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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).
Compared with gonadotropin treatment, pulsatile GnRH therapy in WHO 1 anovulation needs little or no monitoring and yields a much higher rate of monofollicular ovulation. Hence, multiple pregnancy rates are very low, and severe OHSS essentially does not occur (10). Also in OI cycles with anti-estrogens, OHSS is a very rare event (LOE 3). The introduction of low-dose FSH protocols for OI has almost completely eliminated the prevalence of severe OHSS. A Cochrane review from 2001 reported an OHSS incidence of 0 – %–7.6% in low- dose FSH protocols; (15) (LOE 1a).
Urinary LH test measurements are a cost-effective and convenient way of ovulation detection at home. Although the overall test accuracy is good, false positive results are possible with high follicular phase LH levels that are present in some PCOS patients. Furthermore, the presence of a LH surge does not always result in ovulation. LH surge configurations can be spiked, biphasic, or plateaued. In women with a regular menstrual cycle, the LH surge duration ranged from 3 to 11 days (16) (LOE 3).
Mid-luteal serum progesterone (P4) measurement is a well-established method to discover ovulation in retrospect. An elevated level of P4 ≥16–25 nmol/L in the luteal phase is accepted as proof for ovulation (17). Most live birth–related cycles in oligo- and anovulatory women treated with gonadotropin for OI had even more elevated P4 levels. Therefore, a mid-luteal P4 level >31.8 nmol/L may represent a more appropriate threshold for proof of ovulation resulting in live birth. Multiple pregnancies were associated with higher mean mid-luteal P4 levels (18) (LOE 3).
A menstrual calendar could give additional information because the cycle length may be a relevant indicator of ovulation. Short, that is, <26 days, and long cycles, that is, >35 days, are associated with increased odds of anovulation (19) (LOE 3).
Discussion
There are very few studies restricted to ovulation disorders that compare different monitoring methods in OI with each other. There are no studies on cost-effectiveness in OI monitoring. In order to make the treatment process less invasive, safe, and to minimize costs, US monitoring is currently the most used monitoring method. It is debatable if US should be recommended for monitoring in non-gonadotropin treatment cycles. A strategy could be to monitor the first cycle, and if mono-follicular growth and ovulation is detected, to instruct the patient how to go on without US monitoring. The patient could use a menstrual calendar and urinary LH tests to monitor OI treatment at home. In gonadotropin cycles, US monitoring is compulsory. Adding other methods of monitoring, such as serum E2 levels, to increase safety and prevent multiple pregnancies is questionable. On the one hand, E2 measurement adds significantly to costs, and on the other hand, there is growing attention to preventing multiple pregnancies/OHSS with strict cancellation criteria and with mild stimulation protocols. It has to be taken into account that if E2 detection is used as a monitoring strategy, the reported values in the literature are not universally valid because values depend on the analytical method and the reagent manufacturer. Even when the same kits are used, different laboratories can obtain different results.
Cycle cancellation is advisable if there is no adequate growing follicle on cycle day 20 in CC treatment cycles. The management in gonadotropin cycles depends on the treatment approach. If there is no growing follicle on US, the gonadotropin dosage has to be adjusted until there is growing tendency.
The role of serum P4 measurement in the luteal phase to confirm ovulation is well established. The disadvantages of this method are its retrospect character, that is, ovulation timing is not possible; its invasiveness; and that it requires an additional visit.
Conclusions
Because of the inhomogeneity of studies, there is not enough evidence to determine which method or combination of methods for OI monitoring should be preferred, particularly with regard to safety and cost-effectiveness. US monitoring is the most frequently used method and could be seen as gold standard for monitoring purposes. It is a quick, efficient and noninvasive way of recording follicular development.
Level of Evidence of Statements
|
Statement |
Level of Evidence |
|
There is insufficient evidence to define which monitoring methods are the most safe and costeffective. US monitoring is the most advisable method for monitoring in OI. |
4 |
|
The pregnancy-related diameter of the leading follicle in CC cycles varies between 18 and 22 mm. |
3 |
|
The pregnancy-related diameter of the leading follicle in gonadotropin cycles varies between 17 and 21 mm. |
3 |
|
There is insufficient evidence about a pregnancy related cutoff point for endometrium thickness in OI cycles. |
3 |
|
There is insufficient evidence that US monitoring in CC cycles improves pregnancy rates. There is no sufficient evidence to suggest that US monitoring in CC cycles reduces multiple pregnancy rates. |
1a |
|
US monitoring in gonadotropin cycles is mandatory. |
4 |
Grade of Strength for Recommendations
|
Recommendation |
Grade Strength |
|
Vaginal US to monitor follicular growth during ovulation induction is advisable at least in the first treatment cycle when anti-estrogens are used, but it is considered mandatory in all gonadotropin cycles. |
GPP |
|
There is no sufficient evidence that US monitoring in CC cycles improves pregnancy rates. There is no sufficient evidence to suggest that US monitoring in CC cycles reduces multiple pregnancy rates. |
A |
|
Ovulation induction should only be initiated if patient and physician are prepared to cancel cycles with hyper-response in order to prevent OHSS and multiple pregnancies. |
GPP |
|
The pregnancy-related diameter in CC cycles is optimal when the leading follicle reaches 18–22 mm and in gonadotropin cycles when the leading follicle reaches 17–21 mm. |
C |
|
In order to avoid multiple pregnancy, achieving mono-follicular or maximal double follicular ovulation is advisable. |
GPP |
|
Specific cancellation criteria to prevent multiple pregnancies are recommended, such as no more than two follicles ⩾14 mm, with the largest >17 mm and E2 concentrations <600–1000 pg/ml. |
D |
|
Mid-luteal serum progesterone (P4) measurement and urinary LH tests are well-established methods to detect ovulation in OI treatment. |
D |
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