Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI)
Abstract
Background
During a cycle of in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI), women receive daily doses of gonadotropin follicle‐stimulating hormone (FSH) to induce multifollicular development in the ovaries. Generally, the dose of FSH is associated with the number of eggs retrieved. A normal response to stimulation is often considered desirable, for example the retrieval of 5 to 15 oocytes. Both poor and hyper‐response are associated with increased chance of cycle cancellation. Hyper‐response is also associated with increased risk of ovarian hyperstimulation syndrome (OHSS). Clinicians often individualise the FSH dose using patient characteristics predictive of ovarian response such as age. More recently, clinicians have begun using ovarian reserve tests (ORTs) to predict ovarian response based on the measurement of various biomarkers, including basal FSH (bFSH), antral follicle count (AFC), and anti‐Müllerian hormone (AMH). It is unclear whether individualising FSH dose based on these markers improves clinical outcomes.
Objectives
To assess the effects of individualised gonadotropin dose selection using markers of ovarian reserve in women undergoing IVF/ICSI.
Search methods
We searched the Cochrane Gynaecology and Fertility Group Specialised Register, Cochrane Central Register of Studies Online, MEDLINE, Embase, CINAHL, LILACS, DARE, ISI Web of Knowledge, ClinicalTrials.gov, and the World Health Organisation International Trials Registry Platform search portal from inception to 27th July 2017. We checked the reference lists of relevant reviews and included studies.
Selection criteria
We included trials that compared different doses of FSH in women with a defined ORT profile (i.e. predicted low, normal or high responders based on AMH, AFC, and/or bFSH) and trials that compared an individualised dosing strategy (based on at least one ORT measure) versus uniform dosing or a different individualised dosing algorithm.
Data collection and analysis
We used standard methodological procedures recommended by Cochrane. Primary outcomes were live birth/ongoing pregnancy and severe OHSS. Secondary outcomes included clinical pregnancy, moderate or severe OHSS, multiple pregnancy, oocyte yield, cycle cancellations, and total dose and duration of FSH administration.
Main results
We included 20 trials (N = 6088); however, we treated those trials with multiple comparisons as separate trials for the purpose of this review. Meta‐analysis was limited due to clinical heterogeneity. Evidence quality ranged from very low to moderate. The main limitations were imprecision and risk of bias associated with lack of blinding.
Direct dose comparisons in women according to predicted response
All evidence was low or very low quality.
Due to differences in dose comparisons, caution is warranted in interpreting the findings of five small trials assessing predicted low responders. The effect estimates were very imprecise, and increased FSH dosing may or may not have an impact on rates of live birth/ongoing pregnancy, OHSS, and clinical pregnancy.
Similarly, in predicted normal responders (nine studies, three comparisons), higher doses may or may not impact the probability of live birth/ongoing pregnancy (e.g. 200 versus 100 international units: OR 0.88, 95% CI 0.57 to 1.36; N = 522; 2 studies; I2 = 0%) or clinical pregnancy. Results were imprecise, and a small benefit or harm remains possible. There were too few events for the outcome of OHSS to enable any inferences.
In predicted high responders, lower doses may or may not have an impact on rates of live birth/ongoing pregnancy (OR 0.98, 95% CI 0.66 to 1.46; N = 521; 1 study), OHSS, and clinical pregnancy. However, lower doses probably reduce the likelihood of moderate or severe OHSS (Peto OR 2.31, 95% CI 0.80 to 6.67; N = 521; 1 study).
ORT‐algorithm studies
Four trials compared an ORT‐based algorithm to a non‐ORT control group. Rates of live birth/ongoing pregnancy and clinical pregnancy did not appear to differ by more than a few percentage points (respectively: OR 1.04, 95% CI 0.88 to 1.23; N = 2823, 4 studies; I2 = 34%; OR 0.96, 95% CI 0.82 to 1.13, 4 studies, I2=0%, moderate‐quality evidence). However, ORT algorithms probably reduce the likelihood of moderate or severe OHSS (Peto OR 0.58, 95% CI 0.34 to 1.00; N = 2823; 4 studies; I2 = 0%, low quality evidence). There was insufficient evidence to determine whether the groups differed in rates of severe OHSS (Peto OR 0.54, 95% CI 0.14 to 1.99; N = 1494; 3 studies; I2 = 0%, low quality evidence). Our findings suggest that if the chance of live birth with a standard dose is 26%, the chance with ORT‐based dosing would be between 24% and 30%. If the chance of moderate or severe OHSS with a standard dose is 2.5%, the chance with ORT‐based dosing would be between 0.8% and 2.5%. These results should be treated cautiously due to heterogeneity in the study designs.
Authors' conclusions
We did not find that tailoring the FSH dose in any particular ORT population (low, normal, high ORT), influenced rates of live birth/ongoing pregnancy but we could not rule out differences, due to sample size limitations. In predicted high responders, lower doses of FSH seemed to reduce the overall incidence of moderate and severe OHSS. Moderate‐quality evidence suggests that ORT‐based individualisation produces similar live birth/ongoing pregnancy rates to a policy of giving all women 150 IU. However, in all cases the confidence intervals are consistent with an increase or decrease in the rate of around five percentage points with ORT‐based dosing (e.g. from 25% to 20% or 30%). Although small, a difference of this magnitude could be important to many women. Further, ORT algorithms reduced the incidence of OHSS compared to standard dosing of 150 IU, probably by facilitating dose reductions in women with a predicted high response. However, the size of the effect is unclear. The included studies were heterogeneous in design, which limited the interpretation of pooled estimates, and many of the included studies had a serious risk of bias.
Current evidence does not provide a clear justification for adjusting the standard dose of 150 IU in the case of poor or normal responders, especially as increased dose is generally associated with greater total FSH dose and therefore greater cost. However, a decreased dose in predicted high responders may reduce OHSS.
PICOs
Plain language summary
Individualised stimulation dose using ovarian reserve markers in women doing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI)
Background
In planning an IVF cycle, doctors often decide the dose of stimulation drugs based on certain characteristics of each woman, such as their age. New tests have been developed that some specialists believe can better predict a woman's response to IVF stimulation. These are called ovarian reserve tests and are a general measure of the number of eggs available in the ovaries. It is unclear whether tailoring the doses of stimulation drugs based on the individual ovarian reserve tests can help to increase the chance of the woman getting pregnant and having a baby. It is also unclear whether the tests help to improve the safety of the IVF cycle, such as reducing the chances of a serious condition known as ovarian hyperstimulation syndrome (OHSS).
Study characteristics
We included two types of studies in this review. Direct dose comparison studies recruited women predicted to respond to IVF stimulation either poorly, normally, or excessively based on their ovarian reserve test. Researchers then randomly assigned these women to different doses of FSH to see whether the different doses would impact on IVF outcomes.
The ORT‐algorithm studies divided a broader group of women into those whose stimulation dose was based on the women's ovarian reserve test and those receiving a standard dose of stimulation medication or a dose based on another characteristic about the women (other than their ovarian reserve).
In total we included 20 randomised controlled trials involving 6088 women.
Key results
1. Direct dose comparison studies (low or very low quality evidence)
In women predicted to respond poorly or normally to stimulation based on their ovarian reserve test, increasing the dose of stimulation medication did not seem to influence the chance of getting pregnant or having a baby, or the chance of OHSS. However, the included studies were small and compared different doses of medication. This made it difficult to say for sure that there is no difference between doses. For women predicted to respond poorly, if the chance of live birth with 150 IU is 11%, then the chance with 300/340 IU would be between 3.8% to 16%. For women predicted to have a normal response, if the chance of live birth or ongoing pregnancy with 150 IU is 19%, then the chance with 200/225 IU would be between 12% to 31%.
In women predicted to have an excessive response to stimulation, reducing the stimulation dose may or may not affect the chance of having a baby. If the chance of live birth with 100 IU is 26%, then the chance with 150 IU would be between 18% to 33%. However, it may reduce the rate of OHSS. If the chance of moderate or severe OHSS with a lower dose is 1.6%, then the chance with a higher dose would be between 1.3% and 9.6%.
2. ORT‐algorithm studies
Moderate quality evidence from these studies suggested that using an ovarian reserve test to decide on the stimulation dose generally did not have much effect on the chance of getting pregnant and having a baby, but there could have been a relatively small difference one way or another. It did generally appear to reduce the chance of having OHSS when compared to giving all women the same dose of stimulation medication, but this evidence was low quality. Our findings suggest that if the chance of live birth with a standard dose were 26%, the chance with dosing based on an ovarian reserve test would be between 24% and 30% and that if the chance of moderate or severe OHSS with a standard dose were 2.5%, the chance with dosing based on an ovarian reserve test would be between 0.8% and 2.5%.
Quality of the evidence
We assessed the quality of the evidence as ranging from very low to moderate, due to limitations in study design (as researchers and participants often knew which treatment was assigned) and statistical imprecision, as the studies included too few women to provide meaningful results for the most important outcomes, such as having a baby.
