Gynecology_Novak

Gynecology_Novak. Transvaginal Ultrasound Compared to hysteroscopy, transvaginal ultrasound has a 75% positive predictive value and 96.5% negative predictive value for intracavitary polyps but a 0% positive predictive value for intrauterine adhesions. Similar to HSG, it has a sensitivity of 44% for uterine malformations (233). However, this may be improved significantly with the use of three-dimensional technology.


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Gynecology_Novak. Sonohysterography Saline infusion sonography (SIS), synonymous with sonohysterography, involves the transcervical instillation of saline, often via a balloon catheter, during transvaginal ultrasound to distend the uterine cavity and delineate the endometrium. As with office hysteroscopy and HSG, SIS is performed during the follicular phase of the cycle and anesthesia typically is not required. Endometrial polyps appear as hyperechogenic pedunculated lesions, submucous fibroids have mixed echogenicity, and adhesions contain densely echogenic and cystic areas (234). Compared to hysteroscopy, SIS has 100% sensitivity, specificity, and


Gynecology_Novak

Gynecology_Novak. Congenital Anomalies of the Uterus positive and negative predictive values for uterine polyps (233). Because of a smaller volume of distension media used, SIS is generally better tolerated than HSG or hysteroscopy (231,234). Another advantage of SIS is the ability to evaluate the myometrium and the adnexa for fibroids or adenomyosis. When combined with three-dimensional technology, SIS is particularly good at assessing the overall uterine contour and delineating congenital anomalies such as septate uteri (234). Standard SIS has somewhat lower sensitivity of 77.8% in detecting uterine congenital anomalies when compared to hysteroscopy, but this is higher than both two-dimensional transvaginal ultrasound and HSG. Hysterosalpingogram and SIS perform similarly for intrauterine adhesions, each having approximately 50% positive predictive value and greater than 90% negative predictive value (233).


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Gynecology_Novak. Magnetic Resonance Imaging Although transvaginal ultrasound, HSG, SIS, and hysteroscopy may suggest congenital uterine anomalies, pelvic MRI is considered the gold standard for imaging and is particularly useful for diagnosing rudimentary uterine horns (235). Pelvic MRI has the best sensitivity and specificity for intramural and submucous myomas compared to pathologic examination and is especially useful for detecting large or multiple fibroids (236,237). MRI has been suggested as a tool to differentiate fibroids from adenomyosis, but routine substitution for ultrasound is not recommended (237,238).


Gynecology_Novak

Gynecology_Novak. Congenital uterine anomalies occur in 3% to 4% of women. This increases to 5% to 10% in women with early pregnancy loss and up to 25% in those with second and third trimester pregnancy losses (235). During female embryonic development, the paired paramesonephric or m¨ullerian ducts elongate toward each other and fuse in the midline. This is followed by resorption of the intervening septum to form the upper vagina, cervix, uterus, and fallopian tubes by week 20 of gestation. Failure of any of these steps leads to absent uterine development or development of unicornuate, bicornuate, arcuate, didelphic, or septate uteri. Because of the proximity of the paramesonephric ducts to the urinary system, renal anomalies often coexist with m¨ullerian anomalies. Appropriate urologic imaging should be performed whenever a m¨ullerian anomaly is diagnosed (235,239). Uterine anomalies are more closely associated with pregnancy wastage and poor obstetric outcomes than with infertility, as the


Gynecology_Novak

Gynecology_Novak. be performed whenever a m¨ullerian anomaly is diagnosed (235,239). Uterine anomalies are more closely associated with pregnancy wastage and poor obstetric outcomes than with infertility, as the prevalence of congenital uterine defects is generally similar among fertile and infertile women. The exception to this is m¨ullerian agenesis. Patients with m¨ullerian agenisis can have genetically related children only through the use of IVF and a gestational carrier. The arcuate uterus is the mildest congenital uterine anomaly and typically live birth rates are comparable to those in women with normal uteri (235). Surgical uterine repair to improve obstetric outcomes is controversial for most anomalies. However, rudimentary uterine horns require removal on diagnosis, and hysteroscopic metroplasty of the septate uteri significantly reduces the rates of pregnancy loss, but not infertility (235,240). The number of reproductive-age patients presenting with in utero exposure to DES is declining


Gynecology_Novak

Gynecology_Novak. of the septate uteri significantly reduces the rates of pregnancy loss, but not infertility (235,240). The number of reproductive-age patients presenting with in utero exposure to DES is declining rapidly and will continue to decline in the future, because the substance was banned in 1971. Women whose mothers were exposed to DES have higher rates of uterine malformations (e.g., T-shaped uterus) and associated obstetric complications (235).


Gynecology_Novak

Acquired Abnormalities of the Uterus

Gynecology_Novak. Acquired Abnormalities of the Uterus


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Gynecology_Novak. Leiomyomas Leiomyomas, also called myomas or fibroids, are benign monoclonal uterine myometrial tumors that affect 25% to 45% of reproductive-age women, particularly African Americans (241). The mechanisms by which fibroids cause infertility are unknown, but may involve altered uterine contractility, impaired gamete transport, or endometrial dysfunction (242). Among women with infertility and uterine leiomyomas, pregnancy rates are primarily affected by leiomyoma location (236,242). Subserosal fibroids do not appear to affect fertility or obstetric outcomes, while intramural (regardless of cavity distortion) and submucosal myomas are associated with lower implantation and live birth rates (236,242,243). It remains unclear whether the size of intramural fibroids determines pregnancy rates and obstetric outcomes, because lower or unchanged pregnancy rates have been reported among patients with fibroids of varying sizes including >2cm, >4cm, or 4–8 cm when compared to patients without


Gynecology_Novak

Gynecology_Novak. and obstetric outcomes, because lower or unchanged pregnancy rates have been reported among patients with fibroids of varying sizes including >2cm, >4cm, or 4–8 cm when compared to patients without fibroids (242).


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Gynecology_Novak. Myomectomy In women desiring fertility who require treatment for fibroids, myomectomy is the preferred approach, and uterine artery embolization is relatively contraindicated (242). Removal of cavity-distorting intramural and submucous myomas is generally recommended prior to proceeding with infertility treatment. The utility of surgical removal of non-cavity-distorting intramural fibroids is presently unknown (236,242, 243).


Gynecology_Novak

Gynecology_Novak. Myomectomy can be performed hysteroscopically, via laparotomy, laparoscopically (alone or with robotic assistance), or vaginally (237,241,244–246). Hysteroscopic removal is generally preferred for small submucous fibroids without intramural involvement, while use of the other methods generally depends on patient preference, operator skill, or the presence of other pelvic pathology (237,241,244,245). The utility of pretreatment with GnRH agonists prior to surgery is debatable. GnRH agonists may shrink larger fibroids (5 to 6 cm) enough to allow hysteroscopic resection and may decrease the risk of intraoperative blood loss and postoperative anemia. Fluid overload and uterine perforation are the most common complications of hysteroscopic myomectomy, while bleeding and adjacent organ injury are more often associated with alternative approaches (237,241). Fibroids that are located low on the uterus and posteriorly are less amenable to laparoscopic resection. Transmyometrial approaches


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Gynecology_Novak. are more often associated with alternative approaches (237,241). Fibroids that are located low on the uterus and posteriorly are less amenable to laparoscopic resection. Transmyometrial approaches raise concern for uterine rupture during pregnancy, although this risk appears to be very low (241).


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Gynecology_Novak. Endometrial Polyps The incidence of asymptomatic endometrial polyps among women with infertility has been reported to range from 6% to 8%, but may be as high as 32% (247–249). Risk factors for polyp development include obesity, unopposed estrogen exposure, and polycystic ovary syndrome. The mechanisms by which endometrial polyps may impair fertility are incompletely described but may relate to disordered endometrial receptivity (250). One report localized 32% of endometrial polyps in infertile women to the posterior uterine wall, indicated that 40.3% of patients had multiple polyps, and stated a 6.9% hyperplasia rate (251). Polypectomy is generally performed via curettage, blind avulsion, or hysteroscopic removal (249). Although the efficacy of polypectomy prior to infertility treatment has not been clearly established, a prospective randomized trial showed a 2.1-fold higher rate of pregnancy among women who underwent the procedure prior to IUI (249,252). Higher pregnancy rates have


Gynecology_Novak

Gynecology_Novak. has not been clearly established, a prospective randomized trial showed a 2.1-fold higher rate of pregnancy among women who underwent the procedure prior to IUI (249,252). Higher pregnancy rates have been noted for polyps removed from the uterotubal junction when compared to those removed from other locations (251). Smaller nonrandomized studies provide conﬂicting data on the negative fertility effects of polyps less than 1.5 to 2 cm (251,253,254).


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Gynecology_Novak. Intrauterine Synechiae or Asherman’s Syndrome Severe trauma to the basalis layer of the endometrium with subsequent tissue bridge formation leads to intrauterine synechiae or Asherman’s syndrome. Symptoms of severe disease include amenorrhea, menstrual irregularities, spontaneous abortion, and recurrent pregnancy loss. The causes of intrauterine adhesions are often iatrogenic, with patients typically reporting intraoperative or postoperative complications of uterine evacuations for incomplete pregnancy loss, pregnancy termination, or postpartum hemorrhage. Myomectomy, hysterotomy, diagnostic curettage, cesarean section, tuberculosis, caustic abortifacients, and uterine packing are less-common causes in Western countries (255). In developing countries, Asherman’s syndrome resulting from genital tuberculosis is quite common (256). Hysteroscopic resection of synechiae is the preferred treatment to restore fertility in women with Asherman’s syndrome, and success rates are generally very


Gynecology_Novak

Gynecology_Novak. tuberculosis is quite common (256). Hysteroscopic resection of synechiae is the preferred treatment to restore fertility in women with Asherman’s syndrome, and success rates are generally very high. Patients with genital tuberculosis have a very poor prognosis. Postoperative prevention of adhesion reformation disease may involve estrogen therapy alone for 1 month or in combination with intraoperative placement of an intrauterine device (such as a small Malecot catheter or pediatric Foley catheter) for 1 to 2 weeks. There is no standard regimen for estrogen therapy, but oral conjugated estrogens 2.5 mg daily overlapping with progestin or estradiol valerate 2 mg injections daily have been suggested (255,257).


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Gynecology_Novak. Mechanisms The luteal phase is normally characterized by progesterone secretion by the corpus luteum and appropriate endometrial secretory transformation that allow for embryonic implantation in the endometrium and support of early pregnancy for the first 7 to 8 weeks of gestation (258,259). Luteal phase defect (LPD) is a failure to develop a fully mature secretory endometrium during the implantation window and is thought to account for 4% of infertility (260,261). Proposed mechanisms for LPD include inadequate production of progesterone following ovulation, improper GnRH pulsatility causing insufficient gonadotropin production during the LH surge, and inadequate endometrial responsivity to progesterone (260– 262). ART or gonadotropin ovulation induction medications may induce iatrogenic LPD via disruption of granulosa cells from follicular aspiration and suppression of endogenous LH secretion through a combination of supraphysiologic estradiol levels and GnRH agonist or antagonist


Gynecology_Novak

Gynecology_Novak. LPD via disruption of granulosa cells from follicular aspiration and suppression of endogenous LH secretion through a combination of supraphysiologic estradiol levels and GnRH agonist or antagonist therapy (259,262).


Gynecology_Novak

Gynecology_Novak. Diagnosis Diagnostic criteria for LPD have been varyingly defined, but have included a low mid-luteal phase serum progesterone levels of less than 5 to 10 ng/mL, a delay of 2 days or more in endometrial histology when compared to chronologic cycle day in two or more cycles, a BBT rise lasting less than 11 days, and a shortened luteal phase of less than 14 days (259–261). Unfortunately, the characteristic pulsatile secretion of progesterone during the luteal phase of the menstrual cycle combines with wide temporal variations (even within a 60-to 90-minute time span) to make interpretation of midlueal progesterone levels difficult (258). Similar rates of shortened luteal phase are found in fertile and infertile women, and there is significant variability of luteal phase length from cycle to cycle in an individual woman (261). Finally, there is significant interobserver variability in pathologic interpretation of endometrial biopsies from infertile women, and out-of-phase biopsy results


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Gynecology_Novak. cycle in an individual woman (261). Finally, there is significant interobserver variability in pathologic interpretation of endometrial biopsies from infertile women, and out-of-phase biopsy results poorly discriminate between fertile and infertile women (263,264).


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Gynecology_Novak. Treatment Progesterone therapy is considered standard practice during ART cycles, but is more controversial during non-ART fertility treatments (258,259,262). When used, progesterone supplementation can be administered via oral, vaginal, or intramuscular routes. Intramuscular progesterone is dosed at 25 to 50 mg daily. Most products are delivered in oil, and caution should be used to ascertain the presence of sesame or peanut allergies. Oral micronized progesterone is associated with erratic absorption and decreased bioavailability, so it is typically administered via an off-label delivery route—vaginally 200 to 600 mg daily, and often in divided doses. The side effects of this delivery route, however, can include vaginal discharge and irritation. Other vaginal preparations include a once-daily gel and a 100 mg insert that is given two to three times daily. There remains no consensus regarding the superiority of vaginal versus intramuscular administration. Progesterone therapy


Gynecology_Novak

Gynecology_Novak. a once-daily gel and a 100 mg insert that is given two to three times daily. There remains no consensus regarding the superiority of vaginal versus intramuscular administration. Progesterone therapy typically begins 3 to 4 days following the hCG trigger or LH surge and, if pregnancy occurs, continues for at least 8 to 9 weeks of gestation (258,259,262). Although some progestins can stimulate the androgen receptor, there is no evidence of teratogenicity with the progesterone supplementation described herein (258).


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Gynecology_Novak. Pelvic Factor Endometriosis Endometriosis affects 6% to 10% of all women during their reproductive years but is present in 25% to 50% of infertile women (212,265). It is characterized by the presence of endometrial tissue growing outside the uterine cavity and is found primarily on the peritoneum, ovaries, and rectovaginal septum (265). Fecundability rates in affected patients are estimated at 2% to 10% per month (266). Possible mechanisms for infertility among women with endometriosis include anatomic distortion from adhesions or fibrosis and the known presence of inﬂammatory mediators that exert toxic effects on gametes, embryos, tubal fimbria, and eutopic endometrium (265,266). Laparoscopy for direct visualization remains the mainstay in the diagnosis of endometriosis. The disease is staged laparoscopically according to the Revised American Society for Reproductive Medicine’s classification, with stages III and IV (moderate to severe) including ovarian endometriomas, dense tubal or


Gynecology_Novak

Gynecology_Novak. laparoscopically according to the Revised American Society for Reproductive Medicine’s classification, with stages III and IV (moderate to severe) including ovarian endometriomas, dense tubal or ovarian adhesions, and/or cul-de-sac obliteration (265). However, laparoscopy can miss deep disease that may better be detected by ultrasound (i.e., endometriomas) and rectovaginal examination (267). It is unclear whether the presence of endometriosis negatively affects IVF outcomes, although some reports indicate a worse prognosis for more severe disease (stages III and IV) (221,268).


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Gynecology_Novak. Endometriosis Infertility Managment Hormonal suppression of endometriosis typically has a minimal benefit for endometriosis-related infertility (265). In minimal to mild disease, laparoscopic ablation appears to significantly improve pregnancy rates when compared to diagnostic laparoscopy alone, although there remains some dissent (267,269). One major randomized trial reported 31% versus 17% pregnancy rates over 3 years with a subsequent meta-analysis supporting these findings (265,266,270,271). Although authors have estimated that eight laparoscopies involving treatment of mild or minimal endometriosis would need to be performed for each pregnancy gained, that number is likely to be much higher given that not everyone who undergoes laparoscopy will have endometriosis (267,270). The benefit of surgical management of endometriosis is even less clear for moderate to severe disease, although removal of endometriomas may be indicated prior to IVF when they would interfere with oocyte


Gynecology_Novak

Gynecology_Novak. of surgical management of endometriosis is even less clear for moderate to severe disease, although removal of endometriomas may be indicated prior to IVF when they would interfere with oocyte retrieval (265–267). Endometrioma resection during IVF or ICSI treatment is associated with decreased ovarian function in up to 13% of cases (272,273). Furthermore, 40% of endometriomas recur postoperatively, and conﬂicting reports exist that show increases and decreases in pregnancy and live birth rates after surgery (267,272,273). Therefore, IVF is considered a reasonable first-line therapy for endometriosis-associated infertility because of the short time to pregnancy and avoidance of surgery (221).


Gynecology_Novak

Gynecology_Novak. Adhesions Adhesions may result from sharp, mechanical, or thermal injury, infection, radiation, ischemia, dessication, abrasion, or foreign body reaction. Adhesiolysis improves pregnancy rates by 12% at 1 year and by 29% at 2 years in infertile women with adnexal adhesions. Use of adhesion barriers reduces adhesion formation following laparoscopy and laparotomy, but there is no evidence to date for improvement in pregnancy rates (274,275).


Gynecology_Novak

Gynecology_Novak. Unexplained Infertility Thirty percent of couples are diagnosed with unexplained infertility, in which the basic infertility evaluation reveals normal semen parameters, evidence of ovulation, patent fallopian tubes, and no other obvious cause of infertility. Patients with unexplained infertility may be reassured that even after 12 months of failed attempts, 20% will conceive in the following 12 months and over 50% in the following 36 months. This suggests that in couples with the good prognostic factors of female age less than 30, less than 24 months of infertility, and a previous pregnancy in the same partnership, unexplained infertility may merely reﬂect the lower extreme of normal fertility. It is likely that current technology is limited in terms of diagnosing all causes for infertility, and the utility of evaluations other than basic testing in an infertile couple has yet to be proven (2,150,276).


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Gynecology_Novak. Luteinized Unruptured Follicle Syndrome This condition involves luteinization of a follicle that has failed to rupture and release its oocyte, leading to a normal menstrual cycle but infertility. It is thought to occur in up to 25% of patients with unexplained infertility, more than twice the incidence in fertile women (138). The diagnosis may justify the use of IVF whereby follicles are aspirated and oocyte are retrieved and fertilized in vitro.


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Gynecology_Novak. Immunologic Factors Although serum antiphospholipid antibodies and antithyroid antibodies are more prevalent among patients with unexplained infertility than among fertile women, the presence of antiphospholipid antibodies has not been found to adversely affect IVF outcomes, so screening is discouraged (277,278). The association between the presence of antithyroid antibodies and infertility is inconsistent, so screening is not recommended (279–282). Unexplained infertility has been associated with antisperm antibodies, but the extent to which these antibodies affect fertility treatment outcomes and whether IUI, ICSI, or glucocorticoids should be used remains unclear (280,282,283). A similar lack of consensus exists concerning the assessment of peripheral natural killer cell number and/or activity in infertility patients (276,282).


Gynecology_Novak

Gynecology_Novak. Decreased Endometrial Perfusion Using ultrasound-based endometrial Doppler studies, women with unexplained infertility have been shown to exhibit abnormal endometrial perfusion when compared to fertile women, but, at present, there is no direct link to fertility treatment outcomes and no recommendations to act on these findings (284). Infection C. trachomatis and related clinical and subclinical infections have been discussed in the “Tubal Factor” section. To date, no consistent associations have been reported between chlamydial species, M. hominis, and unexplained infertility in men or women (207,285,286).


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Gynecology_Novak. U. urealyticum and M. genitalium, however, may be more of a concern (287). Prophylactic doxycycline (100 mg twice daily for 4 weeks) given to infertile couples improved pregnancy rates only for those couples in which the male partner was able to clear a ureaplasma infection (288). Antimicrobial prophylaxis is often given for ART, but it is not clear the extent to which clearance of these organisms improves pregnancy rates (287,289). Undiagnosed Pelvic Pathology Following a negative infertility workup, laparoscopy has been proposed to evaluate for peritubal adhesions and endometriosis. However, there is a lack of consensus as to the frequency of these abnormalities in women with unexplained infertility, and many practitioners will forgo laparoscopy in lieu of a few cycles of less invasive interventions in such patients (290–292).


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Gynecology_Novak. Occult Male or Oocyte Factors Occult male factor despite normal semen analysis and oocyte factors, such as premature zona hardening, mitochondrial dysfunction, and/or aberrant spindle formation, has been suggested as a mechanism for unexplained infertility (293).


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Gynecology_Novak. Treatment of Unexplained It is reasonable to discuss no intervention or expectant management with younger patients Infertility presenting with unexplained infertility. Some patients will want to proceed with diagnostic (and potentially therapeutic) laparoscopy. Typical interventions proceed stepwise with superovulation (first with clomiphene or letrozole for three to four cycles, then gonadotropins for three to four cycles) combined with intrauterine insemination, followed by ART (294). ART options for unexplained infertility include conventional IVF, split IVF/ICSI, and full ICSI, even though no male factor has been identified. Risks with clomiphene, letrozole, and non-ART gonadotropins, as well as gonadotropin preparations, have been discussed above.


Gynecology_Novak

Gynecology_Novak. Baseline Ovarian Cysts Prior to beginning therapy, a baseline ultrasound may be performed on cycle day 2 or 3 during menses (or following GnRH agonist suppression) to confirm an optimally thin (<4 mm) endometrium and quiescent ovaries. With clomiphene citrate cycles, the presence of ovarian cysts on a baseline scan was associated with decreased rates of ovulation but not of pregnancy, although cyst size was not predictive of response (295). Ovarian cysts on baseline evaluation have been associated with decreased pregnancy rates in ovulation induction cycles employing gonadotropins (296). In IVF patients, functional (estrogen-producing) cysts are seen in 9.3% of women following GnRH agonist suppression (297). Although nonfunctional ovarian cysts up to 5.3 cm did not affect IVF outcomes, functional ovarian cysts (mean diameter 2 cm and baseline estradiol 180 pg/mL) have been associated with increased gonadotropin requirements (dosing and duration), higher cancellation rates, fewer


Gynecology_Novak

Gynecology_Novak. functional ovarian cysts (mean diameter 2 cm and baseline estradiol 180 pg/mL) have been associated with increased gonadotropin requirements (dosing and duration), higher cancellation rates, fewer retrieved oocytes, poorer embryo quality, and lower pregnancy rates per cycle (9.6% vs. 29.7% in cyst-free cycles) (297,298). Ovarian cysts greater than 10 mm that are seen on the baseline scan tend to resolve spontaneously within 1 to 2 months, and oral contraceptive administration does not appear to hasten their resolution (299). However, oral contraceptive pretreatment prior to GnRH agonist cycles is associated with decreased risk of cyst formation (300). Functional cyst aspiration prior to gonadotropin stimulation, which is commonly performed to expedite initiation of treatment, did not improve IVF outcomes in one large study (297).


Gynecology_Novak

Gynecology_Novak. Superovulation (Controlled Ovarian Hyperstimulation) Unlike ovulation induction, in which the goal is to stimulate the release of a single oocyte in a women who was not previously ovulating, the explicit goal of superovulation (for non-ART or ART purposes) is to cause more than one egg to be ovulated, thereby increasing the probability of conception in women with unexplained infertility (136). In most superovulation protocols, a baseline scan is performed on day 2 of the menstrual cycle to assess antral follicle count and the presence or absence of ovarian cysts. Baseline estrogen and progesterone levels are typically obtained on this day (301). Starting daily doses in superovulation cycles are higher for both clomiphene (100 mg for 5 days) and gonadotropins (150 to 300 IU daily) than those used for ovulation induction (111,301,302). Superovulation with clomiphene is otherwise conducted as described above for ovulation induction. When gonadotropins are used for normal responders with


Gynecology_Novak

Gynecology_Novak. used for ovulation induction (111,301,302). Superovulation with clomiphene is otherwise conducted as described above for ovulation induction. When gonadotropins are used for normal responders with unexplained infertility, FSH doses of 225 IU and 300 IU lead to similar outcomes with IVF (111). The maximal gonadotropin dosage is typically 450 IU per day because higher dosages do not increase ovarian response (301). In most superovulation protocols, gonadotropins are started on day 2 or 3 of menses (301–303). The starting dose of gonadotropins is maintained each day until cycle day 6 or 7 (stimulation day 4 or 5), when the serum estradiol level and transvaginal ultrasound are first measured to document ovarian response (111,302,303). Gonadotropin dosage is increased by 50 to 100 IU per day every 2 to 4 days until a response is evident (304). Estradiol levels typically double every 48 hours, with follicle growth of 1 to 2 mm daily after a 10 mm diameter is reached (305). Triggering of


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Gynecology_Novak. every 2 to 4 days until a response is evident (304). Estradiol levels typically double every 48 hours, with follicle growth of 1 to 2 mm daily after a 10 mm diameter is reached (305). Triggering of ovulation typically occurs when at least two follicles have reached an average diameter 17 to 18 mm and the endometrial thickness is 8 mm or more (111,302,303,306–308). For non-ART cycles, cancellation should be strongly considered for E2 levels 1,000 to 2,500 pg/mL, for three or more follicles 16 mm or more, or for two or more follicles 16 mm or more plus two or more follicles 14 mm or more (141). Ultrasound monitoring of IVF cycles without estradiol levels can be considered (309).


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Gynecology_Novak. Treatment Outcomes It should be noted that pregnancy rates in unexplained infertility patients vary widely among studies, even when the same treatments are used, perhaps as a result of heterogeneity in treatment protocols and patient age. Interpretation of data on the use of clomiphene in patients with unexplained infertility is particularly difficult because the studies are heterogeneous and their results conﬂicting (150,151). One meta-analysis of 1,159 participants with unexplained infertility involving seven randomized controlled trials of clomiphene citrate with and without IUI indicated no improvement in pregnancy or live birth rates when compared to no treatment or placebo (151). Still, oral therapies continue to be used, and clomiphene and letrozole have recently been shown to have comparable efficacy when combined with IUI for treating unexplained infertility, with pregnancy rates approximately 18% per cycle (310). Combined therapy with gonadotropins and IUI is more likely to


Gynecology_Novak

Gynecology_Novak. comparable efficacy when combined with IUI for treating unexplained infertility, with pregnancy rates approximately 18% per cycle (310). Combined therapy with gonadotropins and IUI is more likely to result in pregnancy


Gynecology_Novak

Gynecology_Novak. Process of Assisted Reproductive Technologies (9% per cycle) than either superovulation (4%) or IUI (5%) alone (302). Laparoscopy to treat minimal or mild endometriosis is associated with live birth rates similar to those in patients with unexplained infertility who receive COH/IUI (70% over four cycles) (311). In women over the age of 40, non-ART therapies are much less effective and IVF should be offered as an initial or early treatment option (312). Pregnancy rates per cycle for unexplained infertility in women who are less than 40 years old have been grouped by treatment modality and reported as follows: (i) clomiphene/IUI 7.8%, (ii) gonadotropin/IUI 9.8%, and (iii) IVF 30.7% (313). The use of ICSI or splitting sibling oocytes between IVF and ICSI has been proposed as an approach to unexplained infertility patients to diagnose and treat underlying occult male or oocyte factors (293,314). Although ICSI does improve fertilization rates and reduce fertilization failure, no


Gynecology_Novak

Gynecology_Novak. to unexplained infertility patients to diagnose and treat underlying occult male or oocyte factors (293,314). Although ICSI does improve fertilization rates and reduce fertilization failure, no differences have been noted in pregnancy or live birth rates when comparing IVF to ICSI for unexplained infertility (314,315).


Gynecology_Novak

Gynecology_Novak. Cost-Effectiveness According to computerized decision-tree modeling, laparoscopy followed by expected management for unexplained infertility may be cost-effective when compared to no intervention, non-ART treatment, or IVF (294). Given that 15 gonadotropin/IUI cycles are needed to produce one additional pregnancy when compared to intracervical insemination alone, IVF seems a reasonable option (150). In Massachusetts, where insurance companies are required to cover infertility treatment, the cost-effectiveness of IVF in the treatment of unexplained infertility was determined. Couples were randomized to accelerated treatment with three cycles of clomiphene citrate/IUI followed by up to six cycles of IVF if no pregnancy occurred (n = 256) versus conventional treatment with clomiphene/IUI for three cycles, then injectable gonadotropins/IUI for three cycles, then IVF for six cycles (n = 247). Median time to pregnancy was 8 months in the accelerated versus 11 months in the conventional


Gynecology_Novak

Gynecology_Novak. for three cycles, then injectable gonadotropins/IUI for three cycles, then IVF for six cycles (n = 247). Median time to pregnancy was 8 months in the accelerated versus 11 months in the conventional treatment groups. The authors used an average cost per cycle with clomiphene/IUI of $500, with gonadotropin/IUI of $2,500, and assuming IVF costs were less than $17,749 per cycle. They reported that the accelerated treatment protocol resulted in a savings of $2,624 per couple and lowered the per delivery charges by $9,856 compared to conventional treatment regimens. The study concluded that couples with unexplained infertility who have not achieved pregnancy after three cycles of clomiphene/IUI should proceed directly to IVF (313).


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Gynecology_Novak. ART include IVF, ICSI, gamete intrafallopian transfer (GIFT), zygote intrafallopian transfer (ZIFT), cryopreserved embryo transfers, and the use of donor oocytes. Because of improved success rates associated with IVF-embryo transfer, the performance of GIFT and ZIFT has declined in the United States, so this review will focus primarily on IVF and ICSI (316). Both processes involve: Prevention of a premature LH surge Transfer of fresh embryos Cryopreservation of surplus embryos Prevention of Premature Luteinizing Hormone Surge


Gynecology_Novak

Gynecology_Novak. Luteinizing Hormone surge and Premature Luteinization Without GnRH agonist or antagonist suppression, LH surges occur in IVF cycles resulting from high estradiol levels in the early follicular phase. This, in turn, results in a lower oocyte yield and reduced pregnancy rates (317). Spontaneous ovulation prior to oocyte retrieval is reported to occur in 16% of nonsuppressed IVF cycles (318). The premature LH rise typically occurs after 5 to 7 days of stimulation (317). In contrast, premature luteinization is a somewhat misleading term that refers to a rise in serum progesterone (cutoffs vary from 0.8 to 2 ng/mL) observed on the day of hCG administration and occurs in the setting of low LH levels secondary to gonadotropin-suppressive medications (319). The incidence of premature luteinization has been estimated at 6% to 7% when the progesterone cutoff level is set at greater than 1.5 ng/mL, but it may be as high as 35%. Mechanisms underlying premature luteinization may include incomplete


Gynecology_Novak

Gynecology_Novak. has been estimated at 6% to 7% when the progesterone cutoff level is set at greater than 1.5 ng/mL, but it may be as high as 35%. Mechanisms underlying premature luteinization may include incomplete pituitary desensitization, increased granulosa cell receptor sensitivity to LH secondary to aggressive COH or innately poor responders, and/or the presence of multiple follicles each producing a normal amount of progesterone consistent with the late follicular phase (319,320). Although the literature on this subject remains inconsistent, the negative effects of premature luteinization have been attributed to endometrial advancement rather than oocyte or embryonic dysfunction (319–321). Methods proposed to address premature luteinization have included earlier triggering with hCG, less aggressive stimulation protocols, cryopreservation of embryos (freeze-all), and administration of the antiprogestin mifepristone at the time of hCG (320,322).


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Gynecology_Novak. GnRH Agonists Native GnRH is rapidly degraded in the circulation. Commercial preparations of GnRH agonists consist of decapeptides similar to GnRH but for modification at two amino acid residues, which increase both the half-life and the receptor binding affinities (323).


Gynecology_Novak

Gynecology_Novak. Over the course of 10 to 14 days, agonists initially bind to and upregulate pituitary GnRH receptor activity, leading to a ﬂare response of increased gonadotropin secretion. This is followed by receptor desensitization (depleted gonadotropin pools along with rapid uncoupling of the GnRH receptor from its regulatory protein and loss of signal transduction) that suppresses circulating levels of pituitary gonadotropins and, with high doses and prolonged use, eventually decreases GnRH receptor numbers (301,317,323–325). Therefore, prolonged use of GnRH agonists induces a menopause-like state characterized by low estradiol levels and accompanied by common side effects such as hot ﬂashes and moodiness. The ﬂare effect may cause ovarian cyst formation as described in the “Unexplained Infertility” section of this chapter (301). GnRH agonists are commercially available for either depot or daily use and can be administered intranasally (buserelin and nafarelin) or by intramuscular or


Gynecology_Novak

Gynecology_Novak. section of this chapter (301). GnRH agonists are commercially available for either depot or daily use and can be administered intranasally (buserelin and nafarelin) or by intramuscular or subcutaneous injection (leuprolide, triptorelin, or buserelin). Intranasal preparations have lower absorption rates when compared to injectable agonists and are associated with milder suppression (326). Typical starting daily doses of leuprolide are 1 mg, 0.5 mg, or 25 μg (microdose) (324).


Gynecology_Novak

Gynecology_Novak. Gonadotropin-Releasing Hormone Agonist Protocols Some of the more commonly used ART medications and protocols are summarized in Fig. 32.6 and Table 32.8. In the long protocol, a GnRH agonist is started in the luteal phase (day 21) of the previous cycle. This diminishes the GnRH agonists ﬂare effect and suppresses endogenous FSH and dominant follicle selection to promote synchronous follicular growth (317). After 10 to 14 days of GnRH agonist administration, a pelvic ultrasound and estradiol level are used to confirm suppression and gonadotropin stimulation begins. The GnRH agonist is continued (the dose may be halved or unchanged) throughout the cycle until the hCG trigger (317,324). Mean serum progesterone levels on the day of hCG administration using the long protocol are reportedly 0.84 ng/mL (320). The long protocol provides for better oocyte yields and pregnancy rates in normal responders when compared with shorter protocols that use later administration or early cessation of


Gynecology_Novak

Gynecology_Novak. 0.84 ng/mL (320). The long protocol provides for better oocyte yields and pregnancy rates in normal responders when compared with shorter protocols that use later administration or early cessation of agonists (317). Shorter protocols using lower GnRH agonist doses have been advocated for poor responders in whom excessive suppression may be undesirable, perhaps from direct negative effects of the agonist on the ovary (324). However, long protocols, particularly those using single-dose depot rather than daily GnRH agonist formulations, are associated with higher gonadotropin dose and duration, which themselves have been associated with lower pregnancy rates (327–329). Alternatively, GnRH microdose ﬂare protocols have been developed that may improve oocyte yield in poor responders. Microdose ﬂare regimens involve pretreatment with 14 to 21 days of combination oral contraceptives. Four days following the


Gynecology_Novak

Gynecology_Novak. Figure 32.6 In vitro fertilization protocols using gonadotropin-releasing hormone (GnRH) agonist or antagonist with gonadotropins in controlled ovarian hyperstimulation. hCG, human chorionic gonadotropin. cessation of the oral contraceptive pills, a microdose (leuprolide 25 μg) of agonist is added in the early follicular phase to take advantage of the agonist ﬂare effect. Gonadotropin stimulation is initiated 1 to 2 days later while continuing the agonist (324).


Gynecology_Novak

Gynecology_Novak. lix) were developed by modifying the GnRH decapeptide at six positions. They compete with endogenous GnRH for binding to pituitary GnRH receptors. Because they have no agonistic activity, GnRH antagonists lead to almost immediate suppression of FSH and LH and do not require the additional time for pituitary down-regulation that characterizes the GnRH agonists. With prolonged use, GnRH antagonists down-regulate GnRH receptors (323). At this time, the only delivery method available for GnRH antagonist is subcutaneous injection, although orally active agents are in development. GnRH antagonists can be given as 0.25 mg daily doses or as a single 3 mg dose with no difference in outcome (325). The time between daily injections should not exceed 30 hours (301). With single dose regimens, avoidance of multiple injections is attractive, but additional small doses starting 4 days after initial dose are required in 10% of cycles (325). Use of GnRH antagonists in ART protocols is typically begun


Gynecology_Novak

Gynecology_Novak. of multiple injections is attractive, but additional small doses starting 4 days after initial dose are required in 10% of cycles (325). Use of GnRH antagonists in ART protocols is typically begun on day 4 to 7 of stimulation. This timing balances the risk for premature LH surges with the need for initiation of endogenous FSH-mediated follicular recruitment and endogenous estradiol production prior to administration (301,317,325).


Gynecology_Novak

Gynecology_Novak. Follicular Recruitment Although the inciting stimulus is unclear, cohorts of small antral follicles (<2 mm) become responsive to FSH stimulation only after 45 days of initial growth. They are then considered recruitable and begin to slowly enlarge in the late luteal phase of the cycle preceding ovulation. Once the antral follicle grows beyond 10 mm, FSH induces the appearance of LH receptors on the granulosa cells. At that point, somewhat contrary to the 2-cell2-gonadotropin model, LH can exert FSH-like actions on the granulosa cell, including stimulation of aromatase. With complete absence of endogenous LH, such as that seen with hypothalamic hypogonadism, exogenous FSH produces fewer preovulatory follicles, inadequate estradiol, lower ovulation rates, and thinner endometrium when compared to ovaries stimulated with exogenous HMG (FSH and LH). Therefore, in the setting of normal hypothalamic function, it seems likely that even with suppressive therapy, enough endogenous LH is present


Gynecology_Novak

Gynecology_Novak. to ovaries stimulated with exogenous HMG (FSH and LH). Therefore, in the setting of normal hypothalamic function, it seems likely that even with suppressive therapy, enough endogenous LH is present to synergize with exogenous FSH to provide adequate stimulation for recruitment (326).


Gynecology_Novak

Gynecology_Novak. Follicular Waves Seventy-five percent of unstimulated human menstrual cycles have two waves of follicular development: one major wave in which a dominant follicle is selected to the detriment of other follicles and one minor wave during which all follicles undergo atresia. When progesterone is available to block LH, the first wave is typically minor and occurs one day after ovulation in the previous cycle. The subsequent major wave occurs around the time of menses, with the dominant follicle being selected by its ability to reach a diameter of 10 mm by cycle day 6 or 7, which coincides with an estradiol rise that inhibits FSH. One-quarter of cycles will exhibit an additional wave that occurs 2 days prior to menses and may be minor or major. If the dominant follicle regresses or is removed, a new follicular wave begins 2 days later. In light of this, future efforts toward greater synchrony during stimulation might include ablation of the early dominant follicle using aspiration or


Gynecology_Novak

Gynecology_Novak. a new follicular wave begins 2 days later. In light of this, future efforts toward greater synchrony during stimulation might include ablation of the early dominant follicle using aspiration or administration of exogenous estrogen and progesterone during the follicular phase (333).


Gynecology_Novak

Gynecology_Novak. Controlled Ovarian Hyperstimulation The goal of gonadotropin stimulation for ART is the synchronous growth of dominant follicles in quantities greater than that associated with non-ART therapy. FSH is the key hormone in this regard (111). Gonadotropin preparations are described in the “Ovulatory Factor” section, while dosing and the relevance of baseline ovarian cysts are described in the “Unexplained Infertility” section. ART pregnancy outcomes are not affected by the source of FSH, the delivery system, or the route of administration (156). In one recent report, women who were predicted to be normal responders using 225 to 300 IU of FSH required 11 days of stimulation, had 11 to 13 follicles 15 mm or larger on the day of hCG trigger, had a peak E2 level of approximately 2,100 pg/mL, and had 10 to 11 oocytes retrieved, of which 82% to 83% were mature (111). Most investigators suggest that the optimal number of retrieved oocytes in a given cycle is between 5 and 15, and the optimal


Gynecology_Novak

Gynecology_Novak. had 10 to 11 oocytes retrieved, of which 82% to 83% were mature (111). Most investigators suggest that the optimal number of retrieved oocytes in a given cycle is between 5 and 15, and the optimal level of estradiol at the time of hCG administration is between 70 and 140 pg/mL per oocyte or follicle (306,329). It should be noted that the utility of estradiol monitoring during ART is controversial, and that ultrasound monitoring alone may be adequate to maximize pregnancy and live birth rates (309). Cycle cancellation in normal responders occurs in up to 6% of the cycles because of inadequate response and 1.5% of cycles for excessive response (111). Cycle cancellation increases with older age and decreased ovarian reserve, but is reportedly decreased by 2% for every additional 100 IU gonadotropins used (328). There appears to be no benefit of exceeding a total daily gonadotropin dose of 450 IU in any patient (301).


Gynecology_Novak

Gynecology_Novak. Follicle-Stimulating Hormone versus Human Menopausal Gonadotropin Higher androgen and lower progesterone levels on the day of hCG trigger are observed when HMG is used for stimulation rather than FSH alone, indicating a more favorable endocrine profile with HMG (334). Concern has been raised that exogenous LH might be needed to address the sudden decrease in endogenous LH that is associated with GnRH antagonist use and the possible excess endogenous LH suppression in long GnRH agonist protocols (326). However, there is no consensus as to whether the addition of LH to exogenous FSH improves pregnancy and live birth outcomes in women with normal hypothalamic function (156,335,336).


Gynecology_Novak

Gynecology_Novak. Less Aggressive Stimulation Although it reduces cancellation rates, each additional 100 IU of gonadotropins is correspondingly associated with a 2% lower rate of clinical pregnancy and live birth (328). This seems to support the findings of premature luteinization and lower pregnancy rates when more aggressive FSH stimulation protocols are used (320). When comparing normal responders using a ﬂexible antagonist protocol and a fixed FSH dose of 150 IU (mild) to those using conventional FSH doses, implantation rates were maximized when a median of 5 oocytes were retrieved in the mild stimulation group, while 10 oocytes were necessary in the conventional dose group. Outcomes were compromised when more than eight oocytes were obtained in the mild group, and only the high dose group experienced poorer outcomes with low oocyte yield. Pregnancy rates seem to level off or decrease when stimulation is pushed beyond a certain threshold, but this threshold is unknown (329).


Gynecology_Novak

Gynecology_Novak. Combined oral contraceptives (OCs) are commonly taken for 14 to 28 days prior to GnRH analogues to ease cycle scheduling, synchronize follicular development, further prevent LH surges, reduce the incidence of ovarian cysts, and reduce cancellation rates resulting from hyperstimulation (331,337,338). Patients can begin OCs anytime between days 1 and 5 of menses (337). For antagonist cycles, COH begins 2 to 5 days after stopping OCs (irrespective of menses) (331). During long GnRH agonist protocols, the agonist overlaps the final 5 days of OC use, followed by initiation of COH on the second or third day of withdrawal bleeding (300,338). As previously discussed, microdose ﬂare protocols involve pretreatment with 14 to 21 days of OC, followed 4 days later by a microdose of agonist. COH typically starts 1 to 2 days later (324).


Gynecology_Novak

Gynecology_Novak. The progestins norethindrone acetate 10 mg orally daily, medroxyprogesterone acetate 10 mg orally daily, or a single intramuscular dose of progesterone (not specified) can be used in place of an OC in ART cycles, but recommendations on the duration of treatment and the timing of initiation vary widely: a duration of 5 to 20 days and initiation anytime between days 1 and 19 of menses have been reported. A dose of 4 mg of daily micronized 17β estradiol or estradiol valerate has been used in lieu of OCs in ART cycles, with initiation between cycle days 15 and 21 and a duration of 10 to 15 days. Although OC pretreatment for antagonist cycles has been shown to increase both the duration of stimulation and the amount of medication used, its effect on pregnancy rates is controversial (331,337). OC pretreatment during GnRH agonist cycles is associated with higher pregnancy rates than those in cycles without pretreatment (300). Progestin and estradiol pretreatment do not affect live birth


Gynecology_Novak

Gynecology_Novak. OC pretreatment during GnRH agonist cycles is associated with higher pregnancy rates than those in cycles without pretreatment (300). Progestin and estradiol pretreatment do not affect live birth rates in either agonist or antagonist cycles (337).


Gynecology_Novak

Gynecology_Novak. Prenatal vitamins should be given to all infertility patients beginning at least 1 month prior to initiation of infertility treatment. Although aspirin is commonly used during IVF regimens, recent studies have failed to demonstrate beneficial changes in pregnancy rates (339,340). Antimicrobial prophylaxis using doxycycline or azithromycin for both partners is often given during ART cycles, particularly those involving assisted hatching procedures, although these medications have not been clearly associated with improved pregnancy rates (287,289,341). Glucocorticoids given to women during the peri-implantation period may improve pregnancy rates in women with autoimmune disease, those undergoing assisted hatching or frozen/thaw embryo transfers, and in women of advanced maternal age (341). Metformin may limit ovarian hyperstimulation (OHSS) in PCOS patients, but shows no benefit for pregnancy or live birth rates (342).


Gynecology_Novak

Gynecology_Novak. Physiology of Oocyte Maturation Prior to maturation, oocytes are arrested in the prophase stage of meiosis I, also known as the germinal vesicle (343,344). Meiosis I oocytes must reach at least the early antral follicle stage to respond to FSH and be competent to resume meiosis. In vivo, LH receptors on the follicle are induced by FSH during later stages of follicular development (345). Therefore, only fully grown oocytes respond to the LH surge in vivo to begin the cytoplasmic and nuclear maturation that are required for developmental progression toward the metaphase stage of meiosis II. At this point, the developmentally competent oocyte will extrude the first polar body, the oocyte-cumulus complex will detach from the ovarian wall, ovulation will occur, and fertilization is possible (343–346).


Gynecology_Novak

Gynecology_Novak. Oocyte Maturation during Assisted Reproductive Technology Cycles Because spontaneous LH surges occur inconsistently during non-ART gonadotropin cycles and are suppressed in ART cycles, hCG has been used to trigger ovulation. In combination with its long half-life, homology between hCG and LH (identical α subunits) allows for cross-reactivity with the LH receptor and induction of final ococyte maturation and ovulation (347). hCG is derived from urine (5,000 to 10,000 IU intramuscularly) or through recombinant technology (250 μg subcutaneously, equivalent to 5,000 to 6,000 IU of intramuscular urinary product) (156). The half-life of hCG is 2.32 days, compared to 1 to 5 hours for LH (347). Ovulation is typically triggered when at least two follicles are 17 to 18 mm or larger in average diameter (but <24 mm) and the endometrial thickness is 8 mm or more (111,302,303,306–308,348). Similar clinical outcomes have been noted when 5,000 IU or 10,000 IU of hCG (349) and urinary or recombinant


Gynecology_Novak

Gynecology_Novak. (but <24 mm) and the endometrial thickness is 8 mm or more (111,302,303,306–308,348). Similar clinical outcomes have been noted when 5,000 IU or 10,000 IU of hCG (349) and urinary or recombinant preparations are used for triggering (348,350). If there is concern for ovarian hyperstimulation syndrome (OHSS, see below), GnRH agonists can be substituted for hCG to trigger ovulation in antagonist protocols or recombinant LH can be substituted for hCG in agonist protocols; however, both protocols are associated with decreased pregnancy rates in nondonor ART cycles (347,351).


Gynecology_Novak

Gynecology_Novak. Oocyte retrieval is performed via transvaginal ultrasound-guided needle puncture into each follicle followed by aspiration of follicular ﬂuid. Either general anesthesia or intravenous conscious sedation may be used (352). Prophylactic antibiotics such as ceftriaxone are recommended at the time of retrieval (353). The vaginal preparation can be performed either with sterile saline alone or with povidone iodine followed by vigorous saline ﬂushing (354,355). The highest oocyte yield is obtained when oocyte retrieval is performed 36 to 37 hours after the hCG injection. Earlier retrieval (35 hours) is associated with a much lower oocyte yield, and later retrieval risks ovulation; spontaneous follicular rupture appears to occur at a mean of 38.3 hours following hCG administration (348).


Gynecology_Novak

Gynecology_Novak. The rationale and regimens for luteal phase support with progesterone are discussed in the “Uterine Factors” section. The timing for luteal progesterone support varies, but lower pregnancy rates have been noted with initiation prior to oocyte retrieval or later than 5 days following retrieval (356,357). Luteal phase estradiol supplementation is not necessary (358,359) .


Gynecology_Novak

Gynecology_Novak. Following semen collection and sperm processing (described in the “Male Factor” section), sperm are incubated in media for 3 to 4 hours to promote sperm capacitation and the acrosome reaction. Before fertilization, retrieved oocytes are cultured in media. Conventional IVF involves insemination concentrations of 100,000 to 800,000 motile sperm/mL per oocyte with each oocyte in a small droplet of media under oil (9,360,361). For every three cycles done for severe male factor, the use of ICSI prevents one case of fertilization failure when compared to conventional IVF (9). The indications for and the procedure and risks of ICSI are discussed under “Male Factor.”


Gynecology_Novak

Gynecology_Novak. Embryo Development Initial embryo development is typically assessed 15 to 20 hours after insemination or ICSI, when fertilization is characterized by the presence of two pronuclei and the extrusion of the second polar body (9,361,362). Embryos are examined again for cleavage after 24 to 30 hours of culture (9). The first embryo cleavage occurs approximately 21 hours after fertilization, and subsequent divisions occur every 12 to 15 hours up to the eight-cell stage on the 3rd day of embryo development (363). Compaction to form the 16-cell morula occurs on the 4th day of embryo development, and differentiation of the inner cell mass and trophectoderm to form a blastocyst (containing a ﬂuid-filled area called a blastocele) is completed by the 5th or 6th day (364,365).


Gynecology_Novak

Gynecology_Novak. Culture Environment Sequential media systems are preferred during embryo culture to adjust for each stage of embryo development. Prior to compaction, the embryo is under genetic control of the oocyte, it uses a pyruvate-based metabolism, it requires at least a few amino acids, and it prefers a relatively oxygenated environment (though much lower than atmospheric oxygen) similar to that found in the fallopian tube. Following compaction, amino acid needs increase (stable dipeptide glutamine instead of glutamine will avoid toxic ammonium buildup), the embryonic genome is activated, and metabolism requires both glucose and a very low oxygen environment similar as that found in the uterus (363,366). Supplementation of culture media with hyaluron and albumin is beneficial in postcompaction media preparations (363).


Gynecology_Novak

Gynecology_Novak. Extended Culture to Blastocyst Although precompaction human embryos can survive when placed in the uterus, the uterine cavity is a nonphysiological location for them, and there is greater uterine pulsatility during this period that may cause the embryos to be expelled. Therefore, the blastocyst stage represents a more physiologic time for embryo transfer. Since nearly 60% of morphologically normal cleavage embryos but only 30% of blastocysts are chromosomally abnormal, extended culture allows for better selection of embryos with improved quality (364,367).


Gynecology_Novak

Gynecology_Novak. Blastocyst versus Cleavage Transfer Outcomes Comparisons involving equal numbers of transferred embryos demonstrate that blastocyst transfer is associated with lower implantation failure, a higher pregnancy rate, and a 7% higher live birth rate than cleavage stage transfer. This is of particular interest in programs that offer elective single embryo transfer (364,367,368). Given that blastocyst formation rates range from only 28% to 60%, disadvantages of extended culture include the possibility that no embryos will survive to transfer (8.9% vs. 2.8% for cleavage transfer) and a reduced opportunity for embryo cryopreservation. Monozygotic twinning rates may be higher with blastocyst culture, although this has not been a consistent finding (364,369).


Gynecology_Novak

Gynecology_Novak. Criteria for Extended Culture There are no established guidelines or criteria that determine when to utilize extended culture. Varying suggestions include maternal age 42 or younger with five or more two pronuclear stage (2PN) embryos on postretrieval day 1; maternal age of 40 or younger and three or more good-quality day 3 embryos having 4 to 10 cells with less than 15% fragmentation; maternal age of 41 to 42 or younger and four or more good-quality day 3 embryos having 4 to 10 cells with less than 15% fragmentation; and age less than 37 with four or more morphologically good embryos on day 3, or four or more embryos with 6 cells and less than 10% fragmentation (362,364,370). Embryo Morphology Embryo morphology guides the choice of embryo for transfer. Pronuclear embryos are assessed by their distribution and number of nucleoli, the position of the second polar body relative to the first, and cleavage rates (abnormal rates are too fast,


Gynecology_Novak

Gynecology_Novak. Cryopreservation of Embryos too slow, or arrested) (365). Preferred cleavage stage embryos have a normal developmental pattern characterized by early cleavage on day 1, four cells on day 2, and eight cells on day 3. Embryo fragmentation should be 10% or less, the blastomere size should be regular, and there should be no multinucleation (362). The Gardner and Schoolcraft system for scoring blastocysts uses a scale from 1 (worst) to 6 (best), with grades 1 to 3 indicating growth of the blastocele until it completely fills the embryo. Grade 4 blastocysts are expanded with a larger blastocele volume and a thinning zona pellucida. The trophectoderm in a grade 5 blastocyst is starting to hatch though the zona, and the grade 6 blastocyst has completely escaped or hatched from the zona. The inner cell mass is graded A to C based on tightness and cellularity (A is best), and the trophectoderm is assessed from A to C based on cohesiveness and cellularity (A is best) (361).


Gynecology_Novak

Gynecology_Novak. Number of Embryos to Transfer High-order multiple pregnancy (three or more fetuses) increases complications for mothers and fetuses, so guidelines have been developed to minimize this adverse outcome (371). Single embryo transfer should be considered for patients younger than age 35, particularly those undergoing their first ART cycle who have a large quantity of good quality embryos or patients who have conceived in a prior cycle. Otherwise, transfer should be limited to two embryos in women under 35 years of age. For older women, the maximum number of transferred cleavage-stage embryos should be three in women aged 35 to 37, four in women aged 38 to 40, and five in women older than 40 years of age. Because of their high implantation potential, no more than three blastocysts should be transferred to any woman regardless of her age. Limits on the number of embryos transferred when the embryos were created from donor oocytes should be based on the age of the donor, rather than the


Gynecology_Novak

Gynecology_Novak. transferred to any woman regardless of her age. Limits on the number of embryos transferred when the embryos were created from donor oocytes should be based on the age of the donor, rather than the recipient (371).


Gynecology_Novak

Gynecology_Novak. Transfer Procedure The goal of transcervical embryo transfer is to atraumatically deliver the embryos to an optimal intrauterine location for implantation. Implantation is more likely after an easy transfer using a soft catheter and when fundal contact is avoided (353). Trial transfer, although not required, allows advance preparation such as cervical dilation or placement of a traction stitch, although uterine position and depth can be different at the time of the actual procedure. When performed at the time of embryo transfer, trial transfer should not go past the internal os. Trial transfer can be combined with an afterloading technique in which the outer sheath of the transfer catheter is left in place and the transfer catheter is threaded through the trial transfer sheath and into the uterus, although there is no advantage when compared to routine transfer (353,372). Soft catheters such as those made by the Cook or Wallace companies are preferred to rigid catheters to minimize


Gynecology_Novak

Gynecology_Novak. the uterus, although there is no advantage when compared to routine transfer (353,372). Soft catheters such as those made by the Cook or Wallace companies are preferred to rigid catheters to minimize prostaglandin release after cervical and/or endometrial trauma (353). The utility of cervical mucus removal prior to embryo transfer in improving embryo delivery remains controversial (353,372). Although intrauterine infections decrease pregnancy rates, the efficacy of antibiotic administration at the time of transfer is not clear. During a conventional embryo transfer, embryos are suspended in 20 μL of media at the tip of a syringe with air on either side of the ﬂuid. This creates an air–ﬂuid interface easily seen with ultrasound.


Gynecology_Novak

Gynecology_Novak. Abdominal ultrasound visualization during embryo transfer is useful to ensure deposit of the embryos 1.5 to 2 cm from the uterine fundus. Once the embryos are deposited, the inner and outer sheath should be removed as a unit to avoid suction within the device (353). No changes in patient position are necessary (372). Following transfer, the catheter is checked for retained embryos. If present, retained embryos should be transferred because there is no detriment in pregnancy rates (353).


Gynecology_Novak

Gynecology_Novak. Embryo cryopreservation at the pronuclear, cleavage, and blastocyst stages has allowed for multiple transfer cycles from a single oocyte retrieval. Because transfer of cryopreserved embryos is less expensive than a second fresh cycle, overall fertility treatment costs can be optimized. Embryo cryopreservation can be considered as a means to prevent ovarian hyperstimulation syndrome. Techniques for embryo cryopreservation include slow freezing and rapid freezing or vitrification. Slow freezing protocols use lower concentrations of cryoprotectants but are more time-consuming when compared to vitrification, which uses high-concentration cryoprotectants for rapid cooling and is less expensive. Embryo thawing is accomplished by brief exposure to air and warm water followed by rehydration (373). Although pregnancy rates for freeze/thaw transfer (FET) cycles using the two cryopreservation methods are similar, vitrification is associated with higher postthaw embryo survival (93% vs. 76% with


Gynecology_Novak

Gynecology_Novak. Although pregnancy rates for freeze/thaw transfer (FET) cycles using the two cryopreservation methods are similar, vitrification is associated with higher postthaw embryo survival (93% vs. 76% with slow freezing) (374). Infant outcomes are reassuring for slow freezing but are more limited for the newer technique of vitrification (375). Overall, use of frozen embryos results in lower pregnancy rates when compared to fresh transfer cycles, but this may be a result of embryo selection (the best embryos are typically


Gynecology_Novak

Gynecology_Novak. Figure 32.7 Regimens of ovarian stimulation and hormone replacement used to synchronize the development of ovarian follicles in the oocyte donor and the endometrial cycle in the recipient. hCG, human chorionic gonadotropin; OCP, oral contraceptive pill; GnRH-a, gonadotropin releasing hormone antagonist; TVA, ultrasound-guided transvaginal aspiration of oocytes. (Adapted from Chang PL, Sauer MY. Assisted reproductive techniques. Stenchever MA, ed.; Atlas of clinical gynecology, Mishell DR, ed, Reproductive endocrinology. Vol. 3. Philadelphia, PA: Current Sciences Group, 1998, with permission.) used for fresh transfer and lesser quality embryos are frozen) (373,376). Frozen transfer outcomes are heavily dependent on the characteristics of the fresh cycle that generated the frozen embryos; excellent pregnancy rates are noted when the fresh cycle resulted in conception or when all the embryos were frozen from the fresh cycle (376).


Gynecology_Novak

Gynecology_Novak. Endometrial Preparation for Frozen Embryo Transfer When FET is combined with a recipient’s natural cycle, no exogenous treatment is given, and transfer is timed to spontaneous ovulation. In medicated FET cycles, estradiol supplementation begins in the early follicular phase and is continued for 13 to 15 days (373). Multiple estradiol preparations have been described for use in FET cycles, but none has been proven superior (377). Transvaginal ultrasound is used to assess endometrial thickness during estrogen therapy, and estrogen administration continues until an optimal thickness of greater than 8 mm is reached (373). Progesterone supplementation begins 48 to 72 hours prior to transfer when cleavage-stage embryos are used and 6 to 7 days prior to transfer when blastocysts will be thawed (373,377). Again, several progesterone preparations have been described for use in FET cycles, but none has been proven superior (discussed in the “Uterine Factors” section). GnRH agonists are commonly


Gynecology_Novak

Gynecology_Novak. Again, several progesterone preparations have been described for use in FET cycles, but none has been proven superior (discussed in the “Uterine Factors” section). GnRH agonists are commonly used during medicated cycles to prevent premature LH surges that might adversely affect endometrial maturation (377) (Fig. 32.7).


Gynecology_Novak

Gynecology_Novak. The production of hCG by the blastocyst can be detected as early as 7 days posttransfer, and serum quantitative hCG levels may be obtained 11 to 14 days following embryo transfer (373,378). A serum threshold of 200 mIU/mL of hCG measured 12 days after transfer is 92% and 80% predictive of ongoing pregnancies for day 3 and day 5 embryos, respectively, with levels normally rising approximately 40% per day. If normally rising hCG levels are detected, transvaginal ultrasound is planned at 6 to 7 weeks of gestation to determine the location of the pregnancy, the number of gestational sacs, and pregnancy viability (378).


Gynecology_Novak

Gynecology_Novak. Since 1992, all clinics performing ART in the United States have been required to submit annual success rates to the Centers for Disease Control and Prevention (379). Success rates of IVF vary from program to program. The most comprehensive assessment of the efficacy of ART programs in North America comes from the database of the Society for Assisted Reproductive Technology (SART). Information on SART and registered ART clinics are accessible by the public online. Because ICSI and IVF rates are similar, statistical analyses combine them for the annual SART reports. IVF success rates are largely dependent on maternal age, and data from recent studies, including those from SART, are summarized in Table 32.10 (380). SART statistics should not be used to compare IVF clinics since success rates are largely dependent on patient demographics, including the cause of infertility, which will be different for each individual clinic. Lifestyle factors affecting IVF success are discussed under


Gynecology_Novak

Gynecology_Novak. are largely dependent on patient demographics, including the cause of infertility, which will be different for each individual clinic. Lifestyle factors affecting IVF success are discussed under “Causes of Infertility.” Since SART does not publish success rates for non-ART cycles, it can often be helpful for physicians to assist patients in comparing the success rates for clomiphene, gonadotropins, and IVF, although rates vary widely between studies (Table 32.11).


Gynecology_Novak

Gynecology_Novak. A new approach to predicting live birth probabilities focuses on the use of machine learning or the mining of clinic-specific IVF outcomes data to provide a personalized per-cycle prognosis that pertains to the clinical scenario of each patient (381). Brieﬂy, a live birth prediction model was developed by boosted tree analysis of baseline clinical data, uterine response to a patient’s first IVF treatment, and embryo developmental parameters, with no preselection of prognostic factors. The model predicted live birth outcomes in a subsequent IVF treatment cycle. Validation by an independent dataset and comparison with a control model that is based on chronological age alone showed that the boosted tree model was more than 1,000 times better in fitting new data and improved discrimination (i.e., the ability to discern among patients with different prognoses) by receiver–operator curve analysis. Approximately 60% of patients were found to have significantly different predicted live birth


Gynecology_Novak

Gynecology_Novak. the ability to discern among patients with different prognoses) by receiver–operator curve analysis. Approximately 60% of patients were found to have significantly different predicted live birth probabilities when compared to the use of age categories. Further testing across different clinics will be required to determine whether this approach may be generally valid and applicable. Nevertheless, the nonredundant and unique


Gynecology_Novak

Gynecology_Novak. Table 32.10 In Vitro Fertilization Success Rates CPR, clinical pregnancy rate; Birth, live birth rate; SAB, spontaneous abortion, N/A, not available.. From refs. 379,380,420,421,423. Table 32.11 Fertility Treatment Success Rates CC, clomiphene citrate; TI, timed intercourse; IUI, intrauterine insemination; INJ, injectable gonadotropins; IVF, in vitro fertilization. From refs. 313, 379, 380, 418–422. (looks like these are the correct refs) contribution of the patient’s age to predicting outcomes was found to be limited if data pertaining to the response to gonadotropins and embryo development in the first IVF treatment were available. These findings may move prognostic counseling away from an age-centric paradigm and toward a more objective extraction of predictive value from simultaneous analysis of a wide array clinical factors.


Gynecology_Novak

Gynecology_Novak. Cessation of Therapy Patients must be accurately informed of estimated success rates and reasonable expectations for all therapeutic interventions. Patients with a very poor prognosis have a 2% to 5% chance of achieving a live birth with fertility therapy, and those with a futile prognosis have a 1% or less chance. Refusing or limiting therapy may be justified if the risk of intervention outweighs the potential benefits (382).


Gynecology_Novak

Gynecology_Novak. When gametes and the ability to gestate a pregnancy are compromised through circumstances or disease, other reproductive options can be considered. These include use of donor sperm (discussed in “Male Factor”), donor oocytes, donor embryos, a gestational carrier, or a combination of these approaches. In contrast to donor gametes (sperm or oocytes), the decision to donate embryos is typically made after the embryos have been generated and there is a known surplus. A gestational carrier receives and gestates birth embryos created from the intended mother’s oocytes. Patients who choose to utilize a gestational carrier may have irreparable uterine factor infertility or suffer from medical conditions that contraindicate pregnancy. In true surrogacy, the birth mother is the genetic mother but not the intended mother. Legal and psychosocial counseling are suggested for all parties embarking on any form of third party reproduction.


Gynecology_Novak

Gynecology_Novak. Donor Oocyte Patients with ovarian failure, poor oocyte quality, poor ovarian response to stimulation, or failed fertilization or implantation after multiple ART cycles may be candidates to receive donated oocytes. A female same-sex couple may choose to have one partner undergo IVF and place the resulting oocytes fertilized with donor sperm into the other partner (383). At present, donor oocytes must be used to create embryos during the retrieval cycle, because oocyte freezing is considered experimental (384). With carefully selected donors, live birth rates per cycle of donor oocyte IVF are 50% to 60% regardless of the recipient’s age (Table 32.10). However, recipients must be aware that advanced recipient age is associated with higher risk for preeclampsia, diabetes, and cesarean section (385–387). Oocyte donors must endure all the interventions and risks of the ART process described herein except for embryo transfer and luteal support. Because of the intensity of therapy and the


Gynecology_Novak

Gynecology_Novak. (385–387). Oocyte donors must endure all the interventions and risks of the ART process described herein except for embryo transfer and luteal support. Because of the intensity of therapy and the potential infectious disease and genetic risks for donor, recipient, and the resulting offspring, oocyte donors must be screened for infectious and heritable disorders similar to those performed for sperm donors (see “Male Factor”) and undergo meticulous informed consent and a comprehensive psychosocial evaluation. Oocyte donors may be anonymous or known to the recipient (96). Oocyte recipients undergo endometrial preparation (as described in the “Process of Assisted Reproductive Technologies” section), but GnRH analogues are not required if there is no endogenous ovarian function. Recipients may initiate progesterone one day prior, on the same day, or one day after the donor’s oocyte retrieval, but a randomized trial found lower pregnancy rates when progesterone was initiated prior to the


Gynecology_Novak

Gynecology_Novak. initiate progesterone one day prior, on the same day, or one day after the donor’s oocyte retrieval, but a randomized trial found lower pregnancy rates when progesterone was initiated prior to the retrieval (377). Other topics, such as methods for donor recruitment and financial compensation for the donor, are much more challenging issues (388).


Gynecology_Novak

Gynecology_Novak. Complications of Assisted Reproductive Technology Cycle Cancellation Cycle cancellation in normal responders occurs in up to 6% of cycles because of inadequate stimulation response and in 1.5% of cycles because of excessive response (111). In 0.2% to 7% of retrievals, no ooctyes will be obtained. Two proposed explanations include human error during the administration of hCG and early oocyte atresia despite normal follicular response (346). Oocyte Retrieval The risks of oocyte retrieval include bleeding requiring transfusion, injury to adjacent structures requiring laparotomy, formation of a pelvic abscess leading to loss of reproductive function despite prophylaxis, and risks related to anesthesia (389).


Gynecology_Novak

Gynecology_Novak. Multiple Gestation As the majority of ART cycles involve the transfer of more than one embryo, multiple gestation occurs at higher rates than the 3% rate for spontaneous conception. This has social, medical, emotional, and financial ramifications (379,380). Although the majority of complications of multiple gestations occur with high-order (three or more) multiples, twins have increased risks for low birth weight, preterm birth, and neurologic deficits when compared to singletons (380,390). Despite this, 20% of infertile patients view multiple pregnancy as a desired outcome. Because most patients lack insurance coverage for IVF, patients may push their physicians to take greater risks when deciding on the number of embryos to transfer (379). The multiple pregnancy risk is higher in patients under the age of 35 who are undergoing IVF because their embryos are typically of better quality and implantation rates are higher, but multiple pregnancy can occur at any reproductive age (371).


Gynecology_Novak

Gynecology_Novak. under the age of 35 who are undergoing IVF because their embryos are typically of better quality and implantation rates are higher, but multiple pregnancy can occur at any reproductive age (371). From 1998 to 2007, the overall twinning rate in ART cycles remained stable at 29% to 32%, but the rate of high-order multiples decreased from 6% to 2%. In 2007, the live birth rates for twins and triplets or more for women under the age of 35 who underwent ART in the United States were 33.2% and 3.5%, respectively. Women aged 43 or 44 had twinning live birth rates of 10.6% and triplet or more live birth rates of 0.8% (380). Most multiple pregnancies arising from ART are dizygotic, but monozygotic twinning occurs in 3.2% of IVF cycles (compared to a background rate of 0.4%) (379). Concerns have been raised that monozygotic twinning might increase after blastocyst culture, but this finding has not been consistent (364,369). With increasing adherence to guidelines suggesting limitations on the


Gynecology_Novak

Gynecology_Novak. raised that monozygotic twinning might increase after blastocyst culture, but this finding has not been consistent (364,369). With increasing adherence to guidelines suggesting limitations on the number of embryos to transfer in a given ART cycle (discussed in “Process of Assisted Reproductive Technologies”) and improved implantation rates that allow single embryo transfer, the multiple pregnancy rates associated with ART should continue to decrease.


Gynecology_Novak

Gynecology_Novak. Selective Reduction Ten percent of multifetal pregnancies spontaneously lose at least one gestational sac during the first trimester. This loss rate increases to 21% in women older than 35 years of age. The spontaneous reduction rate to twins or singletons is much higher for triplets (14%) than for quadruplets (3.5%) (391,392). Selective pregnancy termination or multifetal reduction may be an option for some patients in whom spontaneous reduction does not occur by 11 to 13 weeks. This involves first karyotyping each fetus through transabdominal chorionic villous sampling to preferentially reduce those that are abnormal, then injecting potassium chloride into the heart of the targeted fetus. Although selective reduction carries a 3% to 7% risk of losing the entire pregnancy when performed prior to 19 weeks, this is still lower than the 15% chance of spontaneously losing an entire triplet pregnancy (390,393). Selective fetal reduction is typically considered for triplet or higher


Gynecology_Novak

Gynecology_Novak. prior to 19 weeks, this is still lower than the 15% chance of spontaneously losing an entire triplet pregnancy (390,393). Selective fetal reduction is typically considered for triplet or higher pregnancies, but even reduction from twins to singletons may have benefit (390).


Gynecology_Novak

Gynecology_Novak. Ectopic and Heterotopic Up to 3.4% of ART pregnancies are ectopic (implantation outside the uterus) and require


Gynecology_Novak

Gynecology_Novak. Pregnancy treatment with either surgery or methotrexate. The absence of an intrauterine pregnancy on transvaginal ultrasound evaluation in conjunction with a maternal serum hCG level above a threshold of 1,500 mIU/mL suggests the diagnosis (394,395). Heterotopic pregnancy involves concurrent intrauterine and ectopic pregnancy, usually within the fallopian tube, but ovarian implantations have been reported (395,396). The incidence of heterotopic pregnancy, which is normally rare, is particularly high (1%) after IVF treatment. Multiple gestation, smoking, previous tubal surgery, and prior PID are potential risk factors in addition to ART. As with standard ectopic pregnancies, pain and bleeding are the most common presenting findings with heterotopic pregnancies. Heterotopic pregnancies are most often diagnosed in the first 5 to 8 weeks of gestation using laparoscopy or laparotomy. Only 26% of heterotopic cases can be diagnosed with transvaginal ultrasound, possibly as a result of


Gynecology_Novak

Gynecology_Novak. are most often diagnosed in the first 5 to 8 weeks of gestation using laparoscopy or laparotomy. Only 26% of heterotopic cases can be diagnosed with transvaginal ultrasound, possibly as a result of difficulties in sonographic interpretation in the presence of concomitant ovarian hyperstimulation. After treatment of a heterotopic gestation with laparoscopy, laparotomy, or ultrasound-guided injection of potassium chloride into the extrauterine pregnancy, the overall delivery rate for the intrauterine pregnancy is nearly 70% (395).


Gynecology_Novak

Gynecology_Novak. OHSS is a medical complication that is both completely iatrogenic and unique to stimulatory infertility treatment (397). Its symptoms are the result of ovarian enlargement and fragility, extravascular ﬂuid accumulation, and intravascular volume depletion. Proposed mechanisms for the characteristic ﬂuid shifts that accompany OHSS include increased protein-rich ﬂuid secretion from the stimulated ovaries, increased renin and prorenin within follicular ﬂuid, and increased capillary permeability mediated by angiotensin. Vascular endothelial growth factor (VEGF), whose expression in granulosa cells and serum is augmented by hCG, and a variety of other inﬂammatory cytokines have been implicated in the pathogenesis of this disease (398). Two distinct patterns of OHSS onset have been described. Early OHSS occurs 3 to 7 days following the hCG trigger and is associated with the administration of exogenous hCG. Late onset disease occurs 12 to 17 days after the hCG trigger; it is the result of


Gynecology_Novak

Gynecology_Novak. Early OHSS occurs 3 to 7 days following the hCG trigger and is associated with the administration of exogenous hCG. Late onset disease occurs 12 to 17 days after the hCG trigger; it is the result of endogenous hCG secretion from the pregnancy and tends to be more severe with multiple gestation. Pregnancy outcomes are inconsistently affected by the presence of OHSS, with higher rates of biochemical losses but similar rates of clinical losses when compared to patients without OHSS (399).


Gynecology_Novak

Gynecology_Novak. Severity Classification Mild OHSS (grades 1 and 2) is associated with high serum estradiol levels and ovarian enlargement to less than 5 cm and has minimal clinical significance. Grade 3 moderate OHSS is accompanied by mild abdominal distention and has minimal clinical significance (397). Grade 3 OHSS occurs in one-third of all COH cycles (398). Grade 4 moderate OHSS is accompanied by gastrointestinal upset and ovarian enlargement to 5 to 12 cm (397). The presence of ﬂuid shifts from intra-to extravascular spaces are the hallmark of severe disease, and grade 5 OHSS includes tense ascites or hydrothorax. Grade 6 OHSS is accompanied by hemoconcentration, coagulation abnormalities, respiratory failure, and renal dysfunction (397). Other markers of severe OHSS include hyponatremia, hyperkalemia, elevated liver function tests, and an elevated white blood cell count (397,398). Concerning symptoms for severe disease include rapid weight gain (≥2 lb per day), increased measurable abdominal


Gynecology_Novak

Gynecology_Novak. elevated liver function tests, and an elevated white blood cell count (397,398). Concerning symptoms for severe disease include rapid weight gain (≥2 lb per day), increased measurable abdominal girth, hypotension, tachypnea, tachycardia, oliguria, and severe abdominal pain. The latter symptom is suggestive of ovarian cyst rupture or hemorrhage (398).


Gynecology_Novak

Gynecology_Novak. Risk Factors Mild OHSS occurs in 13.5% of clomiphene cycles, but more severe disease is rare. With gonadotropin injections, the incidence of moderate disease is 3% to 6% and severe OHSS occurs in 0.1% to 2% of patients. Polycystic ovary syndrome, polycystic ovarian morphology with attendant elevated antim¨ullerian hormone levels (>3.36 ng/mL), and previous episodes of OHSS are major risk factors for the disease; the impact of young age and lean body mass is controversial (351,398,400). Estradiol levels greater than 800 pg/mL on day 9 of stimulation have been associated with a 55.8% risk for the development of OHSS (severity not specified). Estradiol concentrations of greater than 3,500 pg/mL and greater than 6,000 pg/mL at the time of hCG trigger were associated with severe OHSS in 1.5% and 38% of patients, respectively. During antagonist cycles, the presence of 13 or more follicles at 11 mm or greater average diameter was predictive of the development of OHSS. More than 20


Gynecology_Novak

Gynecology_Novak. in 1.5% and 38% of patients, respectively. During antagonist cycles, the presence of 13 or more follicles at 11 mm or greater average diameter was predictive of the development of OHSS. More than 20 preovulatory follicles were associated with a 15% incidence of severe OHSS. When 20 to 29 oocytes were collected at retrieval, 1.4% of patients developed severe OHSS; this raised to 22.7% with 30 or more oocytes (400).


Gynecology_Novak

Gynecology_Novak. Management If outpatient management is appropriate, the patient should be instructed to limit her activity, to weigh herself daily, and to monitor her ﬂuid intake (at least 1 L per day of mostly electrolyte-balanced ﬂuid) and output. Daily follow-up by telephone or visit is important and the patient should be reassessed if she notes worsening of the symptoms or if her weight gain increases to more than 2 lb per day. Indications for hospitalization include an inability to tolerate oral hydration, hemodynamic instability, respiratory compromise, tense ascites, hemoconcentration, leukocytosis, hyponatremia, hyperkalemia, abnormal renal or liver function, and decreased oxygen saturation. Fluid intake and urine output need to be carefully measured, and admission to an intensive care setting can be considered if the patient has hyperkalemia, renal failure, respiratory failure, or thromboembolic disease. Although intravenous ﬂuids may worsen ascities, they are essential to correct


Gynecology_Novak

Gynecology_Novak. setting can be considered if the patient has hyperkalemia, renal failure, respiratory failure, or thromboembolic disease. Although intravenous ﬂuids may worsen ascities, they are essential to correct hypovolemia, hypotension, electrolyte abnormalities, and oliguria. Albumin 25% can be dosed 50 to 100 mg intravenously every 4 to 12 hours if further intravascular volume expansion is needed. Diuretics can be considered to improve weight gain and oliguria only after hypovolemia has been corrected. Thromboembolic prophylaxis should be given. Single or repeated transvaginal or transabdominal ultrasound-guided paracentesis may relieve pain, hydrothorax, or persistent oliguria. Rapid large-volume ﬂuid removal can be considered, as compensatory ﬂuid shifts are unlikely to occur in this typically young healthy population as long as the patient is carefully monitored (398).


Gynecology_Novak

Gynecology_Novak. Prevention No method will prevent OHSS completely, but steps can be taken to decrease risk. Careful gonadotropin stimulation for monofollicular development is discussed under “Ovulatory Factor.” For ART, stimulation protocols for high-risk patients include lower initial COH doses of 150 IU and GnRH antagonists for LH surge prevention, which reduce the total dosage and duration of gonadotropin stimulation (401,402). Reintroduction of GnRH antagonists following retrieval may be of benefit (351).


Gynecology_Novak

Gynecology_Novak. Decreasing the dose of hCG to reduce the incidence of OHSS is controversial (401,402). Exogenous recombinant LH is available for COH, but the dose required to trigger ovulation has not been established (402). The very short half-life of endogenous LH may in turn reduce the incidence and/or severity of OHSS (351). GnRH agonists can be used instead of hCG during antagonist cycles to induce an endogenous LH surge. As GnRH agonist triggers are associated with lower pregnancy rates, these may be a better option for oocyte donors or for patients who are not planning a fresh embryo transfer (351,402).


Gynecology_Novak

Gynecology_Novak. Coasting may be considered when estradiol levels are less than 4,500 pg/mL and/or there are 15 to 30 mature follicles present. During coasting, gonadotropin stimulation is withheld and estradiol levels are checked daily (351). An initial rise of estradiol is typically observed within the first 48 hours of the coast, but the levels should subsequently plateau or decrease (402). The patient may then be triggered when serum estradiol levels fall to less than 3,500 pg/mL. If GnRH agonists are used for initial LH surge suppression, switching to an antagonist during the coast has been associated with improved outcomes (351). The cycle should be cancelled and the trigger withheld if there are greater than 30 mature follicles, the coast duration is more than 4 days, or if estradiol levels rise to more than 6,500 pg/mL during coasting (351,402).


Gynecology_Novak

Gynecology_Novak. The adjunctive use of metformin is associated with decreased OHSS rates in PCOS patients (342). Cabergoline, a dopamine agonist that inhibits VEGF production, decreased OHSS rates when given at 0.5 mg daily for 7 or 8 days following retrieval. Long-term use of cabergoline may be associated with valvular heart disease (351,401,402). Albumin given at oocyte retrieval does not appear to decrease subsequent rates of OHSS (401). Cryopreservation of all embryos without transfer will prevent late onset OHSS (402), but pregnancy outcomes vary for frozen/thaw transfers and early onset OHSS may still occur (401,402). More information on embryo crypreservation can be found in the “Process of Assisted Reproductive Technologies” section.


Gynecology_Novak

Gynecology_Novak. In vitro oocyte maturation completely obviates the need to stimulate the ovaries with gonadotropins. During in vitro oocyte maturation cycles, immature follicles are aspirated following hCG administration, and the retrieved oocytes are grown in vitro until mature. Mature oocytes are then fertilized by insemination or ICSI. Randomized trials are still needed to further evaluate this technique (403). Risk of Cancer after Infertility by itself is a predisposing factor for ovarian cancer and breast cancer (404,405).


Gynecology_Novak

Gynecology_Novak. Fertility Therapy Although treatments that promote incessant ovulation and elevated estrogen levels offer biologic plausibility for further increased cancer risk, data regarding the impact of infertility therapy on neoplasias have been inconsistent and conﬂicting (406). A retrospective cohort study of women in the United States found no association between prior use of clomiphene or gonadotropins and subsequent development of ovarian or breast cancer, although the authors suggested that very high doses or long duration of administration may warrant closer attention (404,405). A large British cohort of women with ovulatory disorders who were given ovulation-stimulation drugs did not find evidence to suggest causation for cancer of the breast, ovary, colon, skin, or thyroid. However, there was a dose–response relationship between the development of uterine cancer and prior use of clomiphene, particularly with a lifetime exposure of 2,250 mg or more (406).


Gynecology_Novak

Gynecology_Novak. Stress Stress, as manifested by anxiety or depression, is thought to be increased among women experiencing infertility (407). Stress is the most common reason for patients, even those with insurance coverage, to terminate fertility treatment (408). However, it is not clear whether stress worsens infertility, nor is there clear evidence that psychological treatment improves fertility (407). If psychological disorders are present, treatment should be offered regardless of fertility status.


Gynecology_Novak

Gynecology_Novak. The primary indication for preimplantation genetic diagnosis (PGD) is to improve the chances of having healthy infants in families at high risk for a specific genetic disease (409). Following embryo biopsy, genetic testing can be performed on a blastomere (cell from day 3 embryo), polar body, or on blastocyst trophectoderm prior to transferring the embryo. Aneuploidy in embryos most commonly affects chromosomes X, Y, 13, 14, 15, 16, 18, 21, and 22. Fluorescence in situ hybridization (FISH) is a technique that assesses aneuploidy, translocation, other structural chromosomal defects and sex chromosome content (410). FISH is technically limited by the number of distinct chromosomes that can be evaluated, which results in an inherently high false-negative rate. Newer methods are being developed that assess the entire genome using comparative genomic hybridization or DNA microarrays (411). One-quarter of the cases of PGD are performed for single gene disorders, most commonly myotonic


Gynecology_Novak

Gynecology_Novak. that assess the entire genome using comparative genomic hybridization or DNA microarrays (411). One-quarter of the cases of PGD are performed for single gene disorders, most commonly myotonic dystrophy, Huntington disease, cystic fibrosis, fragile X syndrome, spinal muscular atrophy, tuberous sclerosis, Marfan syndrome, thalassemia, and sickle cell anemia. Because polymerase chain reaction (PCR) is required for single gene disorder diagnosis, ICSI is performed during ART to avoid contamination from sperm bound to the zona pellucida. PGD can be used for HLA antigen tissue matching in an effort to produce a child whose cord blood or stem cells could potentially help an existing affected child. Disadvantages to PGD include decreased postbiopsy embryo survival, requirements for extended culture with an associated possibility that no embryos will be available for transfer or cryopreservation, false-positive and false-negative testing results, and controversies regarding disposition of


Gynecology_Novak

Gynecology_Novak. with an associated possibility that no embryos will be available for transfer or cryopreservation, false-positive and false-negative testing results, and controversies regarding disposition of nontransferred embryos (409,410). PGD is not synonymous with preimplantation genetic screening (PGS), which is performed in couples without known chromosomal anomaly, mutation, or other genetic abnormality. Although it seems intuitive that replacing only euploid embryos should improve pregnancy and live birth rates in patients with advanced age, recurrent pregnancy loss, or implantation failure, study outcomes have not been consistent (409,410,412–415).


Gynecology_Novak

Gynecology_Novak. Preservation of Fertility in Cancer Patients


Gynecology_Novak

Gynecology_Novak. Improved cancer treatments such as chemotherapy, surgery, and radiotherapy have greatly enhanced survival, such that many cancer survivors contemplate parenthood. Unfortunately, those life-saving treatments can diminish fertility potential in both men and women. Cancer itself does not usually affect oocytes, but certain chemotherapeutic drugs or radiation damage may adversely affect ovarian reserve and uterine function, particularly in older women (416). Ovarian transposition prior to radiation therapy seems to be effective in preserving ovarian function (417). It is unclear whether ovarian suppression with GnRH analogues or oral contraceptives before or during chemotherapy or radiation is beneficial. If time allows prior to commencement of cancer treatment, women can undergo IVF with embryo cryopreservation (oocyte and ovarian tissue preservation are not routine). In women with cervical cancer, radical trachelectomy allows for retention of the uterus, those with uterine cancer may