Fig. 20.1
Calculating endometrial thickness – the sum thickness of the two opposing endometrial layers in the mid-sagittal plain
Use of clomiphene citrate for ovulation induction in anovulatory women is common, since it will induce ovulation in approximately 70–80 % of properly selected women [14]. However, in a minority of these women treatment with clomiphene may have anti-oestrogenic effects and inhibit endometrial growth [15]. Contrary to the belief, several studies in women treated with clomiphene and IUI exhibiting a thin endometrial stripe did not find a reduction in pregnancy rates [16, 17].
In ART cycles numerous trials have failed to observe a clear correlation between endometrial thickness or appearance (trilaminar vs. homogenous) on the day of hCG administration and cycle outcomes. Since these endometrial characteristics are not predictive of ongoing pregnancy outcomes, its routine assessment may not be justified.
20.3.1.2 Doppler Studies
Doppler velocimetry is a useful tool for evaluating uterine receptiveness in fertility treatments. Uterine artery Doppler flow indices (vascularization index (VI), flow index (FI) and vascularization flow index (VFI)) of endometrial and sub-endometrial regions have been linked to pregnancy outcome in ART. It has been shown that greater vascularization on the day of oocyte retrieval correlates with higher live birth rates [18]. In COS and IUI treatment a lower pulsatility index (PI) in uterine and intra-ovarian arteries around the time of ovulation was exhibited by women who conceived, as opposed to those who did not [19]. A uterine PI >3 is a poor predictor of pregnancy outcome in ART [20].
20.3.2 The Follicles
20.3.2.1 Measuring Follicular Size
During fertility cycles routine assessment of follicles is mandatory in order to predict ovulation (in IUI cycles or timed coitus) or time hCG administration. In the normal ovulatory cycle the recruited cohort of antral follicles can be identified by cycle day 5–7 and the dominant follicle by day 8–12. The growth rate thereafter is approximately 1–3 mm per day. When the LH surge occurs the dominant follicle measures about 20–24 mm in diameter. Follicles which arrive at maturity ‘naturally’ (without ovulation induction) may not be quite the same as those that reach maturity via ovulation induction. Moreover, different induction protocols achieve oocyte maturity at different time frames, according to the gonadotropin supplied. In gonadotropin-stimulated cycles, dominant follicles reach maturity at a lesser diameter and over a wider range of sizes. While 80 % of the follicles will ovulate when measuring 19–20 mm in diameter, those measuring less than 14 mm ovulate in less than 40 % of the cases [21]. Generally speaking, most agree that follicular maturity is reached at a follicle size ranging between 16 and 22 mm [22]. Follicular growth is monitored differently according to stimulation protocol. We monitor growth as follows:
In natural cycles (in women with regular menstruation) or IUI cycles without stimulation – ultrasound is performed typically from day 10 of menstrual cycle.
In gonadotropin-stimulated cycles and IUI – ultrasound is performed typically from day 10, after 5 days of stimulation, except for special cases (poor responders in whom the first ultrasound is performed later than day 10 and hyper-responders, with risk factors for OHSS, in whom the ultrasound is performed earlier than day 10 of stimulation).
In IVF cycles – ultrasound is performed after 5 days of stimulation.
Follow-up intervals are scheduled according to follicular size, growth rate and blood hormone concentrations of oestradiol. Normally for IUI and natural cycles we perform follow-up every 2–4 days, according to the response rate. For IVF cycles we usually perform follow-up every other day.
20.3.2.2 Timing of Ovulation
Timing ovulation induction by ultrasound only is limited, as it may miss premature LH surges, if given too late, or result in triggering an immature follicle, when given too early. Therefore, while some clinicians monitor ovulation induction by ultrasound only, most coordinate IUI cycles with LH surge detection in urine or blood. A Cochrane review concludes that either way is possible, since both result in similar rates of pregnancy and live birth rates [23].
20.3.2.3 hCG Administration
hCG should be administered according to the size of the dominant follicle and the number of follicles. For ovulation induction a single follicle, and no more than 3–4 dominant follicles, is the goal. The physician may opt to cancel the cycle if more than two follicles are likely to ovulate. For super-ovulation multiple follicular development is the goal. We administer hCG as follows:
In natural cycles and clomiphene citrate-stimulated cycles – when the dominant follicle is 20–24 mm
In gonadotropin-stimulated cycles and IUI – when the dominant follicle is larger than 18–20 mm
In IVF cycles – when three follicles above 17–18 mm are present
Measurement of ovarian follicles can be achieved by two- and three-dimensional ultrasound, as well as by automatic ultrasound counting software. Two-dimensional measuring is performed by measuring the greatest follicular diameter and averaging the two greatest diameters measured (Fig. 20.2). In super-ovulation, when the goal is obtaining multiple large follicles, such a task can be tedious and inaccurate. An emerging technology, Sonographic Automated Follicular Volume Calculation (Sono AVC) using 3D US software, may be preferable in such cases; however, it is still under investigation. A recent review comparing this method to other validated measurement methods found that automated volume measurements are in very good agreement with actual volumes of the assessed structures. This technique seems to provide fast, reliable and highly reproducible results under a variety of conditions, including COS and IVF. It can replace or be used interchangeably with conventional 2D measurements as a method of quality control and may also create opportunities for developing hCG criteria based on follicular volume [24]. Its main disadvantage is in the evaluation of follicles smaller than 10 mm (Fig. 20.3).
Fig. 20.2
Calculating follicular size. Two dimensional measuring is performed by measuring the greatest follicular diameter and averaging the two greatest diameters measured
Fig. 20.3
(a, b) Follicle count and volume in a stimulated ovary with SonoAVC
20.4 Monitoring COS with Ultrasonography Only
Fertility cycles are monitored traditionally by both ultrasonography and measurements of oestradiol (E2) serum levels. Current evidence from meta-analysis of RCTs concludes that monitoring COS cycles with ultrasonography only is unlikely to substantially alter the chances of achieving a clinical pregnancy or affect the number of oocytes retrieved per cycle [25]. Moreover, the addition of E2 measurements to ultrasound monitoring of IVF cycles in normal responders seldom changes the timing of hCG administration or the risk of OHSS [26]. According to a Cochrane review, when monitoring IVF and ICSI (intra-cytoplasmic sperm injection) cycles similar pregnancy and live birth rates were achieved with combined ultrasound and E2 as with ultrasound alone. However, until a sufficient RCT to test different ways of monitoring OHSS (a rare but life-threatening complication) is done, cycle monitoring by ultrasound and serum oestradiol is recommended as a precautionary good practice point [27].
20.5 Embryo Transfer
Embryo transfer can be performed under ultrasound guidance or in a tactile manner. With the ultrasound guided transfer technique an abdominal ultrasound transducer is placed supra-pubically to allow clear visualization of the uterus. The transfer catheter loaded with the embryo(s) is gently guided through the cervical opening into the uterine cavity under observation. Once the ultrasound image confirms that the catheter is properly placed, the embryos are injected into the uterus, and the catheter is slowly withdrawn (Fig. 20.4). Several studies have examined the effect of the distance of blastocyst dislodgement, as determined by air bubble position, from the uterine fundus on pregnancy rates. Air bubbles within 10 mm from the fundus are associated with greater pregnancy rates as opposed to placement further away from the fundus [28]. While some believe that the optimal placement of the inner catheter tip is 1.5–2 cm from the fundal endometrial surface [29], others state that pregnancy rates do not differ as long as the catheter tip is placed in the middle to upper third of the uterus [30].
Fig. 20.4
Ultrasound guided embryo transfer
Ultrasound-guided transfer has many potential advantages, such as facilitating the placement of soft catheters, avoiding stimulation of the fundus and endometrial lining and blocking of the catheter tip with blood or mucus and placement of the catheter in cases of an elongated cervical canal. Also, when performed under ultrasound guidance a full urinary bladder is required, which straightens the cervical canal and facilitates access to the uterus [31].
A Cochrane meta-analysis of four trials concluded that the clinical pregnancy rate and ongoing pregnancy rates were significantly greater with ultrasound-guided embryo transfer as opposed to the ‘clinical feel’ approach. The rate of ectopic pregnancies was not affected by the method of transfer [32]. Other trials have found that the advantage of ultrasound-guided transfer is culture day dependent – exists if transfer is performed after 3 or 4 days of culture but not when performed for 5-day-old embryos [33].
20.6 Complications During COS: Sonographic Diagnosis and Treatment
Although generally safe, COS treatments are associated with complications that, albeit rare, can have significant morbidity. The rate of major complications is 0.7 % [34]. All physicians, and not only those performing COS treatments, should be aware of the increased frequency of potential complications and should keep them in mind when treating women undergoing fertility treatments. The role of ultrasonography is not only in the diagnosis of these conditions but may also aid in resolving them.
20.6.1 Follicle Rupture and Bleeding
Bleeding during oocyte aspiration is divided into minor and major episodes. Minor vaginal bleeding is reported to occur in 0.5–8.6 % of oocyte retrievals [35]. In most cases it subsides after brief local compression, and only rarely suturing is required.
According to a recent retrospective study of 973 cycles of COS, cyst rupture and intra-abdominal bleeding following oocyte retrieval are very rare complications, occurring in 0.1 % of the cases [34]. Similar rates were also reported previously [36]. It is caused by puncture of vessels, such as the ovarian capsule vessels, the sacral plexus or the iliac vessels. This life-threatening complication can be avoided by careful ultrasound visualization of the peripheral follicles in a cross-sectional view before puncture and by the use of colour Doppler if available [37] (Fig. 20.5).
Fig. 20.5
Color Doppler aids in visualization of blood vessels during ovum pick up
20.6.2 Pelvic Infections
The risk of infectious complications following oocyte retrieval is low (0.3–0.6 %), even without antibiotic prophylaxis. Therefore, the use of prophylactic antibiotics 30–60 min before retrieval or immediately after the procedure is controversial. Alternatively, some reserve it for women at increased risk of infection (those with a diagnosed endometrioma or a history of pelvic inflammatory disease) [35, 38]. Nearly half of the cases of infection present as tubo-ovarian abscesses, 1–6 weeks after oocyte retrieval [35] (Fig. 20.6). An ultrasound is key to the diagnosis of this important complication. A complex adnexal cystic lesion following trans-vaginal oocyte retrieval that is accompanied by persistent fever and leukocytosis should lead to an early presumptive diagnosis of tubo-ovarian abscess.
Fig. 20.6
Tubo-ovarian abscess with pyosalpinx
20.6.3 Adnexal Torsion
Torsion of the ovary is a serious complication of ovarian stimulation and should be considered in any patient with complaints of sudden abdominal pain accompanied by nausea, appearing during or after ovarian stimulation. Since ovarian cysts are the main risk factor for torsion, the rate is higher among women exhibiting OHSS. It is 11 times more common in ART pregnancies than in non-ART pregnancies [39]. While the absolute incidence of ovarian torsion is 0.8 % in all IVF cycles [36], it can reach 7.5 % in patients with OHSS [40]. The most consistent imaging finding is asymmetric enlargement of the twisted ovary [41], frequently due to an underlying mass. Obstruction of venous outflow in torsion also causes enlargement, as well as stromal oedema and stromal heterogeneity due to haemorrhage and oedema. Peripheral displacement of follicles due to oedema may also be noted, as well as free pelvic fluid. Doppler sonography can aid in the diagnosis and decrease the morbidity associated with this condition. However, studies have found normal Doppler findings in 45–61 % of torsion cases, so they should not be relied on too heavily. Lastly, a sensitive sign is the ‘whirlpool sign’, seen at both grayscale and colour Doppler US as coiled vessels representing a twisted vascular pedicle [42, 43]. In rare cases the fallopian tube can undergo torsion without involving the ipsilateral ovary. In these cases colour Doppler may not facilitate the diagnosis. Due to the limited diagnostic value of sonography in ovarian torsion, management decisions should still be based on clinical grounds.
Distinguishing ovarian torsion from mild OHSS can be challenging, both clinically and radiologically. Clinically, both entities may manifest with abdominal pain, nausea and vomiting. Radiologically, there is overlap in the grayscale US appearance of these conditions, since both may demonstrate ovarian enlargement and heterogeneous ovarian stroma [41]. Peripheral migration of follicles, a finding associated with torsion, may not be evident in the hyperstimulated ovary, due to the increase in follicles. Moreover, free pelvic fluid, a common finding in torsion, is also present in nearly all cases of OHSS. A possible diagnostic hint to differentiate between the two entities is the finding of cortical cysts separated by thickened parenchyma in the twisted ovary, as compared with ovarian follicles separated by thin walls in OHSS [44] (Fig. 20.7).
Fig. 20.7
Torsion of an enlarged (hyperstimulated) ovary. Thickened echogenic parenchyma separates the cortical cysts, distinguishing torsion from OHSS
20.6.4 Ectopic or Heterotopic Pregnancy
While the incidence of ectopic pregnancy in spontaneous gestations is approximately 2 % [45], its incidence following ART ranges from 2.1 to 8.6 % [46]. Many of the risk factors associated with ectopic pregnancies, such as increasing age, prior tubal pregnancy and history of salpingitis, are also characteristic of the ART population. In contrast to the discriminatory threshold of an intra-uterine pregnancy of a beta-hCG level of 1,500, there is no such threshold for the diagnosis of an extra-uterine pregnancy. Moreover, it is important to note that up to 35 % of ectopic pregnancies may not display any extra-uterine mass [47]. The sensitivity of trans-vaginal sonography can be improved by performing 3D imaging in asymptomatic patients [48]. In cases of high clinical suspicion, a normal ultrasound does not exclude the diagnosis. Most ectopic pregnancies resulting from ART are tubal, as in spontaneous pregnancies; however, the frequencies of cervical, interstitial and abdominal pregnancies, though remaining rare, are increased in ART treatments [49, 50]. Interstitial pregnancy is worth noting, due to its potential catastrophic outcome. This type of pregnancy occurs when an embryo implants in the intra-myometrial portion of the fallopian tube. Its sonographic appearance is of an eccentrically located gestational sac surrounded by a thin layer of myometrium measuring less than 5 mm [51] (Fig. 20.8). A specific additional finding is the ‘interstitial line sign’, an echogenic line that likely represents the interstitial portion of the fallopian tube [52]. These ectopic pregnancies tend to manifest later, and rupture may result in the rapid extravasation of blood to the abdominal cavity due to proximity to the uterine artery.