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Monitoring of Ovulation Induction Cycles
Introduction
Ovulation induction (OI) is frequently applied in anovulatory patients as a first step in infertility treatment. Although OI is highly effective in establishing ovulation, it is, however, not without any risk. There is an ongoing debate on which type of monitoring and which cancelation criteria are best in terms of safety and cost-effectiveness in order to prevent (high-order) multiple pregnancies but maintaining an acceptable pregnancy rate. In this chapter, we describe different methods for monitoring OI in terms of efficacy and safety on the basis of the existing literature. Monitoring OI should help clinicians in predicting (1) the moment of ovulation, (2) inadequate ovarian response, (3) cycles with high risk of multiple pregnancies, and (4) ovarian hyper-response with increased risk of ovarian hyperstimulation syndrome (OHSS).
Overview of Existing Evidence
The size of a follicle with maximum pregnancy competence differs between different types of OI medication. Studies in ovulatory women have observed a larger maximal follicle diameter with clomiphene citrate (mean 20.8 ± 0.7 mm) and letrozole (mean 19.7 ± 0.6 mm) cycles compared with natural cycles (mean 18.2 ± 0.4 mm) (LOE 3). The duration of the follicular phase with clomiphene citrate (CC) was similar to the duration in natural cycles but reduced in cycles with letrozole or gonadotropin (1–3) (LOE 3). Most recent studies propose to administer hCG in the presence of a follicle of 18–22 mm in CC and letrozole cycles and in the presence of a follicle of 17–21 mm in gonadotropin cycles (4,5) (LOE 3).
There is no clear evidence for an endometrium thickness cutoff point in OI cycles. A prospective study on treatment with CC in a mixed population with ovulatory and dysovulatory patients has evaluated the impact of endometrial thickness on pregnancy rates. They found that endometrial thickness was not a predictive factor with a mean thickness of 7.7 ± 0.3 mm in cases of successful pregnancy versus 8.1 ± 0.4 mm in cases of failure (6) (LOE 3). A retrospective study on treatment with gonadotropins has evaluated the impact of endometrial thickness on pregnancy rates and found that a peri-ovulatory endometrial thickness ≥10 mm defined 91% of conception cycles, and no pregnancy occurred when the endometrium measured <7 mm (7) (LOE 3).
In 2006, the Royal College of Obstetricians and Gynaecologists (RCOG) and the National Institute for Clinical Excellence (NICE) both state that ultrasound (US) monitoring is essential during treatment with CC. However, a systematic review of Galazis et al. from 2007 (8) found that there was insufficient evidence to suggest that US monitoring improved pregnancy rates or reduced multiple pregnancy rates. There was, on the other hand, no indication that treatment with CC is safe without US monitoring. No reliable conclusions could be drawn because of the small number of relevant studies and the heterogeneity in the methodology of each study (LOE 1a). In 2013, the NICE guideline (9) advised to offer US monitoring in CC treatment during at least the first cycle of treatment, to ensure a dose that minimizes the risk of multiple pregnancy. Furthermore, the guideline recommended that US monitoring should be an integral part of gonadotropin therapy in order to reduce the risk of multiple pregnancy and the risk of ovarian hyper stimulation (LOE 4).
Although the recruitment of more than one follicle increases the likelihood of pregnancy, it also increases the likelihood of multiple pregnancies. There is a strong link between the number of follicles ≥14 mm, the E2 concentration on the day of hCG/LH surge, and the rate of multiple pregnancies (LOE 3). There is no consensus about cancellation criteria for cycles with a high risk of multiple pregnancies. In CC cycles, the risk of (high-order) multiple pregnancy may be reduced considerably by ultrasound monitoring and cancellation of the cycle if more than two follicles >15 mm diameter are seen (10) (LOE 3). In gonadotropin-induced cycles, a number of studies have analyzed risk factors for multiple pregnancies using US monitoring and determination of serum estradiol concentration (E2). However, heterogeneity observed in the methodologies of these studies and contradictory results make it difficult to establish strict cancellation criteria or define the most effective and safe method of monitoring. On the basis of the available evidence, a group of experts have reached consensus regarding challenges in polycystic ovary syndrome patients (11). They stated that US is an excellent monitoring method in gonadotropin cycles, and documentation of all follicles greater than 10 mm may be helpful to predict the risk of multiple pregnancies. Furthermore, they proposed to cancel gonadotropin cycles under the age of 38 without any other infertility factor in the presence of more than two follicles ≥16 mm or more than one follicle ≥16 mm and two additional follicles ≥14 mm (11) (LOE 4). Others proposed to use more strict criteria with no more than two follicles ≥14 mm with the largest >17 mm (12) (LOE 4). Determination of serum E2 concentrations could be used to cancel or adjust medication in gonadotropin cycles in order to reduce the risk of multiple pregnancies and OHSS. In the literature, there are no specific cutoff values for E2 concentrations although some large retrospective trials report E2 levels <600–1000 pg/ml to prevent (high-order) multiple pregnancies (13) (LOE 3). Other groups stated that monitoring of serum E2 levels provides no additional information compared with US scan monitoring alone and is therefore not recommended (14) (LOE 3).
