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Ultrasonography and the Embryo Transfer — 117
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patients in the study were not truly randomized: subjects were
assigned to treatment and control groups on an alternating basis,
and even though the compared characteristics of the two groups
showed no significant difference, the scheduling order of patient
transfers could have introduced bias, which could have resulted
in failure to reject the null hypothesis. Additional study of these
newer catheters may be justified.
Alternate Techniques to Improve Transfer; Confounding
Variables on Ultrasonographically Guided Transfer
Mock transfer to facilitate actual embryo transfer is a frequently
employed technique. However, the optimal timing and method
for performing mock transfer are not clear. Some practitioners
prefer to perform mock transfer in the cycle preceding transfer,
at the start of stimulation or immediately before the true embryo
transfer. Concerns regarding timing the trial transfer center on
possible traumato the endometrium immediately before embryo
transfer, which could lower success rates. However, the uterus is
not rigidly fixedwithin the pelvis andperformanceofmocktransfer weeks before transfer may not accurately present the clinical
situation at time of transfer. An algorithm for mock transfer permits selection of an appropriate catheter by using progressively
more rigid catheters.
Difficult embryo transfers were associated with a statistically
lower pregnancy rate in a study comparing outcomes in cases
where a mock transfer had been performed.[12] Patients having
a difficult transfer, characterized by degree of effort required to
place the catheter successfully, had a statistically lower implantation rate than easy transfers (4% vs. 20.4%, P = 0.005), and
patients having mock transfers before transfer had a higher pregnancy rate (22.8% vs. 13.1%, P = 0.02) and implantation rate
(7.2% vs. 4.2%, P = 0.03) than those who did not. At time of
embryo transfer, there were no difficult transfers in patients who
had a prior mock transfer, whereas 37.6% of the control group
had difficult transfers.
One descriptive study of mock transfer performed immediately before embryo transfer showed that difficulty of transfer,
scored separately from the type of catheter required, was associated with transfer outcome. Those requiring “strong manipulation and pressure” were significantly less likely to achieve
pregnancy.[13] Twenty of the 113 transfers performed (17.7%)
were noted to have blood on the catheter tip, though in this study
a difference in pregnancy outcome for these cases was not seen.
Additional techniques, like having the patient maintain a full
bladder before transfer, may facilitate the ease of transfer in a
patient with an anteverted uterus by straightening the uterocervical angle. A full bladder will also improve visualization when
concurrent transabdominal ultrasonography is performed during transfer.
Whether ultrasound improves the ease of transfer, however,
is unclear. Although theposition of the catheter within the uterus
and its relationship to the uterine fundus or other landmarks can
be measured, theintroduction of thecatheterto the cervical canal
may not be facilitated because the images may not reveal small
details of the canal. With two-dimensional (2-D) imaging, the
full length of the canal and endometrial stripe may not be visible
in a single plane. Resolution maximums, related to the frequency
of sound wave and the resulting echotexture of the tissue, may
further limit visual information gained by the scan. Finally, the
vaginal speculum may block much of the electromagnetic signal,
interfering with visualization of the catheter as it passes through
the cervix.
In a prospective, randomized trial of Frydman, Wallace, and
TDT catheters, although outperformed by the other catheters,
pregnancy rates using the TDT catheter were significantly
improved with theapplication of ultrasonography(19.4 vs. 9.2%,
P ≤ 0.05).[14]Theeffectofultrasonographywasnotassessedwith
the competing catheters. The metal mandrel of the TDT catheter
improved visualization of its placement, and this characteristic
was thought to be the cause of improved pregnancy rates when
ultrasonography was employed during these transfers. However,
whether this characteristic is correlated with an improved result
has not yet been determined with specially designed, echogenic,
soft catheters.
When performing transabdominal ultrasonography, having
the patient maintain a full bladdermay facilitate image resolution
by providing a medium for the propagation of sound waves, and
may also serve to straighten the cervical canal of an anteverted
uterus, facilitating transfer. This clinical pearl may not improve
performance related to the use of the ultrasound, but to manipulation of existing anatomic relationships. Conversely, a full bladder in the case of a retroverted uterus may only exacerbate uterocervical angle deflection.
Possibly, mechanical effects associated with performing
transabdominal ultrasonographyareat the root of improvements
in transfer, such as pressure against the anterior abdominal wall
with the transducer and distention of the bladder, which can
straighten the uterocervical angle.
However, in a randomized study, no difference in clinical
pregnancy rates was notedamongpatientsreceivingclinicaltouch
transfer (35.7%) or transabdominal ultrasound-assisted embryo
transfer with or without a distended bladder (39% and 38.7%,
respectively).[15] When thebladder wasfull, therequirement for
using an obturator was less often necessary (13.4%) than when
ultrasonography was performed without a full bladder (32.8%)
and when ultrasonography was not used (32.5%, P ≤ 0.02). Sim-
ilarly, a full bladder was associated with a decreased need for a
tenaculum (8.9% vs. 26.5% vs. 25%, P ≤ 0.002) or the use of a
hysterometer (1.5% vs. 14% vs. 15%, P ≤ 0.002).
In a randomized study of 100 patients with a history of
“easy” mock embryo transfers, investigators examined whether
the use of transabdominal ultrasonography enhanced IVF outcome in these cases.[16] Easy mock transfers, performed before
controlled ovarian hyperstimulation, were defined as those in
which a Frydman catheter was placed without effort and without
cervical manipulation. All patients underwent ICSI after a standardized stimulation protocol. After stimulation, embryo transfer was performed to within 0.5 to 1 cm of the uterine fundus
confirmed with ultrasound guidance or, in controls, based on
the prior uterine cavity measurement. Treatment characteristics between groups were similar. As compared with the control
group, there was no advantage to ultrasound guidance in the
resulting implantation (19.6% vs. 16.3%), pregnancy (42.0% vs.
30.0%), or miscarriage rates (4.7% vs. 13.3%), though the study
was underpowered to eliminate the possibility of a type II statistical error (failing to reject the null hypothesis when the alternate
hypothesis is true) with the highest confidence (α = 0.05, β
= 0.80), which would have required 267 subjects, assuming the
pregnancy rates held constant.
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A study of recipients of donated oocytes demonstrated an
increase in pregnancy rate, defined by detection of hCG, and
implantation rate in transfers guided by ultrasound compared
with historical controls.[17] Although thisstudyeliminatedsome
issues of confounding by using an oocyte donation model, the
modality of ultrasound employed varied (transvaginal, n = 75;
transabdominal, n = 20) and patients having transfers without
ultrasound guidance had uterine depth measured immediately
before transfer by direct contact with the uterine fundus using a
Tom Cat catheter (Kendall), whereas in the ultrasound-assisted
cases, the uterine fundus was avoided and no mock transfer was
performed. Improvement in outcomes was seen only in easy
transfers: pregnancy rate (63.1% vs. 36.1%) and implantation
rate (28.8% vs. 18.4%).
REPEAT TRANSFERS AND VISUALIZATION
OF THE CATHETER
Repeat placement of transfer catheters has no effect on outcome.
No significant difference in pregnancy rates was observed in a
retrospective analysis of embryo transfers between 1135 successful first attempts and 69 transfers requiring additional attempts
(24.7% vs. 23.2%).[18] In addition, the distribution of multiple
pregnancies was similar between groups. Factors contributing
to retained embryos were difficult transfer and blood or mucus
contamination of the catheter. No difference was seen in the rate
of retained embryos when Wallace (2.3%), Embryon (6.3%), or
other catheters (7.1%) were used. The authors of this study did
not aspirate cervical mucus before transfer. Multiple attempts
to place transfer catheters were not associated with a decrease in
presence of a gestationalsacwhen the causewasretained embryos
or when imposed time restrictions on the duration of transfer
lapsed.[4]
When ultrasonography is used, the to-and-fro movement
used to identify poorly visualized transfer catheters because of
patient characteristics, such as obesity or significant uterine
retroflexion, may have the same effect on the endometrium as
completewithdrawalandreinsertionofthecatheter. This suggests
that the advantages of echogenic catheters, specifically designed
for use in ultrasound-assisted transfer, might not confer additional benefits, exceptas a tool to teach embryo transfertechnique
or for quality assurance and retraining if one operator’s results
deviated from practice normsof agroup. However, no conclusive
trials using these catheters have been reported.
Additional benefits to using a specially designed echogenic
catheter include providing reassurance to the operator, confirming catheter placement, and,when the ultrasound image is visible
to the patient, providing distraction during the transfer process.
OPERATOR AT TRANSFER
The operator performing the transfer can have profound effects
on the cycle outcome: In a program with a 46% clinical pregnancy rate, the success rate of cycles stratified according to the
provider performing the embryo transfer ranged from 17.0% to
54.3%.[19] With this in mind, it becomes difficult to assess how
the addition of any technique or protocol can improve outcomes,
given the number of possible confounding influences.
The embryo transfer is a critical and highly sensitive component of the IVF cycle. Even when techniques are standardized,
outcomes are uncertain. When instituted, some techniques may
requirea “learning curve” beforeequivalencyamongalloperators
is achieved.[20] This may apply not only to performing embryo
transfer but also to improvement when adjunct techniques are
incorporated, such as the addition of visual feedback using ultrasound images.
As hasbeen shown, embryo transfer technique can be taught.
An evaluation of nurses trained to perform transfer showed no
difference comparedwith physicians.[7] The use ofultrasonographymayservetoassisttraining protocols,providingconfirmation
and confidence for operators learning the technique.
Just as experience can affect the outcome of embryo transfer, it is likely that experience with performing ultrasoundguided transfers affects its utility as an adjunct technique. Identification of the endometrial cavity, the transfer catheter, and
other pelvic structures requires practice, as does optimization
of acquired images and correlation between visual and tactile
feedback. Because of anatomic differences among patients, the
scanning parameters can be adjusted to improve image quality;
however, changes in scale alter the corresponding visual and
physical depth ratio, so care must be taken when advancing
the catheter. The ability to individualize image acquisition will
permit transfer of any advantages using this technique to all
patients.
Outcomes haveimprovedbyprevious performance of amock
embryo transfer to assess the difficulty of catheter placement and
to provide guidelines for transfer, by permitting notations about
the direction of the cervical canal, the length of the uterus, and
potential obstructions or hazards. The timing of mock transfer
has varied among practitioners: before the IVF stimulation, during stimulation, and immediately before embryo transfer.
TRANSABDOMINAL ULTRASONOGRAPHY
The advantages of routine ultrasonography at embryo transfer
appear clear; however, because of design limitations, many studies showing an improvement in outcome are less than ideal and
may overstatethe contribution ofultrasound to the desired effect.
Despite findingsthat didnot reach statistical significance, a trend
toward improved pregnancy outcome encouraged the authors of
one study to recommend the use of ultrasound in all difficult
transfers and in older women.[21] Comparing 93 patients who
underwent transabdominal ultrasound–assisted transfer when
an ultrasonographer was available to 94 patients who received
clinical touch transfer showed a trend toward increasing pregnancy rates, definedbythe presence of a gestationalsac (37.8% vs.
28.9%), though the increase was not significant. A trend toward
improvement was also noted in difficult transfers (54.5% vs.
10.0%). Clinical touch transfer was performed by placing the
catheter as close as possible to the uterine fundus without touching it; embryos were deposited within 1 cm of the fundus in the
intervention group. No prior uterine sounding or measurements
were reported. This study was limited by lack of true randomization and unreliable technique. Because the length of the uterine
cavity is not standardized among patients, subjective placement
of the cathetertowithin10mmofthefunduswithout specific data
on eachpatient and without coming in contact with the fundusis
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a challenging task. Under these conditions, ultrasound guidance
would be expected to improve pregnancy rates, and although it is
interesting to note that no statisticaldifference was noted, thiswas
likely because of the sample size. If clinical touch transfer patients
are systematically disadvantaged compared with patients receiving ultrasound-assisted embryotransfer,ultrasound guidance for
all cases would be appropriate.
A retrospective study showing improvement in clinical outcomes when transabdominal ultrasound was performed (38.4%
vs. 25.4%) was similarly complicated by comparing the performance of true clinical touch transfers with ultrasound-guided
transfers that avoided contact with the uterine fundus.[22] An
additional confounding factor was a concurrent increase in the
use of soft transfer catheters over the study period; the independent effects of ultrasound guidance, avoidance of the fundus,
and employing flexible catheters cannot be easily disassociated,
though in regression analysis, the catheter choice, but not use
of ultrasound, was associated with significant differences in outcome.
Another controlled, randomized study of 330 subjects
demonstrated an increaseinimplantationrates(19.6%vs.12.6%)
and clinical pregnancy rates (37.1% vs. 25.0%) when transabdominal ultrasound guidance was used.[23] The authors touted
the use of ultrasound in its ability to permit assessment of the
uterocervical angle and therefore to permit pretransfer catheter
preparation to accommodate this variable. Presumably, this
improvedtheeaseoftransfer,buttheauthorsdidnotcomparethis
variable between groups. In addition, the ability to assess uterine
cavity position and depth was lauded because it permitted individualization of transfer depth. However, patients in the control
group all received transfer to a fixed distance (6 cm), and this
may have contributed to the study result because transfer depth
was not individualized. A prior sounding might have minimized
differences for both of these variables: pretransfer assessment of
the uterocervical angle and embryo transfer depth.
A quasi-randomized study of transabdominal ultrasound
guidance was performed applying ultrasound based on the availability of the ultrasonographer.[9] Neither pregnancy rates (29%
vs. 30.3%) nor implantation rates (15.5% vs. 14.2%) were different in the presence or absence of the ultrasound machine in the
178 transfers performed.
In a randomized, controlled study, transabdominal ultrasonography wasdemonstrated to increaseimplantation and clinical pregnancy rates, the presence of a gestational sac, compared
with clinical touch transfer.[24] Mock transfer was performed in
all patients before ovarian hyperstimulation and notations made
regarding the position of the uterus and direction of the cervical
canal so thattransfers performedwithout ultrasound couldavoid
touching the uterine fundus using these records as a guide. However,although a Frydman catheterwas usedin all transfers, in the
ultrasound group, its outer guide was not employed, whereas it
was routinely used in the control group. By protocol, a degree of
difficulty was assigned, depending on the need for a tenaculum,
metal sound, oradditionalmaneuvers,suchas cervical dilation.A
statistically higher proportion of transfers were technically easy
compared with controls, and a trend toward higher pregnancy
rates was seen with easy transfers, although not statistically significant.
In a prospective, quasi-randomized study, 1069 embryo
transfers were split between ultrasound guidance and clinical
touch transfer accordingto room assignment for embryo transfer
(an ultrasound machinewasavailable in only oneofthe two operating rooms used).[25] Patients in this study received embryo
transfer 3, 4, or 5 days following oocyte retrieval, according to
the number and quality of embryos available. Patients lacking
at least one good-quality embryo were excluded from the study.
Although differences in characteristics between the transfer subgroups were not observed, a statistical difference in pregnancy
rate was seen between the patients undergoing ultrasound-guided
embryo transfer on days 3 (45.9 vs. 31.7%, P = 0.001) and 4
(43.5% vs. 27.0%, P = 0.035), but not day 5 (56.3% vs. 45.7%).
The authors postulated that changes in endometrial receptivity can be provoked by traumatic embryo transfer, resulting
in advancement of the putative “window of receptivity,” causing premature decidualization and disrupting synchrony between
embryo developmental stage and the endometrium; once a specific developmental stage has been achieved, external influences
cannot disrupt the timeline andare lesslikelytoinfluenceimplantation. This would account for the decreasing strength of difference in outcome on subsequent transfer days. An additional
explanation offered suggested that the number of patients receiving day 5 transfer were not sufficient to demonstrate a statistical
difference. The authors did not, however, report whether use of
ultrasound was correlated with ease of transfer, decreased blood
in the catheter, number of attempts, time required to perform
the transfer, additional maneuvers, such as tenaculum or volsellum use, or other parameters that might correlate with less traumatic embryo delivery, because the expert gynecologist performing the transfer presumably minimized confounding that might
otherwise becaused by multiple orinexperienced operators. Why
ultrasound guidance would improve transfer only on days 3 and
4 remains unclear, especially given the conflicting results seen in
other studies.
A prospective, randomized studyof 800 embryotransfers was
designed to detect an 8% increase in pregnancy rate with 80%
power at 5% significance based on an average 17% pregnancy
rate in the clinic in which it was performed.[26] Both fresh and
frozen transfers were included. No differences in patient characteristics, including the distribution of fresh and frozen transfers,
were observed. Despite use ofultrasonography, no significant difference was observed between the treatment and control groups
(26.0% vs. 22.5%), although a statistically significant difference
in implantationrate wasobserved (15.3%vs. 12.0%, P = 0.048.)
The relatively low pregnancy rate, compared with more recent
studies, may beits own confounding variable.Although the study
was appropriately designed based on a historical average, other
factors, such as lab conditions, not correctable by ultrasound
transfer may limit the study results. In addition, fixed distance
of transfer (6 cm) may be suboptimal for a large subpopulation
of patients; it does not take advantage of the individualization
that ultrasound transfer or clinical touch transfer based on prior
sounding permits, which may be thecritical factor accounting for
observed improvements in pregnancy ratesseen by some authors.
Two studies assessing the use of transabdominal ultrasound
showed significant increases in outcome variables when the
technique was employed. In a prospectively randomized study,
362 subjects undergoing fresh embryo transfer on postretrieval
days 2, 3, 5, and 6 were assigned to clinical touch transfer or
transabdominal ultrasound–guided transfer.[27] A statistical
increase in implantation was noted (25.3% vs. 18.1%, P ≤ 0.01),
120 — Eric Flisser and Jamie A. Grifo
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as was an increase in the pregnancy rate (50.0% vs. 33.9%,
P ≤ 0.002). Ultrasound-guided transfer wasperformed by watch-
ing the catheter advance until it was approximately 15 to 20 mm
from the uterinefundus; clinical touch transferwas performed by
subjective assessment ofthe operator, trying to place theembryos
as close tothefundusaspossiblewithout touchingit.Thecomparison is imperfectbecausethe depth of transferwas not individualized in the clinical touch group, touching the fundus might have
occurred by error (establishing a cause for the increased pregnancy rates in the treatment group), and differences existed in
the location of embryo deposition: 15 to 20 mm in the treatment
group and as close as possible to the fundus without touching in
the control group. No difference was seen in the ease of transfer
between groups.
In the second study, frozen–thawed embryo transfers were
examined.[28] One hundred eighty-four patients undergoing
frozen embryo cycles were randomized to clinical touch and
ultrasound-assisted transfer. Again, a statistical increase in
implantation (19.1% vs. 11.7%, P ≤ 0.05) and clinical pregnancy
(34.4% vs.19.8%, P ≤ 0.05) was observed. Clinical touchtransfer
in these cases was performed by attempting to place the embryos
15 to 20 mm from the fundus, as with the ultrasound-assisted
transfers, using prior ultrasound measurement of uterine cavity
length, performed within the 3 months preceding the transfer, to
assist correct catheter placement. Although this technique likely
improved the clinical transfer, use of ultrasound to measure uterine cavity length may not provide a reliable estimate and may
have disadvantaged subjects in the control group.[29]
The advantages of transabdominal ultrasonography demonstrated in these studies might stem from avoidance of contact
with the uterine fundus, minimizing uterine contractions and
endometrial trauma, andbyconsistencyin depositing transferred
embryos to an optimal implantation site, 15 to 20 mm from the
fundus. However, these methods may be employed without the
use of ultrasonography by using prior uterine soundingmeasurements to guide catheter placement.
An excellent randomized, controlled trial of transabdominal ultrasound–assisted embryo transfer in recipients of donated
oocytes failed to demonstrate a difference in IVF outcome
between groups.[30] The study was designed to detect a 15%
difference in pregnancy rates, defined by the visualization of fetal
cardiac activity, with β = 0.8 and α = 0.05. Characteristics of
the two groups were not different, and preparation for embryo
transfer, including instructing all patients to have a full bladder
regardless of group assignment, was the same. Embryo transfer
differed only in that the catheter was advanced to within 1 to
1.5 cm of the fundus in the ultrasound group and as close as
possible to the fundus without touching in the control group.
No uterine sounding prior to cycle start was reported. Statistical
analysis demonstrated no differences in pregnancy rates (59.9%
vs. 55.1%), implantation rates, or multiple pregnancy rates. No
difference was noted in ease of transfer or presence of blood
in the catheter. Additional catheter movement in the ultrasound
group used infrequently to help visualize the catheter whenultrasound images were suboptimal could add aconfoundingvariable,
but increased trauma, evidenced by bloodied catheters, was not
present. Although it is possible that a smaller difference in pregnancy rates exists, this study presents the best evidence against
improvement in IVF outcomes when experienced providers perform embryo transfer without ultrasound guidance.
Our quasi-randomized, retrospective comparison of 249
patients supports this conclusion: Outcomes of IVF cycles in
which all embryo transfers wereperformed by onephysician(JG)
with or without transabdominal ultrasound guidance dependent on the availability of the ultrasonographer (EF) were
compared.[31] No patient characteristics studied were significantly different, and no differences in clinical pregnancy rates
were observed (46.2% vs. 46.2%).
A retrospective study comparing 823 embryo transfers raised
important issues when considering the validity ofstudiescomparing outcomes.[32] In this study, no difference was seen in pregnancy between the transabdominal ultrasound–guided group
(48%) and the clinical touch group (44%). Before transfer, a
mock transfer was attempted first with a soft catheter; if it could
not be passed, a more rigid catheter was used. Following transfer,
the difficulty of transfer was rated using a protocol, according
to maneuvers performed by the physician performing the transfer. In the first year of the study, only clinical touch transfers were
performed. In the second year,all transfersweredoneunderultrasound guidance.
The frequency of difficult transfer variesineachstudy, and the
effect of an intervention is dependent on the frequency of a condition’s occurrence; overall, the rate of difficult transfer is low, so
detecting improvement may be difficult to demonstrate. Factors
that have been negatively associated with transfer outcome were
diminished in the ultrasound-guided group (presence of blood,
P = 0.01, or mucus, P = 0.04 in the catheter), though these
characteristics were not associated with differences in pregnancy
rates between groups in the study when logistic regression was
performed. No differences were observed when the number of
embryos transferred was analyzed or when the analysis was performed according to the clinician performing ortheembryologist
assisting the transfer.
The only factor determined to have prognostic significance
in this study was use of a soft-pass catheter, though choice of
catheter was determined before employing ultrasonography. The
use of the soft catheter was statistically more frequent (98%
vs. 95%, P = 0.02) in the ultrasound group, which suggests
that the characteristics of the patients were not entirely similar and that a more exaggerated result of the use of ultrasound
(assuming that it has a positive effect on establishing pregnancy)
would result, yet no statistical difference in outcomes was seen,
despite this bias. The authors noted that placement of the mock
transfer catheter could influence outcome in an unpredictable
fashion; it follows that additional manipulation to place a more
rigid catheter, in addition to use of the more rigid catheter for
transfer, would disadvantage the clinical touch group. Though
graded according to guidelines, the clinician’s opinion of difficulty of transfer could have in part been subjectively biased by
the presence of the ultrasound machine. A significantly higher
distribution of easy transfers was noted in the ultrasound group
(P = 0.01).
The authorscommentedthat the decreasedfrequency of negative factors associated with pregnancy outcome, such as blood
or mucus in the catheter or the use of a tenaculum, made transabominal ultrasound guidance a useful adjunct to embryo transfer. Given the low prevalence of complicated transfers, statistical
evidence justifying its use may be obscured.
One meta-analysis that combined eight prospective, controlled trials of transabdominal ultrasound–assisted transfer
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calculated a significant improvement in pregnancy rate and
embryo implantation when all of these studies (OR 1.51; 95%CI,
1.32–1.73) or when only the subset of truly randomized studies (OR 1.44; 95% CI, 1.18–1.74) was examined.[33] However,
meta-analysis is limited by the quality and design of the studies evaluated, and the possible confounding issues and technical
flawsofthesestudieshavebeendetailed.Themostimportantcontribution of this analysis was the calculation that demonstrating
a 5% improvement in pregnancy rate with 80% power would
have required a 2500-patient study, assuming a pregnancy rate
of 25%. Higher pregnancy rates would necessitate larger studies, as do smaller differences in outcomes. When overall pregnancy rates are low, confounding factors, including steps preceding transfer, such as embryo culture, may contribute to outcome
and may make the observed improvements less likely to represent real effects of the planned intervention. When study conditions are suboptimal, calculating the contribution of an intervention can be difficult. Conversely, under optimal conditions,
a small contribution may be more difficult to detect without an
impractically large study population. A second meta-analysis of
these randomized, controlled trials analyzed additional outcome
parameters, but was inconclusive as to why ultrasound guidance
might improve outcomes.[34] The multiple pregnancy rate, the
miscarriage rate, and the ectopic pregnancy rate were not significantly different. Additionally, differences in study design made
analysis of the effect on the ease of transfer impossible to determine.
Although the utility of ultrasound guidance can be hotly
debated, the most important central tenet in the practice of
medicine holds: No study has demonstrated an adverse effect
of performing ultrasound-guided embryo transfer, meeting an
important primary objective: primum non nocere.
ECTOPIC PREGNANCY
Ectopic pregnancy is a well-documented complication of IVF.
Embryo transfer technique may play a role in its occurrence,
especially if embryos are transferred directly to damaged fallopian tubes. In a nonrandomized comparison, two embryo transfer
techniques were compared: fixed transfer distance to true clinical touch technique.[35] Because the measured maximal length
of the uterocervical canal was 68 mm and the maximal depth
performed by clinical touch was 90 mm, the dangers of ignoring clinical data are demonstrated. The rate of ectopic pregnancy
was significantly higher when the clinical touch technique was
employed (P ≤ 0.05), all were at depths exceeding 60 mm, but a
fixed depth did not prevent ectopic pregnancy from occurring in
the comparison group. The disparities in insertion distance and
measured depth by ultrasound can only be explained by kinking
of the transfer catheter or by placement of the catheter through
the tubal ostium, which could facilitate tubal implantation. In
another study,when the length ofcatheterinsertedinto the uterus
was subtracted from the ultrasonographically measured depth of
the uterine cavity, although not statistically significant, a trend
toward increasing ectopic pregnancy occurred with lower and
negative values.[36]
With transabominal ultrasound guidance, one group
observed a 6.3% rate of ectopic pregnancy in patients with a
history of tubal infertility and a 3.3% rate when all 3543 guided
embryo transfers were examined.[37]
Ectopic pregnancy may also be associated with the size of
the uterine cavity. When all patients received transfer of embryos
to a distance of 5 mm from the uterine fundus, as determined
by prior uterine sounding, those with uterine depth of 7 cm or
less had a significantly higher rate of ectopic pregnancy (P ≤
0.0005) compared with patients with uterine depth of 7 to 9
cm; the frequency of tubal disease and the number of embryos
transferred were not different between groups.[38]
The site of transfer has been shown to be a risk factor for
ectopic pregnancy. When a quasi-randomized study was performed comparing deep transfer (≤5 mm from the fundus) to
midfundal transfer (≥15 mm) based on prior uterine measurement, asignificant increase in the proportion of ectopic pregnancies was seen when deep transfer was performed (1.5% vs. 0.4%,
P = 0.029) without a difference in pregnancy rate (14.2% vs.
12.2%).[39]
Performing true clinical touch transfers was associated with
higher ectopic pregnancy rates compared with when embryos
were transferred to a fixed distance into the uterine cavity
(≤55 mmfrom the externalcervical os).[40] When clinical touch
was performed, catheters were threaded to between 55 mm and
90 mm from the external os. By ultrasonography, the uterine
depth in all study patients was 59.3 ± 4.2 mm (mean ± SD).
Patientswerequasi-randomizedinto each arm of thestudy, which
demonstrated a significantly higher rate of ectopic pregnancy
when trueclinical touch transferwas performed (16.7% vs. 1.8%,
P ≤ 0.05), though pregnancy rates between groups were not sig-
nificantly different.
An analysis of ectopic pregnancy and intrauterine pregnancy
in one IVF program revealed that ectopic pregnancies were more
likely to be associated with difficult transfers (OR 3.91; 95% CI,
1.49–10.23).[41] These transfers were performed using the true
clinical touch technique, which by possibly provoking uterine
contractions, may have contributed to the overall ectopic pregnancy rate.
Although elevated compared with thegeneral population, the
relatively low incidence of ectopic pregnancy in the IVF population may hinder attempts to prove whether ultrasound-assisted
transfer can reduce the occurrence of ectopic pregnancy.To establish a statistical difference, a large sample size must be accumulated. Most studies have shown no significant difference in
ectopic pregnancy between treatment and control groups. Currently, ultrasound guidance does not seem to prevent ectopic
implantations from occurring or to reduce its incidence. Threedimensional (3-D) ultrasonography, which permits visualization
of the depth of the catheter and its deviation from the midline,
may help prevent placing the embryo transfer catheter near the
tubal opening.[42]
TRANSVAGINAL ULTRASONOGRAPHY
Transvaginal ultrasound–guided embryo transfer has not been
assessed as frequently as the technically easier transabdominal
ultrasonography.Becauseofcloser proximitytopelvic organs, the
resolution and detail of transvaginal ultrasonography are often
superior to transabdominal scanning, and it does not require
having a distended bladder to improve visualization. Although it
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does not require having a separate ultrasonographer, intravaginal placement of the ultrasound probe, speculum, and transfer catheter may be cumbersome because of performance of
simultaneous, semi-independent tasks, though practice certainly
decreases the task complexity.
An initial quasi-randomized study of transvaginal
ultrasound–guided embryo transfer that compared 94 cases
to 246 matched controls noted no significant improvement in
pregnancy outcome compared with the control group (20.2%
vs. 17.5%).[43] Randomization was performed based on the
availability of transfer personnel. Anecdotally, the authors
preferred ultrasound guidance because of successful catheter
placement in patients with complicated anatomy.
A retrospective comparison demonstrated improvement
when transvaginal ultrasound–assisted transfer was performed
in 402 subjects compared with 444 historical clinical touch controls.[44] Patient characteristics were similar (age, number of
oocytes retrieved, number of embryos transferred, and difficulty
of transfer), but the resulting pregnancy rate was significantly
different (28.9% vs. 13.1%, P ≤ 0.01). However, the study compared true clinical touch transfers, in which the outer catheter
was placed in physical contact with the fundus and then withdrawn, to a technique in which the catheter did not touch the
fundus. The authors did not comment on the presence of blood
in the transfer catheter, so this confounding variable might have
contributed to the treatment outcome. The ectopic pregnancy
rates were similar between groups.
Another transvaginal ultrasound–assisted embryo transfer
study retrospectively compared patients who had previously
failed IVF to a subsequentcycleinwhichtransvaginal ultrasonography was performed.[45] Twenty-three subjects were identified
that could be paired with previous cycle failures when transvaginal ultrasound was not performed. No significant difference in
patient characteristics from the two attempts was noted, including patient age and cycle characteristics.
Because these cycle characteristics werethe same, the authors
concluded that the use of ultrasound guidance was the key factor
for the difference in outcome. However, because the study was
retrospective and historical control cases were collected over the
preceding 3 years, unaccounted and possibly subtle confounding variables may have played a role in the outcome, such as
changes in lab technique. Additionally, the comparison to previous cycle failure is suboptimal: Even despite optimal stimulation
and lab conditions, with alarge cohort of high-qualityembryos to
select fromfor transfer, some patients inexplicably fail to become
pregnant; a patient not pregnant from one cycle may achieve
pregnancy in the next under identical conditions. The cause of
the first failure cannot be definitively identified, so a subsequent
intervention may not be responsible for a successful outcome.
Though a statistical increase in the pregnancy rate was seen for
all patients 40 years and younger during the 9-month study period
compared with the preceding 3 years, the absence of analysis for
other variables undermines the strength of the association.
THREE- AND FOUR-DIMENSIONAL
ULTRASONOGRAPHY
The role of3-Dand “real-time” 3-D or “four-dimensional”(4-D)
imaging in embryo transfer is still under investigation. Naturally,
the development of this modality and its clinical application,
investigation, and publication add to the lag time in the implementation of the new technology.
An early study in the use of this modality was performed to
assess the accuracy of traditional 2-D ultrasound-guided transfer. Following transfer, the position of the transfer catheter was
maintained and 3-D volumetric image scanning, using either
a transabdominal or transvaginal probe, was performed; the
resulting images were retrospectively compared with the 2-D
technique.[46] In four of the 21 cases in which sufficient images
were obtained for analysis, 3-D modeling wasassessed asdemonstrating a significant deviation in catheter localization compared
with placement determined by 2-D images viewed at the time of
actual transfer. Catheter placement was thought to deviate in an
anterior–posterior or lateral direction, deflecting away from the
ideal, midline position in these cases, including in one case in
which placement of the catheter tip was shown localized to the
cornual region of the uterus.
However, although this study demonstrated that obtaining
3-D images of intrauterine catheters is feasible, it did not address
the impact or utility of using this technique. Because no clinical
decisions were made on images created using 3-D technology,
no comparative conclusions can be drawn. Additionally, because
outcome measures were not reported for these embryo transfers,
the consequence of seeing a misplaced catheter on 3-D images
when correct placement was believed to be obtained from 2-D
scan cannot be evaluated. Without outcomes data, the 3-D data’s
value cannot be assessed.
Three-dimensional images were postulated to improve upon
2-Dimagesbyidentifyingcasesinwhichmigrationofthecatheter,
directed by a path of least resistance, led to malposition within
the cavity. However, the acceptable degree of variance from the
midline is still unknown; therefore, the contributionof this information has uncertain utility. Additionally, it is not known how
far embryos migrate after transfer, either by physiologic interactions with endometrial cells or uterine contractility, or by the
fluid dynamics of the transfer droplet. The precision of embryo
placement may always be susceptible to factors not controlled by
clinical technique.
An observational study using 3-D ultrasonography demonstrated that 81% (26/32) of embryos that implanted successfully
did so at the area of initial transfer, suggesting that in cases in
which uterine contraction–associated movement of the embryo
does not occur, the air bubble serves as an appropriate proxy for
the location of transferred embryos and that implantation location can be biased by the transfer technique.[42] Because ectopic
pregnancies in this study were located on the ipsilateral side to
the location of the air bubble at time of transfer, and because no
ectopic pregnancy occurred when the air bubble remained in the
midfundal area, deviation of the catheter from the midline may
play a role in creating ectopic pregnancy even when the catheter
remains in the uterus, though prevention of ectopic pregnancy
by monitoring catheter alignment to the midline has not been
studied.
Limitations of this equipment include higher complexity of
image acquisition and subsequent interpretation of the acquired
images. Real-time 3-D imaging, like all procedures, will require
experience for optimal use.
Another descriptivestudyof1222consecutivepatientsundergoing embryo transfer using concurrent 4-D ultrasound imaging
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demonstrated the ease of use of this equipment.[47] The authors
used a putative “maximal implantation potential point” as a target for the embryo catheter tip, a point at the intersection of two
lines bisecting the uterine cornua at the junction with the fallopian tubes. Use of this calculated point personalizes the transfer
target to the contour of each patient’s uterus, tailoring thetransfer
to the idiosyncrasies of the patient’s anatomy. The authors recognize, however, that the utility of identifying this point accurately
is debatablebecause of uncertainty regarding thedegree of decrement in implantation potential as a function of the distance from
this “point ofmaximal implantation.”Ultimately, this target may
represent not a highly discriminate point of maximal implantation, but abroader implantation zone, which woulddeemphasize
such a specifictarget, though itmaycontinue to be auseful guidepost. For acceptability of use, there were no measured outcome
variables recorded regarding the ease of transfer and the degree
of effort or of accuracy at reaching the specified target point.
AIR IN THE UTERINE CAVITY; LOCATION
OF TRANSFER; ACTIVITY FOLLOWING
TRANSFER
Catheter loading, using varying amounts of transfer media or
including air in the catheter, is not a standardized technique.
Air bubbles, frequently included in transfer catheters to assist
visualization of the transfer droplet, can be observed ultrasonographically. Air pockets are not normally present in the uterine
cavity, though transferring air along with the media drop does
not appear to have a negative effect on transfer or implantation.
A mock transfer study using equivalent volumes of methylene
blue dye demonstrated that air in the catheter had no effect on
dye expulsion through the cervix.[48] A randomized study of
transfer including or excluding air in the catheter was performed
in 196 patients and demonstrated no difference in establishing
pregnancy when air was included in the catheter.[49]
Movement of the air bubble toward the fundus can be seen
even when the uterus is retroverted, suggesting that an active
transport mechanism exists within the uterus.[50] In one analysis, movement of the transfer-associated air bubble was associated with an increase in the pregnancy rate compared with transfers in which the bubble remained stationary (45.4% vs. 15.6%,
P ≤ 0.001), which the authors suggested is a sign of endome-
trial receptivity.[51] In few cases in the same series (5.0%), the
bubble moved in the directionof thecervix during catheter withdrawal, all 5 mm or less. In all but one case in this series, the
observed movement ranged from 2 to 5 mm, and although ultrasonography was continued until the transfer-associated bubble
became stationary, it is possible that movement resumed after
ultrasonography was discontinued.
In analysis of the effect of the presence of air in the transfer
catheter, no differences in pregnancy rates were seen when the
group was subdivided by the final location of the transfer bubble
as identified by ultrasound, whether in the upper, mid-third, or
lower uterus, although a comparison of the quality and number
of the embryos among these subdivisions was not reported.[49]
However, failure to visualize the air bubble following transfer is
ominous; in cases in which the air bubble from the transfer could
not be located, no pregnancy was established.[44]
The role of providing ultrasound guidance is to verify the
proper location of the catheter. Whether clinical transfer or
ultrasound-guided transfer isperformed,theoptimallocation for
embryo placement must be considered. The use of ultrasonography is notsimply limited to evaluatingthe location ofthe catheter
with a simple binary result; it also permits the operator to judge
specific distances to anatomic landmarks,and in 3-D ultrasonography, the degree of deviation from the midline may be simultaneously assessed.However, despite this ability, there is still debate
as to the best location to deposit embryos. Although early studies
of embryo transfer observed by ultrasonography suggested that
there was no association between the catheter tip location and
establishment of pregnancy [52], more recent literature suggests
that the catheter location plays an important role.
In a descriptive study of 3-D ultrasonography, the location
of the gestational sac following transfer showed that in cases in
whichpregnancywasestablished,theimplantationsitewasbiased
toward the location of the embryo transfer–associated air bubble
at the time of transfer.[42]
In one randomized study, patients were selected to undergo
embryo transfer at the top half or bottom half of the endometrial cavity.[53] The endometrial cavity length was calculated
by transvaginal ultrasound exam performed preretrieval, during
ovarian stimulation, by measuring the distance from the internal
os to theuterine fundus. All transferswere performed by the same
provider using one type of catheter, only transfers in which the
catheter could be visualized were included in the final analysis,
and all transfers were done on the same postretrieval day using a
standard protocol. No difference in outcomes, includingimplantation rate, clinical pregnancy rate, ectopic pregnancy rate, and
spontaneous loss rate, was observed. A power calculation before
the study was designed to detect a 15% difference in resulting
pregnancy rates. Although this study leaves open the possibility
that a smaller difference in outcomes may exist bychoice of transfer site,the similarrate of spontaneous abortion suggests thatsite
of transfer may not play as significant a role as other factors.
One study of ultrasound-guided transfer randomized 180
subjects according to transfer distance from the uterine fundus, as
measured by transabdominal ultrasonography.[54] Patients having transfers at 15 ± 1.5 mm and 20 ± 1.5 mm from the fundus
had significantly higher implantation rates (31.3% and 33.3%,
respectively) than patients receiving transfers at 10 ± 1.5 mm
(20.6%). Because of the possibility of post-transfer embryomovement, the middle depth may be the optimal locale. The authors
noted that no pregnancies occurred in the few patients whose
transfer depth exceeded 20 mm from the fundus (18 cases). If
the transfer droplet can migrate or be transported 2 to 5 mm
from its transfer location, as observed in a prior study [2], the
middle depth (15 mm) would seem most appropriate because it
wouldkeepthemajorityofembryoswithinacceptableboundaries
(≤20 mm and ≥10 mm) from the fundus, even after factoring in
embryo drift or transport.
In one evaluation of the transfer depth, blind uterine sounding performed before stimulation was characterized as an unreliable measure of uterine depth; the transfer distance from the
fundus, as calculated by the difference between the ultrasound
estimates of uterine depth, measured from the endometrial
fundus to the external cervical os, and the length of the
catheter inserted into the uterus were correlated with pregnancy
outcome.[36] Catheter placement was guided to a “suitable
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point” near the fundus using ultrasound guidance, though this
location was undefined. When depth was categorized, patients
receiving transfers to a calculated depth that was less than 0
mm from the measured length of the cavity to the external os
(i.e., the length of catheter inserted from external os to its tip
exceeded the ultrasound measure of the distance from the external os to the fundal endometrium) had significantly worse outcomes. However, for this calculated difference to be negative, the
catheter tip would have to be located in the fallopian tube, in the
myometrium, or in an unknown location, possibly curled within
the cavity. A negative calculated value occurred in 18% of transfers. Ifthe catheter tip was well visualized at transfer, this suggests
that theassessment of uterinedepth by ultrasound was unreliable
and any formula using this value, such as the calculated depth of
transfer, was also inaccurate.
Excellent pregnancy rates were demonstrated when the target
of ultrasound-guided embryo transfer was placed in the thickest
portion of the endometrial cavity.[55]
Ultrasound guidance may permit more precise placement of
the transfer catheter. An analysis of transfer depth performed
by standardized measurements relative to the size of the uterine
cavity demonstratedimprovedimplantation and pregnancy rates
when embryos were placed in an area bounded by the lower third
and midpoint of the endometrial cavity.[56] The catheter depth
was standardized using a mathematical formula to compensate
for variations in size of the human uterus. Patientsreceivingtransfer to thelow to mid-cavity area were noted to have a significantly
higher live birth rate (RR = 1.48; 95% CI, 1.08–2.02; P = 0.02)
and pregnancy rate (RR = 1.44; 95% CI, 1.09–1.91; P = 0.01),
and a higher implantation rate (RR = 1.59; 95% CI, 1.23–2.05;
P ≤ 0.001) when compared with patients receiving transfer
between 0.5 cm and 1.0 cm.
Despite coordinating transfer droplet placement to a specific
site, active and passive transport mechanisms may alter the final
location of theembryos, in addition to complex fluid interactions
among the transfer droplet, the catheter, and endometrial tissue.
Fluoroscopic imaging of radiopaque dye demonstrated
that a transferred bolus of fluid dynamically moves following
transfer.[57]Almost half thepatients studied showedfluid movement immediately after injection, and only 68% of subjects had
all or part of the fluid bolus remaining in the uterus during the
observation period. Although dye differs from transfer medium
in density and viscosity and the quantity used in the study was
greater than typically used at transfer, studies of uterine contraction frequency have demonstrated transfer droplet–associated
movement. Uterine contractions, stimulated by manipulation of
the cervix or by touching the uterine fundus, may play a role
in decreasing implantation. Supraphysiologic levels of hormones
may also contribute to this phenomenon.
Touching theuterinefundus is associated with increaseduterine contraction activity and may interfere with implantation by
relocating embryos to suboptimal sites or expelling the embryos
from the cavity entirely. Using contrast material to mimic transfer medium, an increased contraction rate was seen in oocyte
donors following retrieval 45 minutes following mock transfer after the fundus was deliberately touched with the transfer catheter.[58] No increase in activity was seen when contact
with the fundus was avoided. Additionally, use of a tenaculum to
assist transfer has been associated with an increase in contraction
activity.[59]
Uterine contractions measured immediately before embryo
transfer were inversely correlated to clinical pregnancy rates
(P ≤ 0.001), though the direction of the contraction wave was
not. Plasma progesterone was negatively correlated with uterine
contraction rates (P ≤ 0.001).[60]
Patientsarefrequentlyconcerned aboutembryos“fallingout”
of the uterus and areoftenfearfulthatthey will disrupt theprocess
by moving. Bed rest has traditionally had a role in the care of
patients. In natural conception, bed rest is not necessary, though
the manipulations requiredfortranscervical embryotransfermay
change this requirement. From a theoretical view, the varying
interval from replacement of embryos to implantation suggests
that ambulation should have no effect on outcome.
The persistence of a “catheter track,” a channel created by
placing and removing a catheter in a previously potential space
in the uterus, was observed via ultrasonography to remain for at
least 30 minutes.[1] Whether this artifact of transfer was clinically important was unknown, and so, empirically, patients have
typically been left supine with varying degrees of leg elevation
or in Trendelenburg position for an arbitrary interval following
embryo transfer. Without definitive evidence for its utility, the
rest period has varied substantially, including periods such as 3
to 4 hours [61] and up to 6 hours [1] or longer.
Observational study of the transfer-associated air bubble following the embryo transfer suggests that prolonged (or possibly
any) period of bed rest is unnecessary.[62] In 101 transvaginal
ultrasound–guided embryo transfers, no movement of the bubble occurred in95subjects (94.1%) when patientswerereassessed
via ultrasound after immediately standing following the transfer
procedure. In four patients (4.0%), air bubble movement was
limited to 1 cm or less, and only in two (2.0%) was movement
between 1 cm and 5 cm. Because the embryos are not directly
observed, the significance of air bubble movement is an imperfect proxy: Embryos may move with or independently from this
transfer marker.
Whether promoting prolonged bed rest in patients following embryo transfer can improve implantation has been tested
by several investigators. To test the hypothesis, 182 patients were
randomized to 20 minutes of bed rest versus 24 hours of bed rest
following embryo transfer.[63] Patients in the long-stay group
were transferred to a stretcher and brought to a clinic for prolonged rest. In the short-stay group, no instructions regarding
restriction of activity were given following discharge. No differences were seen in the establishment of pregnancy (24.1% vs.
23.6%), spontaneous abortion rate (19% vs. 14.2%), or multiple
gestation (18.1% vs. 13.6%). The method of randomization was
not reported, and the patient was randomized one time, though
some underwent multiple cycles, which suggests that other factors may have affected the study outcome. The power of the
study may also have been insufficient to detect differences in
outcomes.
In a randomized comparison of 424 patients randomized to
1 hour of bed rest or 24 hours rest, no difference was seen in
clinical pregnancy rates between groups (22% vs. 18%), though
a higher implantation rate was observed in the group with limited rest (14.4 vs. 9%), which was reflected in a significant difference in the multiple gestation rate, despite similarities in the
age of patients, infertility diagnosis, and the quality and number of embryos transferred.[64] The difference in implantation
rates is exceptional and the cause uncertain, though the authors
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postulated a role for the potential psychologic consequences of
restrictions in activity.
One IVFprogram that does not employbed rest afterembryo
transfer compared its results with historical controls from a
national database.[65] The clinic demonstrated a statistically
greaterclinicalpregnancy rate comparedwith the database, which
suggests that a variable bed rest interval might not play a role in
embryo implantation 1ormoredaysfollowing transfer.However,
differences in an individual clinic’s protocols and results compared with a national amalgam might have been great enough
to obscure the detrimental effect of immediate ambulation, if
present. The study demonstrates that pregnancy is not excluded
by immediate ambulation.
To assess the effect of immediate ambulation, 406 patients
undergoing fresh IVF cycles were given the option of ambulation
or bed rest.[66] Although notrandomized, patient characteristics
such asage, number of retrieved oocytes, quality of embryos, and
number of embryos transferred were not different. Between the
167 patients who opted for immediate ambulation and the 239
patients who chose 1 hour of bed rest, no difference in pregnancy
rates was observed (24.6% vs. 21.3%). The study was underpowered to detect a difference in the observed pregnancy rates with
β = 0.8 and α = 0.05, but 4400 subjects per group would have
been required toachievethis level ofsignificance. This studygives
some evidence that anydifferences, if present, will likely be small.
Optimal placement of embryos is still the subject of debate.
However, following transfer movement of the transfer droplet
suggests that there are limitations to the utility of accurate placement, given passive movement of the transfer droplet, from
catheter withdrawal, and active transport, from uterine contractions. Despite the precision afforded by catheter markings, uterine sounding, and visualization by ultrasound guidance, not all
factors can be controlled. After transfer of the embryos into the
uterus, even the most precise of transfers can be altered.
The effect offluid dynamics inthe uterine microenvironment
attributable to transfer failure has not been quantified. However,
a number of observed phenomena have been reported. Following expulsion into the uterine cavity, reversal of flow of transfer medium toward the lower uterine segment along the sides
of the catheter has been termed “capillary flowback”.[61] Capillary flowback presumably results from the adhesive and cohesive
properties of the medium, the catheter, and the endometrium.
Too rapid withdrawal of the embryo transfer catheter may create
negative pressure within the cavity or leave a void, encouraging
the transfer medium (and embryos) to migrate. Surface tension
and the complex interaction of solid and liquid physics, coupled
with possible electromagnetic forces from charged surface proteins, makes prediction of embryo movement impossible.
The proper amount of pressure placed on the plunger has
also never been assessed except in subjective terms: “moderately
rapid” [61], “avoid white-knuckling the fingers” [11], “gently
expelled” [44], “avoid turbulent flow around the catheter tip.” [1]
Certain stimuli can provoke uterine contractions, including manipulation of the cervix. The waves of uterine contractions can cause the embryos to be transported to a suboptimal
implantation site ormay expel theembryos from theuterus completely, resulting in failed cycles or in ectopic pregnancy, if the
embryos are transported retrograde to a fallopian tube. Placement of the catheter through the cervix may be a sufficient stimulus to induce contractions, and whether the duration of the
catheter’s placement has any effect on outcome was examined
in a prospective, randomized trial of 100 subjects. [67]. Patients
were randomized to either immediate removal of the catheter
or to a 30-second delay after the embryos were expelled before
the catheter was removed. Characteristics of the patients were
not different, including the distribution of day of transfer (day 3
or day 5 post retrieval), the age of the patients, the number and
quality ofembryos transferred, the cause ofinfertility, and stimulation parameters. Allthe transfers were defined as“easy”because
none required use of extensive cervical manipulation or the use
of a tenaculum. There was no significant difference in implantation ratesbetween immediate withdrawal and the30-second wait
(60.8% vs. 69.4%).
The authors concluded that no benefit was achieved from
waiting towithdraw thecatheter, though they acknowledged that
the result may have been from lack of statistical power or insufficient delay. However, the authors pointed out that uterine contractions may persist for 45 minutes following embryo transfer,
so longer waiting periods are not realistically employable. The
authors postulated that the act of placing the catheter through
the cervix is the causative event in initiating uterine contractions
via prostaglandin release. Although no transfer was deemed “difficult,” the total time required to position the transfer catheter
once contact was made with the cervix was not examined as an
additional potential determinant of outcome.
Although a prolonged wait following expulsion of the
embryos does not appear necessary, it would be prudent to
remove the catheter slowly to minimize disruption of the
endometrium and to avoid drawing the transfer droplet toward
the lower uterine segment. Additionally, pressure should be
applied continuously to the plunger until the catheter is completely removed from the uterus to prevent creating negative
pressure in the syringe, which could inadvertently withdraw the
droplet and embryos.
ULTRASONOGRAPHY FOR
NONCERVICAL TRANSFER
When transcervical embryo transfer has proven difficult or impossible, surgical embryotransfer under ultrasound guidance has
been attempted. This technique has been used infrequently. Early
attempts toperform this procedure were unsuccessful [68]; however, transvaginal ultrasound–guided transmyometrial embryo
transfer and transabdominal ultrasound–assisted transurethral
embryo transfer successes havebeenreported.[69]One case series
reported good pregnancy rates (36.5%) with a vaginal approach
[70], and a small, independent trial found similar pregnancy
rates.[71] Aprospective,randomized study failed to demonstrate
a difference in outcome between transmyometrial and transcervical embryo transfer in patients with cervical stenosis, because
none of the 15 patients with this diagnosis achieved pregnancy
during the study. [72]
CONCLUSION
There are various determinants that can complicate the success
of anembryo transfer. Each factor contributing to the probability
of successful outcome may have a critical threshold that irrevocably causes IVF cycle failure. Failure to deliver embryos to the
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endometrial cavity, directly or indirectly, will never result in a
viable pregnancy, but the critical factor is rarely so conspicuous.
Studying subtle influences is challenging, given the number of
confounding variables.
The benefit ofultrasonography may existfor only a verysmall
subset of patients in whom an inappropriate transfer site would
have been chosen without visual confirmation. Unfortunately,
identification of these cases is difficult, so physicians will need
to decide whether routine ultrasound guidance is feasible or if it
should beemployedonlyincasesinwhichdifficultyisanticipated,
using a protocol to select cases for ultrasound guidance.
Despite the increasing use of ultrasound assistance, however,
clinical touchtransfer may be more practical for some; the added
benefit of ultrasound guidance in individual cases must always
be considered.[73] Recommending universal adoption of this
technique is premature; improved outcomes have not been conclusively established. However, ultrasonography has never been
demonstrated to detract from IVF success, and it may safely
be used for all transfers. Because of its noninvasive nature and
because performance of transabdominal ultrasound at transfer
can frequently be done with little or no added cost, ultrasound
guidance may become routine.
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