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Ultrasound Oocyte Retrieval 107
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measurement of ovarian size has been shown to decrease in women aged 40 years and older and may be an earlier indicator of menopausal status than menstrual history.[25–28] A correla­tion between ovarian volume and reproductive outcome in IVF cycles has been shown [27], and this test is inexpensive and rel­atively easy to perform, with minimal intra- and interobserver variations. [25]
Antral follicle count (AFC), defined as the number of fol­licles 10 mm or less in diameter detected by ultrasound in the early follicularphase ofthe menstrual cycle, is another parameter found to correlate with age.[29] A recent meta-analysis compar­ing basal FSHlevelsand AFC revealed that AFCis more predictive of ovarian response to infertility treatments [17] and an estimate of the size of the cohort of follicles available for stimulation in a given cycle may be made. A normal basal antral follicle count (BAF) between 8 and 18 typically will produce 8 to 20 oocytes at the time of retrieval following intermediate-dose stimulation with 225 to 300 IU of gonadotropin in women under 35 years of age. For women over 35, consideration for receiving 450 IU of gonadotropin may be given based on their age.
Patients with a high BAF (18) tend to have a polycystic ovary–like appearance with multiple follicles in the periphery of the ovary with an exaggerated stromal component. Low-dose stimulation following GnRH agonistdown-regulationistypically chosen and carefully monitored by serial ultrasound and estra­diol levels to decrease the risk of severe ovarian hyperstimulation syndrome. Patient with alow BAF (8)tendto be low responders who areresistant to stimulation and require more aggressive pro­tocols. These patients will benefitfrom avoiding oversuppression of the pituitary gland as well as use of 450 IU of gonadotropin per day during the stimulation phase.
Stimulation of multiple follicle growth can induce a prema­ture LH surgein the absenceof strategies tosuppress the pituitary gonadotrope. Before theavailability of GnRHanalogues, as many as one in seven cycles was canceled because of premature ovu­lation. Desensitization of gonadotrope is typically accomplished by administering GnRH analogues starting up to 10 days pre­ceding the intended stimulation.[30] The GnRH agonist down­regulation is sometimes associated with failureto respond to sub­sequent stimulation with gonadotropins. This may occur even in women who have regular cycles on their own and are receiv­ing supraphysiologic doses of gonadotropin. Women who are at highest risk for poor responsesubsequenttoGnRHagonistdown­regulation of gonadotrope are those who have low BAF counts, havea history ofpoorresponsivenesstogonadotropin,aregreater or equal to 40 years of age, and have unexplained infertility. In such patients, alternative stimulation using GnRH antagonists or GnRH agonist flare cycles may be used. GnRH antagonists became clinically available in 1999 and are now widely used for stimulation protocols. Asthe gonadotropes are not suppressed at the onset of ovarian stimulation, patients typically receive sim­ilar or lower doses of gonadotropins. The GnRH antagonist is administered when the leading follicle size reaches 12 to 14 mm, at whichpoint an LH-containinggonadotropin or low-dose hCG is supplemented in addition to the gonadotropin doses.
Another alternative protocol that allows prevention of pre­mature LH surge is the use of microdose GnRH analogues to induce endogenous gonadotropin flare to augment the exoge­nous gonadotropin doses.[31] Premature LH surges have been reported but are very rare. Ovarian stimulation is followed by
serial ultrasounds and estradiol levels, initially after 4 days of stimulation and then every 1 to 2 days until at least two follicles reach 16 to 18 mm in average diameter. hCG 5000 or 10,000 IU is administered 35 hours before the transvaginal oocyte retrieval schedule.
TRANSVAGINAL OOCYTE RETRIEVAL PROCEDURE
Proper room and equipment setup is crucial for successful recovery of oocytes with high fertilization and development potential.
Room Setup
An ambulatory suite is useful for this procedure. Equipment includes an operating table with lithotomy position, an ultra­sound machine (Figure 7.3.1) with a transvaginal transducer and needle guide (Figure 7.3.2), heating blocks, test tubes (Figure
7.3.3), a syringe with a blunt needle, a single- or double-lumen echo-tipped 16- to 18-gauge needle (Figure 7.3.4), a suction pump, anesthetic equipment (Figure 7.3.5), and a well-equipped IVF lab (Figures 7.3.6, 7.3.7). The ultrasound transducer is typi­cally of highfrequency (6.5 MHz) andthe endovaginal probe may be equipped with a needle guide for the oocyte retrieval. The IVF lab should be in close proximity to the procedure room (Figure
7.3.8), which will prevent the adverse effects of room tempera­ture on the oocytes. The temperature of the heating block and all the lab tables are set up at 37
C. If there is no heating block avail­able in the operating room, retrieval should be done as quickly as an embryologist can examine the specimens. During eggretrieval, follicular aspirates and all flushes are maintained at 37
C ± 0.5◦C
and a pH of 7.4 ± 0.1.
Vacuum and Needle Setup
Two different types of needles (single- and double-lumen) are available (Figure 7.3.4) with sufficient diameter (16- to 18-gauge) to prevent cumulous oophorous disruption during aspiration.[32] If flushing is done, a double-lumen needle is preferred.[33,34] Needles are echo-tipped and as a result are readily visualized with ultrasound during aspiration. Recovery rate and quality of the oocytes areinfluenced by the suction pres­sure applied to the needle. A negative pressure between 100 and 120 mm Hg is applied to the needle at the instant of follicular puncture and stopped after needle withdrawal. Higher pressures may lead to damaged and fractured oocytes.[33,34]
Anesthesia
Transvaginalultrasound–guidedoocyte retrieval istypically done as an outpatient procedure under conscious sedation. Patients need to have fasted for at least 6 hours before the procedure. A combination of hypnotics suchas propofol ora sedative hypnotic such as midazolam and/or intravenous (IV) opioids are used to achieve adequate relaxation and anesthesia. Multiple studiesindi­cate asteady rise in the level of anesthetic agents in follicular fluid shortly after starting the procedure. The effect of these anesthet­ics on oocyte fertilization is not clear, but some report dose- and
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Figure 7.3.1. An operating table with lithotomy position and ultrasound with a transvaginal transducer.
Figure 7.3.2. Transvaginal transducer and needle guide and probe cover.
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Figure 7.3.3. Heating blocks and test tubes.
Figure 7.3.4. Single- (upper) and double-lumen needle (lower).
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Figure 7.3.5. Anesthetic equipment.
Figure 7.3.6. IVF lab: microscopes. All the tables are set at 37◦C.
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Figure 7.3.7. IVF lab: microinjection device.
Figure 7.3.8. The IVF lab should to be in close proximity to the operating room. Notice the window.
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time-dependent decreases in fertilization rate.[35,36,37] In gen­eral, it is prudent to minimize anesthesia exposure, but the dura­tion of the procedure may vary from 10 to 30 minutes depending on the operator’s skill, number of follicles, evacuation pressure set up, and the flushing technology.
Procedure Description
The patient is placed in the dorsal lithotomy position and after achieving sufficient sedation, the vagina is prepared either with saline lavage alone or a wash with an antiseptic cleanser. If Beta­dine (Purdue) is used, the vagina should be irrigated copiously with normal saline to minimize oocyte toxicity. Today, most cen­ters use normal saline alone, and there appears to be no increase in postprocedure infection [38], particularly when a prophylac­tic antibiotic such as doxycycline is used around the time of the procedure. A high-frequency endovaginal probe covered with a conducting jelly and a sterile latex cover orcondom is introduced into the vagina with its affixed needle guide (Figure 7.3.2). The ovaries are located, and each follicle is in turn aligned with the puncture line on the monitor. The needle is inserted into the closest follicle in the plane of its largest diameter visualized by ultrasound. The tip of the aspirating needle is then advancedinto the center of the follicle along the shortest path. As negative pres­sure is applied, collapse of the follicle is readily visualized and the needle tip may be manipulated to curette the follicle. The follicu­lar content iscollectedin a tubeand transferred toa heating block maintained at 37
C until the assistant hand delivers the sample to the embryologist in the adjoining IVF laboratory. If all the fol­licles in each ovary can be aspirated through a single puncture site, the numberof separate needle puncturesthrough the vaginal wall and into the ovary will be minimized. Care must be taken to identify the location of hypogastric vessels to prevent inad­vertent puncture and serious intra-abdominal bleeding. When the needle is withdrawn from one ovary, it should be flushed with culture medium to clear any retained oocytes from the line. During the procedure, if the aspirates are found not to contain oocytes by the embryologist, or if the patient has only a few folli­cles, flushing may maximize the oocyterecoveryrate and absolute number of oocytes. The use of flushing during oocyte retrieval, however, is somewhat controversial. Multiple follicle flushes are time-consuming procedures,and several prospectivestudies have reported possible detrimental effects of flushing on oocyte qual­ity and fertilization rates.[33,34] If flushing is done, the number of flushings should be limited to two (4 mL). Flushing may be done with two types of media, a commercially available prepared media or heparinized buffered saline prepared by the embryol­ogist. No difference in oocyte recovery, fertilization, or cleavage rate between the two flushing media has been found.[39]
Transvaginal ultrasound–guided oocyte retrieval has a num­ber of advantagesover the laparoscopic approach: (1) oocytescan be recovered in case of severe pelvic adhesions, (2) general anes­thesia is not necessary, (3) transvaginal follicular puncture has lower potential morbidity, (4) the operative and recovery times are reduced, and (5) oocytes are not exposed to carbon dioxide pneumoperitoneum, which may acidify thefollicular fluid. Com­plications from the oocyte retrieval procedure include infection, bleeding, and trauma to the adjacent organs. According to some reports, the incidence of postprocedure infection ranges from
0.2% to 0.58%, including a high rate of tubo-ovarian abscess for-
mation in up to 0.24% of the cases.[40–42] Abscess formation occurs between 1 and 6 weeks following retrieval. Predisposing factors for infection include a past history of pelvic inflamma­tory disease, puncture of an endometriotic cyst, puncture of the hydrosalpinx, and incidental bowel penetration during egg recovery. Puncture of an endometriotic cyst, in particular, may be associated with chemical peritonitis or postoperative abscess formation.[43,44] To reduce these risks, the cyst should be irri­gated with the flushing media and intraoperative prophylactic IV antibiotics are recommended. The endometrioma contents are also considered to be toxic to the oocytes, and care must be taken to flush the needles and use new Petri dishes in the lab. Any pelvic infections post retrieval will likely lead to a lower implantation rate.[42]
Multiple puncture sites in the vaginal vault and/or inappro­priate handling of the vaginal probe will increase the risk of bleeding. The risk of vaginal bleeding has been reported to be as high as 0.09%.[45,47] Bleeding from the vaginal puncture site frequently will stop with pressure applied to the site with the vaginal probe during the procedure. Rarely, there is a need to suture the puncture sites after withdrawing the needle at the end of the procedure. Aspiration of blood from the needle signifies injury to the follicular wall or ovarian blood vessels. Keeping the needle in the center of the follicle minimizes injury to the follic­ular wall. If a retroperitoneal hematoma or internal bleeding is suspected, observation with pelvic ultrasound to ascertain per­sistent bleeding should be done after the procedure and prompt intervention and emergency laparotomy should be done to pre­vent significant blood loss. Ultrasound-guided oocyte retrieval is rarely associated with injury to neighboring organs, such as the bladder, intestines, ureters, and appendix. Although anes­thetic complications are also rare, vagovagal reaction leading to severe bradycardia and cardiac arrhythmia and asystole fol­lowing deep abdominal pressure on very high ovaries has been reported.[45]
Embryo Transfer
Embryos are transferred in most centers at either the third or fifth day after oocyte retrieval, depending on theexperience of the embryology lab. The placement of the embryos into the endome­trial cavity is a critical step that affects the overall success. Echo­tip Teflon-coated embryo transfer catheters have permitted opti­mization of this step under abdominal ultrasound guidance.[48] A trial of mapping for determining the optimal technique for intrauterine catheter placement notedin the cyclebeforethestim­ulation would allow smooth embryo transfer.
Luteal Support
Oocyte retrieval by aspiration of follicles also results in removal of a substantial portion of the granulosa cells. Combined with suppression of the gonadotropes, some patients will have greatly reduced progesterone production in the luteal phase. Luteal sup­port should be done with either exogenous progesterone or addi­tional hCG injections during the luteal phase. Several formula­tions of progesterone are commercially available: intramuscular progesterone in oil, vaginal micronized progesterone capsules, vaginal suppositories, and vaginal gel. Studies comparing them havenotfound anytobe superior over others [49], butnoneofthe
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studies has been large enough to have sufficient power. Proges­terone supplementation is continued until the luteal–placental shift that occurs during the 10th to 12th weeks of gestational age.
REFERENCES
1. Steptoe PC, Edwards RG. Birth after re-implantation of a human embryo. Lancet . 1978;2:366.
2. Centers for Disease Control and Prevention. 2003 Assisted Repro­ductive Technology Success Report. Available at: http://www.cdc. gov/ART/ART2003/nation.htm.
3. Heape W. Preliminary note on the transplantation and growth of mammalian ova within a uterine foster mother. Proc R Soc. 1890;48:457–458.
4. Iwamatsu T, Chang MC. In vitro fertilization of mouse eggs in the presence of bovine follicular fluid. Nature. 1969;224:919–920.
5. Edwards RG. Maturation in vitro of human ovarian oocytes. Lancet. 1965;ii:926–929.
6. Edwards RG, Donahue RP, Baramki TA, Jones HW. Preliminary attempts to fertilize human oocyte matured in vitro. AmJObstet Gynecol. 1966;96:192.
7. Steptoe PC, Edwards RG. Laparoscopic recovering of preovula­tory human oocytes after priming of ovaries with gonadotropins. Lancet. 1970; ii:683–689.
8. Lopata A, Johnstone IWH, Leeton JF, Muchnicki D, Talbot TM, Wood C. Collection of human oocytes at laparoscopy and laparo­tomy. Fertil Steril. 1974;25:1030.
9. Lenz S, Lauritsen JG, Kjellow M. Collection of oocytes for IVF by ultrasonically guided follicular puncture. Lancet. 1981;1:1163.
10. Robertson R, Picker R, O’Neill C, Ferrier A, Saunders D. An expe­rience of laparoscopic and trans-vesicle oocyte retrievals in an IVF program. Fertil Steril. 1986;45:88.
11. Gleicher N, Friberg J, Fullan N, et al. Egg retrieval for in-vitro fertilization by sonographically controlled vaginal culdocentesis. Lancet. 1983;2:508.
12. Russell J, Decherney AH, Hobbins J. A new trans-vaginal probe and biopsy guide for oocyte retrieval. Fertil Steril. 1987;47:350.
13. Lavy G, Restropo-Candelo J, Diamond M, Shapiro B, Grumbeld L, DecherneyAH. Laparoscopic and transvaginal ova recovery: the effect on ova quality. Fertil Steril. 1988;49:1002.
14. Marrs R. Does the method of oocyte collection have a major influ­ence on IVF? Fertil Steril. 1986;46:193.
15. Scott RT Jr, Hofmann GE. Prognostic assessment of ovarian reserve. Fertil Steril. 1995;63:1–11.
16. Bancsi LF, Broekmans FJ, Mol BW, Habema JD, te Velde ER. Per­formance of basalfollicle-stimulatinghormoneinthepredictionof poor ovarian response and failure to become pregnant after in vitro fertilization: a meta-analysis. Fertil Steril. 2003;79:1091–1100.
17. Hendriks DJ, Mol BW, Bancsi LF, te Velde ER, Broekmans FJ. Antral follicle count in the prediction of poor ovarian response and pregnancy afterinvitro fertilization; ameta-analysisand com­parison with basal follicle-stimulating hormone level. Fertil Steril. 2005;83:291–301.
18. Lockwood GM,Mutuukrishna S,LedgerWL.Inhibinsandactivins in human ovulation, conception and pregnancy. Hum Reprod Update. 1998;4:284–295.
19. Klein NA, Illingworth PJ, Groome NP, McNeilly AS, Battaglia DE, Soules MR. Decreased inhibin B secretion is associated with the monotropic FSH rise in older, ovulatory women: a study of serum and follicular fluidlevelsofdimericinhibinAandBin spontaneous menstrual cycles. J Clin Endocrinol Metab. 1996;81:2742–2745.
20. Muttukrishna S,Child T,LockwoodGM,GroomeNP,BarlowDH, Ledger WL. Serum concentrations of dimeric inhibins, activin A,
gonadotrophins and ovarian steroids during the menstrual cycle in older women. Hum Reprod. 2000;15:549–556.
21. Seifer DB, Scott RT Jr, Bergh PA, et al. Women with declining ovarian reserve may demonstrate adecreasein day 3 seruminhibin B before a rise in day 3 follicle-stimulating hormone. Fertil Steril. 1999;72:63–65.
22. Durlinger AL, Visser JA, Themmen AP. Regulation of ovar­ian function: the role of anti-Mullerian hormone. Reproduction. 2002;124:601–609.
23. de Vet A, Laven JS, de Jong FH, Themmen AP, Fauser BC. Anti­mullerian hormone serum levels: a putative marker for ovarian aging. Fertil Steril. 2002;77:357–362.
24. Cook CL, Siow Y, Taylor S, Fallat ME. Serum mullerian-inhibiting substance levels during normal menstrual cycles. Fertil Steril. 2000;73:859–861.
25. Higgins RV, van Nagell JR Jr, Woods CH, Thompson EA, Kryscio RJ.Interobserver variation inovarianmeasurementsusing transvaginal sonography. Gynecol Oncol. 1990;39:69–71.
26. Syrop CH, Willhoite A, Van Voorhis BJ. Ovarian volume: a novel outcome predictor for assisted reproduction. Fertil Steril. 1995;64:1167–1171.
27. Lass A, Skull J,McVeigh E, Margara R, Winston RM. Measurement of ovarian volume by transvaginal sonography before ovulation induction with human menopausal gonadotrophin for in-vitro fertilization canpredictpoor response. Hum Reprod.1997;12:294–
297.
28. Sharara FI, McClamrock HD. The effect of aging on ovarian vol­ume measurements in infertile women. Obstet Gynecol. 1999;94: 57–60.
29. Ruess ML, Kline J, Santos R, Levin B, Timor-Tritsch I. Age and the ovarian follicle pool assessed with transvaginal ultrasonography. Am J Obstet Gynecol. 1996;174:624–627.
30. Meldrum DR, Wisot A, Hamilton F, Gulary AL, Huynh D, Kempton W. Timing of initiation and dose schedule of leupro­lide influencesthe timecourse of ovarian suppression. Fertil Steril. 1988;50:400–402.
31. Scott RT, Navot D. Enhancement of ovarian responsiveness with micro-doses of GnRH agonist during ovulation induction for in vitro fertilization. Fertil Steril. 1994;61:880–885.
32. Scott RT, Hofmann GE, Muasher SJ, Acosta AA, Kreiner DK, Rosenwaks Z. A prospective randomized comparison of single and double lumen needles for transvaginal follicular aspiration. J In Vitro Fert Embryo Transfer . 1989;6:98–101.
33. Kingsland CR,Taylor CT,AzizN, BiskertonN.Isfollicularflushing necessary for oocyte retrieval? A randomized trial. Hum Reprod. 1991;6:382.
34. Tan SL, Waterstone J, Wren M, Parsons J. A prospective random­ized study comparing aspiration only with aspiration and flushing for transvaginal ultrasound directed oocyte recovery. Fertil Steril. 1992;58:356–360.
35. Hayes MF, Succo AG, Savoy-Moore RT, Magyar DM, Endler GC, Moghissi KS. Effectofgeneralanesthesia on fertilization andcleav­age of oocytes in vitro. Fertil Steril. 1987;48:975–981.
36. Soussis I, Boyd O, Paraschos T, Duffy S, Bower S, Troughton P, Lowe J, Grounds R. Follicular fluid levels of midazolam, fen­tanyl and alfetanyl during transvagianl oocyte retrieval. FertilSteril 1995;64:1003–1007.
37. Coetsier T, Dhont M, DeSutter P, Merchiers E, Versichelen L, Rosseel MT. Propofol anesthesia for ultrasound guided oocyte retrieval: accumulation of the anesthetic agent in follicular fluid. Hum Reprod 1992;7:1422.
38. Van Os HC, Roozenburg BJ, Janssen-Caspers HA, Leerentveld RA, Scholtes MC, Zeilmaker GH, Alberda AT. Vaginal disinfectionwith povidone iodine and the outcome of in-vitro fertilization. Hum Reprod 1992;7:349–350.
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39. Biljan MM, Dean N,HemmingsR, Bissonnette F, Tan SL.Prospec­tive randomized trial of the effect of two flushing media on oocyte collection and fertilization rates after in vitro fertilization. Fertil Steril. 1997;68:1132–1134.
40. Howe RS, Wheeler C, Mastroianni L Jr, Blasco L, Tureck R. Pelvic infection aftertransvaginal ultrasound-guided ovumretrieval. Fer- til Steril 1988;49:726–728.
41. Curtis P, Amso N, Keith E, Bernard A, Shaw RW. Evaluation of the risk of pelvic infection following transvaginal oocyte recovery. Hum Reprod 1992;7:625–626.
42. Ashkenazi J, Farhi J, Dicker D, Feldberg D, Shalev J, Ben-Rafael Z. Acute pelvic inflammatory disease after oocyte retrieval: adverse effects on the results of implantation.Fertil Steril 1994;61:526–528.
43. Yaron Y, Peyser MR, Samuel D, Amit A, Lessing JB. Infected endometriotic cysts secondary to oocyte aspiration for in vitro fertilization. Hum Reprod 1994;9:1759–1760.
44. Nargund G, Parsons J. Infected endometriotic cysts secondary
to oocyte aspiration for in vitro fertilization. Hum Reprod 1995; 10:1555.
45. Bennett SJ, Waterstone JJ, Cheng WC, Parsons J. Complication of transvaginal ultrasound-directed follicle Aspiration. A review of 2670 consecutive procedure. J Assist Reprod Genet 1993;10:72.
46. Dicker D, Ashkenazi J, Feldberg D, Levy T, Dekel A, Ben-Rafael Z. Severe abdominal complication after transvaginal ultrasono­graphically guided retrieval of oocytes for in vitro fertilization and embryo transfer. Fertil Steril 1993;59:1313–1315.
47. Serour GI, Aboulghar M, Mansour R, Sattar MA, Amin Y, Aboul­ghar H. Complications of medically assisted conception in 3500 cycles. Fertil Steril 1998;70:638–642.
48. Hurley V, OsbornJ,LeoniM, Leeton J. Ultrasound-guided embryo transfer: a controlled trial. Fertil Steril 1991;55: 559–562.
49. Soliman S, Daya S, Collins J, Hughes EG. The role of luteal phase support in infertility treatment: a meta-analysis of randomized trials. Fertil Steril. 1994;61:1068–1076.
Section 7.4. Ultrasonography and the Embryo Transfer
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Eric Flisser and Jamie A. Grifo
The original description of the “clinical touch” transfer technique described advancing theembryo transfer cathetertipuntilcontact was madewith the uterine fundus andsubsequently withdrawing the catheter 5 to 10 mm before expelling the embryos. However, as follow-up studies on transfer technique have demonstrated the toxic consequences of provoking intrauterine bleeding and the effect of induced uterine contractions, increased emphasis has been placed on atraumatic technique. Because contact with the uterinefundus isnow avoided, the definition of clinical touch transfer has subsequently evolved to include transfers in which contact with the uterine fundus isavoided, but additional machi­nations to identify catheter position, namely ultrasonography, is not performed. This technique, sometimes described as “blind” because visual confirmation of the location of catheter tip is not made, relies on the operator’s subjective sense of catheter place­ment and other visual cues, such as depth markings placed at regular intervals along the catheter, for successful execution.
Ultrasonography as an adjunct to embryo transfer was employed early in the experience of human IVF, but this aspect of assisted reproductive technology did not garner much interest until vast improvements in other aspects of IVF, such as cul­ture techniques, were made. The possibility that this seemingly innocuous step could undermine the complex process that pre­ceded it had been noted, but efforts to assess the utility of ultra­sonography during embryo transfer were lacking. The first study to illuminate the possibilities of ultrasonography and highlight the pitfalls of blind embryo transfer techniques compared 12 transfers performed by clinical touch to 16 using transabdominal ultrasonography.[1] When ultrasonography was performed, the catheter was introduced into the uterine cavity until it was seen curling as a result of contact with the fundus, and then it was withdrawn slightly. In three of 16 transfers guided by ultrasonog­raphy (18.8%), the catheter was observed abutting the posterior wall of the uterus after the operator had deemed the placement satisfactory. The practitioner was unaware of the poorly posi­tioned catheter until alerted by the ultrasound findings, which suggested that clinical cues to catheter position might be insuffi­cient. Ultrasound-assisted transfer was subjectively easier to per­form, though this might have stemmed from operator bias, and less bloodor catheter distortion was observed.The authors noted that they did not have statistical proof that this was a superior method of embryo transfer in the small number of subjects stud­ied, but they recognized further investigation was needed.
The unreliable nature of traditional catheter placement was also revealedinatransvaginalultrasonography studythatdemon­strated transfer catheters abutting the fundus in 17.4% and adja­cent to a tubal ostium in 7.4% of 121 consecutive transfers.[2] Whether complex manipulations required to place the transfer
catheter, remove the speculum, and introduce the vaginal probe played a role in the final catheter location is a possibility, nev­ertheless, the practitioner was unaware of the catheter’s location relative to anatomic landmarks.
ALTERNATE USE OF TRANSABDOMINAL ULTRASONOGRAPHY (NOT ONLY FOR EMBRYO TRANSFER)
The use of ultrasound has typically been to confirm the correct placement of the transfer catheter tip, yet other applications are available. One study assessed whether pretransfer measurement of the uterocervical angle, an angle defined by a line aligning the external and internal cervical os and another line extending from the internal os through the fundus, would have an effect on trans­fer outcome.[3] This quasi-randomized study allocated patients on an alternating basis to ultrasound-assisted or “clinical feel” embryo transfer. Transfers done without ultrasonography were done with straight catheters; those performed after ultrasound assessment of the uterocervical angle had the transfer catheter bent to mimic the degree of flexion. A Frydman TDT catheter was used in all cases by first placing the rigid outer sheath with its obturator, then replacing the obturator with the flexible inner catheter for embryo transfer.
A marked improvement in pregnancy rate was demonstrated when the angle was measured and the outer sheath molded to mimic the degree of bend before transfer (26.3 vs. 18.4%, P ≤ 0.02). The study observed a significant decrease in the pres- ence of blood in the transfer catheter in the ultrasound group (26.3% vs. 33.4%, P 0.05) as well as proportionally fewer diffi­cult transfers (8.4% vs. 26.8%, P 0.00001). However, whether this result arose from the use of ultrasonography or from bend­ing the transfer catheter is unclear, and whether the difficulty of transfer was a preexisting characteristic of these patients, because allocation was not truly random, remains a possibility. Itis possi­ble that placing a bend in the transfer catheter permits it to more easily seek a path of least resistance, self-guiding its trajectory through the cervical canal. Without a bend, the straight catheter might resist conforming to the contour of the canal, abrading the endocervix and initiating bleeding. Because the uterocervi­cal angle was not measured in the control group, it is unclear whether these patients had a higher proportion of steep utero­cervical angles and if they would have benefited from a molded catheter by comparison.
A significantly higher rate of volsellum forceps use was observed in the control group (9.7% vs. 1.6%, P ≤ 0.00001), which might have contributed to the study outcome, given the
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possibility of induced uterine contractions. The authors demon­strated that a wider uterocervical angle was associated with a decreased chance of pregnancy. If ultrasound had been per­formed in both groups, measurement of the uterocervical angle and the consequence of pretransfer catheter preparation could have been more clearly assessed. The study authors, however, did not compare an association with degree of difficulty and the ute­rocervical angle, though difficult transfers alone were not more likely to lead to pregnancy failure. The presence of blood in the catheterwasassociatedwithdecreasedpregnancyrates,asinother studies (OR 0.54; 95% CI, 0.35–0.84). The study suggests that placing a bend in the transfer catheter may facilitate its ease of placement, particularly in cases in which a significant degree of anteflexion or retroversion is suspected or has been previously observed.
The Catheter
Many studies have attempted to determine the optimal embryo transfer catheter.[4–8] Data have been conflicting, though trans­fer techniquesnow favor use of flexible catheters and minimizing cervical manipulation. Atraumatic transferincludes avoidance of contact with the uterine fundus that might provoke uterine con­tractions. The optimal catheter is one that can be reliably and accurately placed with a minimum of tissue trauma.
Ultrasonography has been used as an adjunct in some of these studies. A comparison of the Wallace and Frydman catheters demonstrated no significant difference between catheters when the choice of catheter was initially selected based on trial transfer before the start of ovarian stimulation.[8] During the trial trans­fer, Wallace catheters were used and if successfully placed, slated for use at the time of embryo transfer; if the catheter could not be passed easily, the Frydman catheter was selected. At the time of transfer, 6.5% of patients in the Wallace transfer group were switched to theFrydman catheter becauseof difficulty at transfer. The clinical pregnancy rates (41.6% vs. 36%) and implantation rates (16% vs. 14.4%) were not significantly different between groups, but showed a trend favoring transfer with the Wallace catheter, which might be more clearly revealed in a larger study. Blood, however, was seen on thecatheter morefrequentlywiththe Frydman catheter (7.9% vs. 12.6%, P = 0.02). All transfers were done underultrasound guidance. Because this study wasnot ran­domized and results not analyzed on an intention-to-treat basis, it cannot directly compare whether these catheters yield equiva­lent results or whether prestimulation trial transfer can improve ease of transfer, but suggests that Wallace catheters may be supe­rior, and that additional manipulations to assist transfer with this catheter, such as having the patient maintain a full bladder or using a tenaculum to straighten the uterocervical angle, may be warranted.
In a quasi-randomized study of transabdominal ultrasound­guided embryo transfer, the Wallace and Frydman transfer catheters were compared; randomization for the use of ultra­sound was done by availability of the ultrasonographer, and the transfer catheter was chosenby the embryologist.[9] TheWallace and the Frydman catheters yielded similar pregnancy rates (30.3% and 30.7%, respectively).
As technicalimprovements such as the introduction of “soft” embryo catheters have added to improved outcomes, changes in design, such asimproved echogenicity of these catheters, may also
Figure 7.4.1. Sureview catheter visualized on transabdominal ultra­sonography.
enhance their utility(Figure7.4.1). Whether these design changes improve outcomes, or simply provide additional reassurance for the operator, has yet to be conclusively demonstrated.
One observational study anecdotally reported subjective improvement in visualization of a specially designed flexible coaxial catheter, the Cook Echo-Tip catheter, in 20 embryo transfers.[10] However, no comparisons were made during the study, and whether improvedultrasound visualization would lead to improvedtransfer outcomes was not investigated.The specially designed catheter used an echogenic, stainless steel ring imbed­ded in the distal tip of the inner catheter. The authors postulated that decreased manipulation of the inner catheter in attempts to visualize the catheter during ultrasonography would cause less disruption and trauma to the endometrium and might subse­quently lead to improved outcomes. The sawing motion, they reported, variously employed to identify traditional catheters, might promote endometrial trauma. The authors also suggested that this back-and-forth technique used to assist visualization of the standard catheter might nullify gains achieved by employ­ing ultrasound guidance, and might account for studies demon­strating equivalence in outcomes when ultrasound guidance is tested against blind transfer techniques. However, although vig­orous catheter movements might traumatize the endometrial lin­ing, slight to-and-fro movements of the catheter may not be any more damaging than complete withdrawal and replacement of the catheter, as performed in the case of retained embryos.
A quasi-randomized comparison study of 251 patients com­paring ultrasound assistance using either the Wallace catheter or the Cook Echo-Tip catheter demonstrated no difference in implantation rates (30% vs. 35%) and clinical pregnancy rates (57% vs. 55%).[11] Although the authors reported improved visualization of the specially designed catheter, it was not statis­tically more conspicuous than the standard catheter (100% vs. 95%), though it was subjectively easier to identify during trans­fers with obese patients or when the bladder was insufficiently full. No improvement in outcomes was noted when analysis by degree of technical difficulty was performed. Although no differ­ence was seen, a power calculationwas not reported;additionally,