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INTRODUCTION
Embryo transfer (ET) is the final, yet crucial step in vitro fertilization (IVF). Various steps in an IVF cycle can proceed successfully up to the ET stage in about 80% of the cases. But, unfortunately, only a small percentage of them achieve pregnancy. The technique of ET has not received enough attention, as clearly illustrated from the number of scientific publications on ET in the literature relative to the articles published on IVF in general. A Medline search revealed that the number of scientific publications on human IVF in the years from 1978–2005 is 16,445. Only 394 articles were directed towards the technique of ET.
Obviously, to most clinicians, the ET technique is a simple procedure.
It only means a simple task of inserting the ET catheter in the uterine cavity and ejecting the embryos. Unfortunately, it is not as simple as it looks and it is easier to say than done.
The ET technique may directly influence the outcome of assisted reproduction techniques (ART). It has been demonstrated that there is a significant difference in the pregnancy rates associated with different individuals performing the ET within the same IVF program. In contrast, Visser et al. reported no significant difference among pregnancy rates obtained by three different clinicians. However, when the transfer procedure is standardized, the probability of success in IVF is not dependent on the physician. The need to standardize the protocol for ET technique was regarded as the most important factor influencing the success rate in IVF in a survey of 80 IVF practitioners. Moreover, it is estimated that poor ET technique may account for as much as 30% of all failures in assisted reproduction. Unfortunately, this failure must have affected thousands of infertile couples seeking pregnancy through assisted reproduction every year. Therefore, extra attention and time should be given to the procedure of ET. Meldrum et al. recognized that meticulous ET technique is essential
for IVF success. This final step in assisted reproduction will determine the fate of a long process and great effort, from ovulation induction and oocytes retrieval, to the tedious high-technology procedures in the laboratory, not to mention the desperate hope of infertile couples.
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POTENTIAL NEGATIVE FACTORS ASSOCIATED
WITH THE ET TECHNIQUE
ET is routinely performed using the transcervical route, which is basically a blind technique, associated with multiple potential negative factors that may result in total failure of the whole procedure. There is no sure method to confirm that the embryos have been successfully deposited within the uterine cavity and many ‘‘lost’’ embryos may go undetected. These potential negative factors include the following.
Initiation of Uterine Contractions Initiation of uterine contractions that may lead to an immediate or delayed expulsion of the embryos has always been a big concern in assisted reproduction. In an early study on cows, ‘‘artificial embryos’’ in the form of resin spheres impregnated with radioactive gold were traced after ET. It was found that after 1.5 hr, a large proportion of the spheres had been expelled from the uterus altogether. In human IVF, about 15% of the transferred embryos were expelled after the transfer and had been collected from the external cervical os, the tip of the catheter, and the vaginal speculum. Similarly, Me´ne´zo et al. Were able to demonstrate that only 45% of ‘‘experimental embryos’’ were present within the uterine cavity one hour after the transfer. Experimental studies have been done to demonstrate expulsion of injected material inside the uterine cavity mimicking ET. In a study on humans by Knutzen et al. using radio-opaque dye, mimicking ET, it was found that the dye remained primarily in the uterine cavity in only 58% of cases. It could be concluded from the study that the remainder of the patients would have lost their opportunity for pregnancy as a result of the ET procedure. In a similar study conducted by Mansour et al. using Methylene Blue, it was demonstrated that the dye was visualized at the external cervical os in 42% of the cases, indicating that the uterus extruded the dye at least partially.
As a result, it is possible that the embryos may be expelled from the uterus, partially or totally, after the transfer. In a study by Woolcott and Stanger, it was observed that the embryos could move as easily toward the cervical canal as toward the fallopian tubes. Fanchin et al. noted that more uterine contractions at the time of transfer were associated with a lower clinical pregnancy rate.
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Failure to Pass the Catheter through the Cervix
It is obviously crucial for the ET catheter to pass the internal os and enter the uterine cavity, otherwise the whole procedure will be a total failure. One cause for the failure of the catheter to pass the internal os is the unnoticed curving of the catheter inside the cervical canal, which can be misleading, especially with soft catheters.
Another important cause for the failure of the catheter to pass the internal cervical os is simply a lack of alignment between the catheter (straight) and the utero-cervical angle (curved or acutely angulated). In extremely rare cases, it is very difficult or even impossible to pass the catheter inside the uterine cavity. This may be due to anatomical distortion of the cervix by previous surgery or fibroid or due to congenital anomaly. Scarring of the lower uterine segment or a distorted endometrial cavity create difficulty in catheter introduction.
Cervical Mucus
Proper embryo replacement can be seriously impaired by cervical mucus. It can plug the tip of the catheter, causing difficulty in delivering the embryos, especially with such a small volume of culture media to inject with the embryos. Plugging the catheter tip can cause embryo retention and damage (especially with assisted hatching) and improper embryo placement. Another drawback is the possibility of sticking of the embryos to the mucus around the catheter and dragging them outside during withdrawal of the catheter. Moreover, if the mucus is pushed or injected higher in the uterine cavity, it may interfere with implantation.
In a study by Mansour et al., methylene blue was used in a dummy ET model. It was demonstrated that the dye was extruded at the external os in a significantly higher rate when the cervical mucus was not removed. In clinical IVF, in a large study by Nabi et al., it was shown that the embryos were much more likely to be retained when the catheter was contaminated with mucus or blood. Cervical mucus may be a source of bacterial contamination of the embryos and endometrium with subsequent lower pregnancy rates.
SUGGESTIONS FOR OPTIMIZING THE TECHNIQUE OF ET
Proper Evaluation of the Uterine Cavity Before starting the IVF cycle, it is important in evaluating the uterine cavity to ensure proper embryo replacement. Proper evaluation can be achieved by the following.
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Dummy ET
It has been demonstrated that performing a dummy ET before the IVF cycle significantly improves the pregnancy rate. This procedure is important in evaluating the length and the direction of the uterine cavity and cervical canal as well as the cervico-uterine angulations. It also helps in choosing the most suitable kind of catheter to be used. Another advantage of the dummy ET is to discover any unanticipated difficulty in introducing the catheter such as pinpoint external os, the presence of cervical polypi or fibroids, or anatomical distortion of the cervix from previous surgery or congenital anomaly. If cervical stenosis is diagnosed, it is advisable to perform cervical dilatation before starting the IVF cycle. The use of cervical laminaria one month before the IVF cycle has been demonstrated to be beneficial as a means of cervical dilatation. The procedure of dummy ET is
Recommended to be done one to two months before the start of the IVF
cycle or immediately before the actual ET. It is recommended to perform both.
Ultrasonographic Evaluation
Another important method for evaluating the uterine cavity is using ultrasound (US). The length of the uterine cavity and the cervical canal can be precisely measured. The use of US to determine the accuracy of trial ET was studied by Shamonki et al.. It was demonstrated that approximately 19% of patients had a discrepancy of _1.5 cm and approximately 30% had a difference of _1 cm from trial ET compared of US-guided ET, suggesting a benefit of US-guided ET. Ultrasonography is very important in measuring and evaluating the cervico-uterine angle. Revising the US picture of the uterine cavity, length, and direction before the ET functions as a map or a guide before performing the transfer, which is essentially a blind technique? Ultrasonography is also very important in diagnosing fibroids that may be encroaching on the uterine cavity or distorting the cervical canal, as well as diagnosing any uterine anomalies.
Avoiding the Initiation of Uterine Contractions
The demonstration of endometrial movements has opened a research field that may influence the outcome of assisted reproduction. Every precaution has to be taken to avoid the initiation of uterine contractions.
Avoid Touching the Uterine Fundus It is observed by most gynecologists that if the tip of the catheter touches the uterine fundus, the patients experience immediate discomfort followed by suprapubic pain or heaviness. This is probably associated with the initiation of uterine contractions. It was demonstrated that touching the fundus with the catheter stimulated uterine contractions. Using US visible material in a mock transfer by Lesny et al. demonstrated that touching the fundus with the catheter initiated strong random uterine contractions and the contrast material was relocated from the fundus in six of seven patients. Early sources in IVF described the optimal location for embryo placement as between 0.5 and 1.0 cm from the fundus. Not touching the fundus was ranked high as a prognostic factor for IVF success in a survey
Done by Kovacs.
To avoid touching the fundus, some IVF specialists routinely place the catheter approximately 0.5 cm below the fundus or 1–1.5 cm from the fundus. Depositing the embryos in the mid-fundal area of the uterus was found to be important in improving the pregnancy rate. Waterstone et al. reported a significant increase in pregnancy rate by changing the position of the catheter so as to avoid touching the uterine fundus. Coroleu et al. Demonstrated that the position of the ET catheter 2 cm from
the fundus was superior to 1 cm from the fundus. In a study by Frankfurter et al., the authors demonstrated that the implantation rate as well as the pregnancy and birth rates were significantly higher after middle to lower uterine segment ET compared with fundal ET. Therefore, individual measurement of the cervical canal and the
Uterine cavity lengths are extremely important. It could be done previously during the dummy ET or by US evaluation of the uterine dimensions. However, it has been demonstrated that the use of a fixed-distance technique greatly reduced the variation in pregnancy rates among physicians, probably due to reduction in the rate of touching the fundus as when the clinical touch method was used.
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Catheter Type
Since the beginning of IVF, the value of soft ET catheters has been recognized.
The ideal ET catheter should be soft enough to avoid any trauma to the endocervix or endometrium and malleable enough to find its way through the cervical canal into the uterine cavity. The word ‘‘soft’’ means a combination of physical flexibility, malleability, and smoothness of the tip. It is worth mentioning that in order to benefit from the advantages of the softness of the catheter; the outer rigid sheath should be minimally used to stop short of the internal cervical os. If the outer sheath is introduced first, it will convert a ‘‘soft’’ catheter into a ‘‘stiff’’ catheter. The stimulus of the ET catheter passing through the internal cervical os can also initiate contractions, which are probably mediated by the release of prostaglandins. The mere presence of the ET catheter inside the cervical canal and uterine cavity might be one of the factors that can trigger uterine contractions. Several studies have compared different kinds of catheters and found improved pregnancy rates with soft catheters. Other groups found no difference. In a large prospective randomized study, ET using a soft catheter was compared to a rigid catheter. The results demonstrated that the ongoing pregnancy rate was significantly higher in the soft catheter group. Similarly in another randomized trial comparing soft ET catheter versus firm ones, the pregnancy rate was increased by 50% when soft catheters were used. Changing from rigid to soft catheters has been associated with an improvement in pregnancy rates.
The soft catheter was found to be superior to the stiffer catheter when transferring embryos subjected to assisted hatching. A recent meta-analysis of 10 studies comparing soft ET catheters with more rigid ones revealed that the clinical pregnancy rate was significantly better using the soft catheters (Fig. 1).
Figure 1 Meta-analysis comparing in vitro fertilization outcome using soft versus firm embryo transfer catheters.
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Gentle Manipulation
As a general rule, the ET procedure should be a simple and painless procedure.
Atraumatic delivery of embryos into the endometrial cavity is the prime goal of ET. Gentle manipulation throughout the total procedure of the ET should be the rule, even in introducing the vaginal speculum to avoid unnecessary pushing of the cervix. It was observed that just simple insertion of the catheter results in uterine movement. Obviously, using a volsellum to hold the cervix should be avoided except in rare cases. Stimulation of the cervix results in the release of oxytocin, thus increasing uterine contractility. In a prospective clinical study on humans, serial blood samples were collected in time intervals of 20 sec during the ET procedure in order to measure serum oxytocin concentration. It was demonstrated that in the absence of a tenaculum placement, no increase in oxytocin concentration was observed. When a tenaculum was used, it was temporarily associated with an elevation in oxytocin levels, which remained elevated until the end of the ET procedure. The use of tissue forceps to hold the cervix has been observed to trigger uterine contractions. In some cases of difficult ET, applying 1–2mL of local anesthetic (1% procaine) to the anterior lip of the cervix through a very fine needle and then applying a tenaculum was found to be very acceptable to the patients, caused no discomfort, and did not affect the outcome. A number of studies have shown that technically difficult ETs are associated with reduced pregnancy rates. It probably could be due to the initiation of uterine contractions that expel the embryos. It has been shown that in 87% of the achieved pregnancies, the ET was performed atraumatically and without bleeding. The presence of blood in the catheter was found to be associated with decreased implantation and pregnancy rates. A recent report of 30 case series using direct hysteroscopic visualization to assess the effects of ETs on endometrial integrity showed that clinical perception of the ease of transfer does not correlate well with the degree of endometrial disruption.
Uterine Relaxing Substances
Many researchers have given different drugs in an attempt to decrease uterine contractions during ET. Serum progesterone levels on the day of ET correlate with the frequency of uterine contractions which decreased as the level of progesterone increased. Progesterone was administered starting on the day of oocytes pickup to relax uterine contractility at the time of ET. Starting progesterone administration on the day of pickup did not have additional improved PR as compared to starting it on the day of ET. Nonsteroidal anti-inflammatory drugs (NSAIDs) block the action of cyclooxygenase (COX) and inhibit the production of prostaglandin. Accordingly, 10mg of the NSAID piroxicam was given in a prospective randomized study one to two hours before ET. The results demonstrated significant improvement of implantation and pregnancy rates with the use of piroxicam.
Sedation with 10 mg valium, 30 minutes to 1 hour before ET, was a common practice; however, it did not make any difference. Tacolytic agents or prostaglandin synthetase inhibitor did not have a significant effect. The use of Propofol general anesthesia for ET did not have a significant effect. However, it could be used in some patients who experience severe stress and anxiety during ET.
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Ensuring the Passage of the ET Catheter into the Uterine Cavity
The ultimate goal at the end of an IVF cycle is to safely deposit the embryos inside the uterine cavity. One has to be absolutely sure that the catheter has passed the internal os and has not kinked or curved inside the cervical canal. Soft catheters can sometimes be misleading. This can be discovered by experienced practitioners and by doing the simple test of rotating the catheter by 360_. If it recoils, it means it is curved inside the cervical canal. Choosing the most suitable catheter for each patient should be done before the actual ET by performing a dummy ET, to avoid harshly navigating the cervical canal with the ET catheter loaded with embryos. Neithardt et al. placed the ET catheter first and then the embryo after ‘‘loading’’ was done. One of the most important causes of failure to pass the catheter into the uterine cavity is simply the pronounced curvature or angulations of the cervico-uterine angle (Fig. 2). Proper evaluation of the cervico-uterine angle and determining how much curvature is needed for the catheter should be done before loading the embryos. A situation in which you need to curve the catheter while you have the embryos loaded should be completely avoided. That is why it is important to perform a dummy ET right before the actual one and revise the previously performed US picture of the uterus. It has been demonstrated that molding the ET catheter according to the cervico- uterine angle by US improved the clinical pregnancy and implantation
Figure 2 Curving a rigid but malleable embryo transfer catheter according to the
Cervico-uterine angle overcomes almost all difficult cases.
rates and diminished the incidence of difficult transfers. Straightening the utero-cervical angle can be achieved with a full bladder before ET. This effect is being achieved indirectly by performing ET under US guidance.
Another method to simply facilitate entering the catheter is too gently maneuvering the vaginal speculum (the degree of opening and how far it is pushed inside).
The use of a more rigid catheter is sometimes needed in order to pass the internal os. It is advantageous for these rigid catheters to be malleable. Malleability is essential to allow making the required curve, which will overcome the acute cervico-uterine angulations. Using a malleable stylette to place the outer sheath correctly and negotiate the cervical canal before introducing the soft catheter was found to have no negative impact on implantation and delivery rates.
The use of special introducers designed to overcome difficulties in selected patients in passing the ET catheter was described. Holding the cervix with a volsellum in order to stabilize the uterus while introducing the catheter should be rarely resorted to. The effect of cervical traction with a tenaculum on the utero-cervical angle was studied using radio-opaque guide-wire. The authors found that moderate cervical traction straightens the uterus. It was concluded that routine use of the tenaculum theoretically makes the passage of an ET catheter easier and less traumatic.
On the other hand, it should be remembered that holding the cervix with a volsellum results in the release of oxytocin and initiates uterine contractions. Moreover, holding the cervix with a volsellum is painful and should be done under general anesthesia or local anesthetic. In some rare cases, it is difficult or even impossible to pass the catheter inside the uterine cavity. For these cases, stiffer and more rigid catheters may be used. Another system that has been used in these difficult cases is the coaxial catheter. Canulation of a resistant internal os with the malleable outer sheath of a coaxial soft ET catheter did not affect IVF outcome. A malleable stylette can be used to place the outer sheath of a soft catheter past the internal os. The stylette is then removed and the inner clear catheter loaded with the embryos is inserted. Using this technique, pregnancy rates equivalent to easy transfer were obtained. Hysteroscopic evaluation and/or correction of the endocervix, followed by transcervical placements of a Malecot catheter for an average of 10 days, is a technique that allowed easier entry through the cervical canal in patients for whom previous ET has been difficult . Cervical dilatation may be resorted to in cases of cervical stenosis. A short interval between dilatation and ET is not recommended. Very low pregnancy rates were reported when cervical dilatation was done during oocyte pickup or two days before ET. Performing cervical dilation before the start of IVF cycle resulted in easier transfer and improved pregnancy rates. It is also helpful to place a laminaria approximately one month before starting the IVF cycle or to place hygroscopic rods in the cervix prior to ovarian stimulation. The standard method of dilatation with successively larger dilators may be difficult and traumatic in some tortuous or stenotic cervical canals. Canulation of the cervix under fluoroscopic guidance and dilating the endocervical canal was successfully tried. Sometimes it is even impossible to performtranscervical ET. In an early report in 1985, in 867 ET procedures, 1.3% were impossible, 3.2% were very difficult (manipulation for >5 min or cervical dilatation), and 5.6% were difficult. Twenty years after this report, the current experience of most IVF centers makes the rate of impossible and difficult ET procedures significantly Less Very rarely, when other maneuvers fail, trans-myometrial surgical ET can be used. Surgical transfer of the embryos through the fundus has been tried, originally to avoid the initiation of uterine contractions induced by passing the catheter through the cervix. In 1987, Lenz and Leeton suggested US-guided transabdominal transvesical and transfundal ET; however, none of the 10 patients conceived. Ultrasonic transvesical transmyometrial ET technique has been proposed by Wikland et al.; however, no improved pregnancy rate was achieved over the transcervical route. Surgical ET has been used successfully, achieving results comparable to the transcervical route. This technique is straightforward and requires no greater expertise than that necessary for US-guided oocyte collection and requires no sedation or anesthetics. The surgical ET set is composed of a metal needle (like an oocyte pickup needle) with a stellet and an ET catheter that fits in the needle after withdrawal of the stellet. Under US guidance, the needle is introduced transmyometrially and the tip is stopped in the endometrium just beneath the cavity. At this time, the stellet is replaced with the ET catheter and the embryos are ejected, then the whole set is withdrawn. The results of a small prospective study showed no benefit to electing transmyometrial ET in preference to transcervical ET in patients who had previously failed IVF.
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Getting Rid of Cervical Mucus
Cleaning the cervix of the cervical mucus before ET is advisable to avoid the possible drawbacks mentioned previously. Removing the cervical mucus before ET can be done by repeated gentle aspiration using a 1 cm3 syringe with its tip placed at the external os or using a soft catheter attached to a syringe. The endo-cervix can be cleaned of mucus using a cotton swab and sterile saline initially, then a small amount of culture media (8, 39). Repeated irrigation of the cervical canal with 3mL culture medium and aspiration of the mucus has been described by Silberstein et al.. Vigorous cervical lavage before ET was evaluated by McNamee et al. in a retrospective study and was found to improve the pregnancy rate. In a randomized controlled study by Sallam et al., no significant difference was found in pregnancy rates with or without flushing. Also, a large multicenter study did not show a significant difference.
Prevention of Embryo Expulsion after ET
A technique using the vaginal speculum to prevent embryo expulsion after ET was recently described. The idea is a simple one depending on applying gentle pressure on the cervix using the vaginal speculum (Fig. 3). In summary, after introducing the ET catheter and stopping short of the fundus, the screw of the vaginal speculum is loosened so that its two blades collapse on the cervix applying gentle pressure and occluding the cervix. After waiting for one minute, the embryos are ejected and the catheter is withdrawn slowly. The speculum is kept in place for an average of seven minutes and then removed. Using this technique, the implantation and clinical pregnancy rates were significantly improved.
Other Factors in ET Technique That May Affect the IVF Outcome
ET Under Ultrasonographic Guidance
Performing the ET procedure under US guidance is another way to ensure that the ET catheter has passed internal os and entered the uterine cavity. Various groups described the use of US to facilitate ET and it has proven useful in women with previously difficult ET. Using US guidance for ET was demonstrated by a number of studies to be simple and reassuring, and it significantly improved pregnancy rates by optimizing placement of the embryos. However, other groups found no significant difference in the pregnancy rates when ET was performed under US-guidance and clinical touch ET. A major factor in making the difference between US-guided ET and clinical touch ET is the experience of the practitioner. For easier identification of the ET catheter, some kinds have an ultrasonically visible echo-tip or the presence of air bubbles. A meta-analysis was done for eight prospective controlled studies comparing US-guided and clinical touch ET. The results showed that US-guided ET significantly increased the implantation and clinical pregnancy rates. It was reported recently that transrectal US was used successfully during ET in obese women.
Figure 3 (A) In the study group, the two valves of the vaginal speculum are closed on the cervix. (B) In the control group, the two valves of the vaginal speculum are open.
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Position of the Patient and Bed Rest after ET
The patients usually mistakenly believe that they can contribute to the success of their IVF cycle through their bed position and the amount of bed rest. Theoretically, if the uterus is anteverted it seems preferable to perform ET in the knee chest position. However, in a randomized study there was no difference in the pregnancy rate according to the position of the patients during ET. Most of IVF centers use the lithotomy position or lithotomy in a slightly trendelenburg position. Bed rest after ET was originally practiced in most IVF centers for several hours possibly because of fear of mechanical expulsion of the embryo. In1993, Al-Shawaf et al. And in 1995 Sharif et al. have suggested that there is no justification for bed rest after ET. Then, a randomized prospective controlled study by Botta and Graudzinskas demonstrated that there was no benefit of bed rest after ET. In a large study with a historical cohort–control, there was no benefit of bed rest following ET. The position of the embryos after ET immediately in a standing position was ultrasonically tracked by Woolcott and Stanger. It was demonstrated that standing shortly after ET does not play a significant role in the final position of the embryos. It has also been shown recently in a prospective study of 406 patients that immediate ambulation following the ET has no adverse effect on the pregnancy rate as compared to bed rest for one to two hours.
It is worth mentioning that the so-called endometrial cavity is a potential space and not a real one. The ET catheter only separates the opposed endometrial surfaces and, once the catheter is removed, the endometrial surfaces re-oppose. The embryos and fluid injected into this potential space are then relocated by the endometrial and myometrial peristalsis as well as the surface tension between the fluid–solid interfaces. It is believed that the embryos generally implant where they are deposited and it confirms the importance of careful embryo placement. Mock ET was performed using small microspheres immediately before hysterectomy. The uterine cavity was then inspected and the microspheres were found within 1 cm of the site of deposition. In a study by Baba et al., it was found that 26 of 32 gestational sacs, seen by three-dimensional US, were in the area where the air bubble was seen immediately after transfer.
Withdrawal of the Catheter After ET
The time interval between deposition of the embryos and withdrawal of the catheter has been investigated by many researchers. Waiting before withdrawal of the catheter was suggested so that the uterus can stabilize. The catheter was kept in place for one minute before the embryos were gently injected, then a further one minute waiting period followed before the catheter was slowly withdrawn. Based on a mock ET and visualization of radio-opaque dye, it was recommended to routinely wait 15 seconds after introducing the ET catheter into the uterus before ejecting the embryos and another 60 seconds before catheter removal. Zeck et al. recommended immediate withdrawal of the catheter after ET. However, Martinez et al. demonstrated an improved PR with a delay of 30 seconds before withdrawing the catheter. Negative pressure of capillary action created by withdrawing the catheter could draw embryos into the cervical canal.
Intrafallopian ET
Hypothetically, the intrafallopian environment is more physiological to the embryos after IVF. Based on this assumption, tubal transfer was proposed by some investigators. Naturally, the fallopian tubes have to be healthy. It was found to be promising in cases of male factor infertility. A limited number of investigators have proposed intrafallopian ET as an alternative to the transcervical route. Using this technique through laparoscopy in 10 patients, six patients achieved pregnancies and five patients out of 10. Retrograde tubal transfer was also described in
28 patients and five pregnancies resulted. However, for practical reasons and based on the success rates, the transcervical ET is the routine procedure used by all IVF centers.
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ET Technique as a Cause of Ectopic Pregnancy
The risk of ectopic pregnancy following IVF was found to be 5% in a multicenter study undertaken on 1163 pregnancies. This figure is certainly higher than that in natural conception. The influence of transfer distance from the fundus on the clinical pregnancy rate and ectopic pregnancy rate was investigated by Pope et al. The authors demonstrated that increasing the transfer distance from the fundus significantly increases the PR and lower the ectopic rate. The results suggested that for every additional millimeter embryos are deposited away from the fundus, the odds of clinical pregnancy are increased by 11%. ET technique as a cause of ectopic pregnancy was recognized early by Yovich et al. in 1985. The authors reported an incidence more than three times greater in ectopic pregnancy when the embryos were transferred near the fundus as compared to the mid-cavity position. They concluded that the catheter needs to be inserted only 55mm as a routine and less in patients with a shortened cervix or with hypoplastic uterus. The midfundal technique
Resulted in a lower percentage of ectopic pregnancies and did not negatively affect the pregnancy rate. Transferring the embryos by replacement at 6 cm without tracing the position of the fundus was also demonstrated to improve the pregnancy rates. It was reported that two cases of cervical pregnancy resulted from ET to the lower uterine cavity. Ectopic pregnancy was found to be 3.9 times more frequently associated with difficult ET than with an easy procedure. Moreover, intramural pregnancy was reported following difficult ET. The size of the uterus was shown to be a critical factor in the etiology of ectopic pregnancy in IVF. The study demonstrated that the ectopic pregnancy rate was significantly higher in women with uterine cavity length less than 7 cm. uterine contractions in the early luteal phase are generally cervico-fundal in origin and it may be the cause for some ectopic pregnancy in IVF.
Bacterial Contamination
Cervical infection was found to cause diminished pregnancy and implantation
rates. It was found that cervical mucus tested positive in culture in 71% of patients and 49% of patients had positive culture of the catheter tip. The clinical pregnancy rate was significantly reduced in catheter tip-positive patients. Similarly, Fanchin et al. demonstrated a significant reduction in the pregnancy rates in positive culture patients. A meta-analysis of controlled studies found that the clinical pregnancy rates and implantation rates were significantly diminished in the presence of cervical infection. Pelvic infection is likely to complicate ET. A pelvic abscess was reported after transcervical ET in an oocytes donation recipient. However, the value of routine administration of antibiotics before the IVF cycle or following oocyte retrieval or ET has not been evaluated by randomized controlled studies.
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DESCRIPTION OF AN ET PROCEDURE
The patient is instructed to come fasting as a precaution in case the need for general anesthesia arises. The patient is informed of the fertilization rate, the number of available embryos, and the number of embryos selected for the transfer. The patient is assured that the ET is a simple procedure. If she is very stressed, it is better to perform ET under general anesthesia.
The previously taken US picture of the uterus and the dummy ET is revised to get an idea about the length and direction of the uterus and the degree of cervico-uterine angulation. The patient is put in the lithotomy position and the cervix is visualized
using Cusco’s speculum.
The cervix and the vaginal vaults are cleaned of cervical mucus and vaginal secretions using tissue culture media and sterile gauze. The cervical mucus at the external os is aspirated gently and repeatedly using a 1 cm3 syringe.
A dummy ET is done using a sterilized soft ET catheter. The soft inner catheter is advanced from the outer rigid sheath and introduced through the cervical canal to pass the internal cervical os and enter the uterine cavity. The outer rigid sheath is stopped short of the internal os. The catheter is rotated by 360_ and leave it, if it recoils, it means it is kinked inside the cervical canal and did not pass the internal os. The catheter is withdrawn and tried again after changing the position of the speculum (degree of opening and how far it is introduced). If the soft catheter failed to be introduced, a more rigid but malleable catheter is tried. The catheter is curved according to the curvature of the cervico-uterine angle seen in the US picture. The curved catheter is introduced gently to follow the curvature of the cervix and it is moved in different directions until it passes the internal os. Sometimes you need to increase the curvature of the catheter in order to overcome the acute angulations of the cervico-uterine angle. In almost all cases, it is possible to introduce the rightly curved rigid catheter. In the case of a failed dummy ET, the procedure is stopped and the patient is transferred for general anesthesia. If the dummy ET catheter was successfully introduced, the actual ET can be started. The catheter type is chosen according to the suitable one used for the dummy trial. The ET catheter is flushed with tissue culture medium, and then filled with the transfer medium. About 15 mL of transfer medium is aspirated first and then the embryos are aspirated next in another 10 mL medium. Finally, 10 mL medium is aspirated to withdraw the embryos away from the catheter tip. The loaded ET catheter is introduced through the cervix to pass the internal os and then gently advanced in the mid-uterine cavity and stopped from 1–2 cm short of the fundus.
The screw of the vaginal speculum is loosened so that the two valves of the vaginal speculum apply a gentle pressure on the portio-vaginalis. At this moment, some patients experience suprapubic heaviness and discomfort. After one to two minutes, when this complaint disappears, the embryos are ejected and pressure is kept on the plunger of the syringe while slowly withdrawing the catheter out. The speculum is kept in place for an average of seven minutes and then removed. The catheter is checked for any retained embryos. If found, retransfer is done immediately.
For difficult cases, general anesthesia is given in the form of propofol 2 mg/kg as an induction dose and anesthesia is maintained by inhalation of isoflurosane 1.5% and oxygen 100% through a facemask. The dummy ET is repeated and if not successful a tenaculum is used to stabilize the cervix. As a last resort, a special rigid but malleable introducer may be used. In extremely rare cases, transmyometrial surgical ET may be resorted to.
LUTEAL PHASE SUPPORT
When Edwards and Steptoe started clinical IVF, human oocytes were successfully fertilized and grown in vitro; however, no pregnancy resulted for the first seven years. It was then realized that the failure of embryos to implant was due to luteal phase disruption. Normal luteal function is important for supporting pregnancy. The aspiration of granulosa cells during oocyte pickup can interfere with the production of progesterone, although not consistently (148). It has been demonstrated that removal of the corpus luteum during early pregnancy resulted in complete abortion.
The use of GnRH agonist (GnRHa) in stimulation protocols for IVF has dominated all other protocols and is being used by almost all IVF centers. The agonist may create luteal phase defect due to impairment of the ability of corpus luteum to produce progesterone, thus luteal phase support was considered essential. Recently, GnRH antagonists are used with increasing frequency in ART cycles. It has been demonstrated that luteal function is less impaired in GnRH antagonist than in GnRHa treatment . The question of the need to supplement the luteal phase after the use of GnRH antagonist needs further investigation. All systematic reviews and meta-analysis have confirmed the importance of luteal phase support in ART. Progesterone administration was found to significantly improve the fertility outcomes inART compared to no treatment. Progesterone was found to be equivalent to the use of human chorionic gonadotrophin (hCG) for luteal phase support but had a decreased incidence of OHSS.
The most commonly used method of administration of progesterone is IM injection. It was found to be associated with normal endometrial response. Intramuscular progesterone luteal supplementation versus no treatment or placebo resulted in significantly better clinical pregnancy rate and delivery rate. Compared to vaginal gel or vaginal cream preparations of progesterone, IM injection resulted in a significantly improved clinical pregnancy and delivery rates.
The dose of IM progesterone injection is 50–100 mg/day. In one study, daily injection of 50 mg progesterone was compared with injection of 341 mg of 17a-hydroxyprogesterone caproate every three days and there was no significant difference in the clinical pregnancy rate or abortion rate. Daily IM injection with 25 and 100mg progesterone was compared, and no significant difference in the clinical pregnancy rate or delivery rate was found (168). Oral or vaginal progesterone is given in the form of a micronized preparation of 400–600 mg/day.
The duration of luteal phase supplementation is variable in different studies, from supplementation for two to three weeks only and through 10 to 12 weeks of gestation. Local and systemic allergic reactions to the oil in IM injections of progesterone may result . Two cases of acute easinophilic pneumonia following IM administration of progesterone were reported. Oral progesterone administration was found to be associated with significantly lower implantation and pregnancy rates, high miscarriage rates, or both compared with IM or vaginal route.
The addition of estrogen to the standard progesterone in the luteal phase resulted in significantly higher implantation and pregnancy rates compared with the use of progesterone alone . Estrogen doses varied from 2 to 6 mg oral per day. Phytoestrogens were also found to significantly improve the implantation rates, clinical pregnancy rates, and delivery rates when added to progesterone as compared with progesterone alone.
In conclusion, the routine use of GnRH agonist in IVF cycles creates persistent LH suppression and luteal phase defect. Luteal supplementation with IM progesterone or IM hCG significantly improved the clinical pregnancy rates and delivery rates compared with no treatment. There is no difference between IM hCG and IM progesterone, however, hCG is associated with a significantly higher OHSS. The most benefit is obtained when progesterone is given IM as compared to oral or vaginal use. Addition of estrogen to progesterone improved the implantation rate.
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