Key messages
We did not find clear evidence to support or reject the use of ovarian reserve tests (ORTs) to select the stimulation dose, for either live birth or ovarian hyperstimulation syndrome (OHSS).
Future studies could evaluate the impact of using ORTs to select the stimulation dose, over several treatment attempts.
What is individualised stimulation in IVF treatment?
In vitro fertilisation (IVF) is a type of assisted reproductive technology where eggs are combined with sperm outside a woman’s body. During a typical IVF cycle, doctors give women hormones that encourage a group of eggs to mature. This is referred to as ovarian stimulation.
In planning an IVF cycle, the dose of ovarian stimulation medicines is based on certain characteristics of each woman, such as age. New tests have been developed that may better predict a woman's response to stimulation, called ovarian reserve tests (ORTs). They measure the number of eggs available in the ovaries. It is unclear whether tailoring doses of stimulation medicines based on individual ORTs can help increase the chance of getting pregnant and having a baby, or whether the tests help to improve the safety of the IVF cycle, such as reducing the chances of the serious condition OHSS.
What did we want to find out?
We wanted to establish if ovarian hormone stimulation tailored to individual women based on certain characteristics was better than standard doses for:
- helping women have a live birth;
- avoiding OHSS;
- helping women achieve a pregnancy.
What did we do?
We searched for studies that compared individualised ovarian stimulation dosing to standard dosing or to another type of individualised dosing. We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We found 26 studies involving 8520 women. We grouped these into two comparisons:
- direct dose comparison studies recruited women predicted to respond to IVF stimulation either poorly, normally, or excessively, based on their ovarian reserve test. Women were then randomly assigned to different doses of ovarian-stimulating hormones to see whether the different doses would affect IVF outcomes.
- ORT-based dose selection studies divided women into those whose stimulation dose was based on the women's ORT and those receiving a standard dose or one based on another characteristic.
Main results for direct dose comparison studies
For women predicted to respond poorly or normally to stimulation based on their ovarian reserve test, it was unclear whether increasing the dose of stimulation medication influenced the chance of getting pregnant, having a baby, or the chance of OHSS. However, the included studies were small and compared different doses of medication. For women predicted to respond poorly, if the chance of having a live birth after taking 150 international units (IU) of hormone is 16%, the chance with 300 or 450 IU would be between 13% to 26%. For women predicted to have a normal response, if the chance of live birth or ongoing pregnancy with 150 IU is 29%, the chance with 200/225 IU would be between 22% to 36%.
For 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 25%, the chance with 150 IU would be between 18% to 33%. Reducing the dose may reduce the rate of OHSS. If the chance of moderate or severe OHSS with a lower dose is 1.6%, the chance with a higher dose would be between 1.3% and 9.6%, but this is also unclear.
Main results for ORT-based dose selection studies
There was no notable reduction in ongoing pregnancy or live birth when using ORTs to select a dose, but it is unclear whether there is a benefit. Different methods of using ORT to select the dose might be more or less effective compared to others. If the chance of an ongoing pregnancy or live birth with a standard starting dose were 25%, the chance with dosing based on an ORT would be between 25% and 31%. Individualised dosing did appear to reduce the chance of having OHSS when compared to giving all women the same dose of stimulation medication, but we have little confidence in this evidence. If the chance of moderate or severe OHSS with a standard starting dose were 5%, the chance with dosing based on an ovarian reserve test would be between 2% and 5%.
What are the limitations of the evidence?
We assessed the certainty of the evidence as very low to low, due to limitations in study design (researchers and participants often knew which treatment was assigned) and statistical imprecision, as the studies included too few women to provide clear results for the most important outcomes, such as having a baby.
How up to date is this evidence?
This review updates our previous review. The evidence is current to February 2023.
We did not find that tailoring the FSH dose in any particular ORT population (low, normal, high ORT) affected live birth/ongoing pregnancy rates, but we could not rule out differences, due to sample size limitations. Low-certainty evidence suggests that it is unclear if ORT-based individualisation leads to an increase in live birth/ongoing pregnancy rates compared to a policy of giving all women 150 IU. The confidence interval is consistent with an increase of up to around six percentage points with ORT-based dosing (e.g. from 25% to 31%) or a very small decrease (< 1%). A difference of this magnitude could be important to many women. It is unclear if this is driven by improved outcomes in a particular subgroup. Further, ORT algorithms reduced the incidence of OHSS compared to standard dosing of 150 IU. However, the size of the effect is also unclear. The included studies were heterogeneous in design, which limited the interpretation of pooled estimates. It is likely that different ORT algorithms differ in their effectiveness.
Current evidence does not provide a clear justification for adjusting the dose of 150 IU in poor or normal responders, especially as increased dose is associated with greater total FSH dose and cost. It is unclear whether a decreased dose in predicted high responders reduces OHSS, although this would appear to be the most likely explanation for the results.
During a stimulated cycle of in vitro fertilisation or intracytoplasmic sperm injection (IVF/ICSI), women receive daily doses of gonadotropin follicle-stimulating hormone (FSH) to induce multifollicular development in the ovaries. A normal response to stimulation (e.g. retrieval of 5 to 15 oocytes) is considered desirable. Generally, the number of eggs retrieved is associated with the dose of FSH. Both hyper-response and poor response are associated with an increased chance of cycle cancellation. In hyper-response, this is due to increased risk of ovarian hyperstimulation syndrome (OHSS), while poor response cycles are cancelled because the quantity and quality of oocytes is expected to be low. Clinicians often individualise the FSH dose using patient characteristics predictive of ovarian response. Traditionally, this meant women's age, but increasingly, clinicians use various ovarian reserve tests (ORTs). These include basal FSH (bFSH), antral follicle count (AFC), and anti-Müllerian hormone (AMH). It is unclear whether individualising FSH dose improves clinical outcomes. This review updates the 2018 version.
To assess the effects of individualised gonadotropin dose selection using markers of ovarian reserve in women undergoing IVF/ICSI.
We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, CENTRAL, MEDLINE, Embase, and two trial registers in February 2023.
We included randomised controlled trials (RCTs) that compared (a) 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) or (b) an individualised dosing strategy (based on at least one ORT measure) versus uniform dosing or a different individualised dosing algorithm.
We used standard Cochrane methodological procedures. Primary outcomes were live birth/ongoing pregnancy and severe OHSS.
We included 26 studies, involving 8520 women (6 new studies added to 20 studies included in the previous version). We treated RCTs with multiple comparisons as separate trials for the purpose of this review. Meta-analysis was limited due to clinical heterogeneity. Evidence certainty ranged from very low to low, with the main limitations being imprecision and risk of bias associated with lack of blinding.
Direct dose comparisons according to predicted response in women
Due to differences in dose comparisons, caution is required when interpreting the RCTs in predicted low responders. All evidence was low or very low certainty. 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 (10 studies, 4 comparisons), higher doses may or may not impact the probability of live birth/ongoing pregnancy (e.g. 200 versus 100 international units (IU): odds ratio (OR) 0.88, 95% confidence interval (CI) 0.57 to 1.36; I2 = 0%; 2 studies, 522 women) or clinical pregnancy. Results were imprecise, and a small benefit or harm remains possible. There were too few events for the OHSS outcome to enable inferences.
In predicted high responders, lower doses may or may not affect live birth/ongoing pregnancy (OR 0.98, 95% CI 0.66 to 1.46; 1 study, 521 women), severe OHSS, and clinical pregnancy. It is also unclear whether lower doses reduce moderate or severe OHSS (Peto OR 2.31, 95% CI 0.80 to 6.67; 1 study, 521 participants).
ORT-algorithm studies
Eight trials compared an ORT-based algorithm to a non-ORT control group. It is unclear whether live birth/ongoing pregnancy and clinical pregnancy are increased using an ORT-based algorithm (live birth/ongoing pregnancy: OR 1.12, 95% CI 0.98 to 1.29; I2 = 30%; 7 studies, 4400 women; clinical pregnancy: OR 1.04, 95% CI 0.91 to 1.18; I2 = 18%; 7 studies, 4400 women; low-certainty evidence). However, ORT algorithms may reduce moderate or severe OHSS (Peto OR 0.60, 95% CI 0.42 to 0.84; I2 = 0%; 7 studies, 4400 women; low-certainty evidence). There was insufficient evidence to determine whether the groups differed in rates of severe OHSS (Peto OR 0.74, 95% CI 0.42 to 1.28; I2 = 0%; 5 studies, 2724 women; low-certainty evidence). Our findings suggest that if the chance of live birth with a standard starting dose is 25%, the chance with ORT-based dosing would be between 25% and 31%. If the chance of moderate or severe OHSS with a standard starting dose is 5%, the chance with ORT-based dosing would be between 2% and 5%. These results should be treated cautiously due to heterogeneity in the algorithms: some algorithms appear to be more effective than others.