conducted a randomized
prospective study in 121 women whose endometrium was identified as irregular on
ultrasound, and who underwent fresh IVF-ET cycles. Seven endometrial biopsies were
performed from day 10 onwards. The rates of implantation, clinical pregnancy, and ongoing
or live births per ET were higher in the experimental group than in controls.
The Pipelle procedure is easy to perform and is apparently free of complications. Pipelle
biopsy might be appropriate for women with reduced endometrial receptivity, suspected
intrauterine adhesions, or endometrial irregularity on ultrasound. Although results are
promising, prospective controlled studies are still needed to confirm the effectiveness of this
procedure. Validation of the above in a large randomized study may lead to the routine
performance of endometrial sampling in conjunction with IVF.
Conclusions
It is estimated that 10% to 15% of couples seek professional help for difficulty in conceiving
at some time during childbearing years. The expense, time, stress, and frustration felt by
couples and physicians has led to a search for new drugs and technologies that will increase
success rates. However, progress has been limited. Although some techniques have
increased pregnancy rates in women with poor prognosis due to specific conditions (such as
specific endocrine diseases or long-term gonadotrophin releasing hormone agonists for
women with endometriosis), many infertile women still fail to conceive, despite repeated
transfers of high-quality embryos.
This review shows that none of the available adjuvant therapies has a clear advantage.
Notably, adjuvant therapies have been administered without a diagnosis as to whether the
failure to conceive is due to a maternal or fetal factor. If the embryos are genetically
abnormal, no maternal adjuvant treatment will improve the pregnancy rate, and the genetic
aberration will confound the results. Similarly, PGS will not be effective if implantation
failure is due to a maternal factor. Therefore, some of the therapies that have not been
confirmed may prove efficacious in subgroups of patients. Even when failure to conceive
originates in the woman, certain adjuvant therapies may benefit only women with particular
characteristics. As examples, endometrial biopsy may benefit patients with a thin and
nonresponsive endometrium; IVIg may benefit patients with high NK cell numbers, or
enhanced killing activity. Uncertainty of the effectiveness of sildenafil may be due to the
confounding of fetal factors. Similarly, heparin may be effective against antiphospholipid
antibodies other than lupus anticoagulant or anticardiolipin antibody. Presently, the
diagnosis of IVF failure is not sufficiently specific to indicate definite adjuvant therapy.
In light of patients' easy access to updated articles, physicians need to be especially prepared
to answer questions raised by couples that have repeatedly failed to conceive. Physicians
endeavor to provide treatment that may be beneficial; as their role is not only to withhold
treatment until sufficient randomized trials are conducted. Treatment often needs to be
“tailor-made” to suit the individual patient. Nevertheless, patients are entitled to full
explanations and information about the evidence available (or lack of it) as to the safety,
efficacy, and the unknown potential adverse effects to mother and fetus of the various
diagnostic tests and treatments available. After completing this CME, learners should be able
to answer questions raised by couples that have repeatedly failed to conceive, and are
intrested in adjuvant therapy regarding IVF and provide full explanations and information
about the evidence available (or lack of it) as to the safety, efficacy, and the unknown
potential adverse effects to mother and fetus of the various diagnostic tests and treatments
available.
References
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