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Meta-Analysis
. 2018 Feb 1;2(2):CD012693.
doi: 10.1002/14651858.CD012693.pub2.

Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI)

Sarah F Lensen  1 , Jack Wilkinson, Jori A Leijdekkers, Antonio La Marca, Ben Willem J Mol, Jane Marjoribanks, Helen Torrance, Frank J Broekmans
Affiliations
Meta-Analysis

Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI)

Sarah F Lensen et al. Cochrane Database Syst Rev. .

Update in

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 responseAll 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 studiesFour 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.

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Conflict of interest statement

Sarah Lensen does not have any conflicts of interest to declare.

Jack Wilkinson was funded by a Doctoral Research Fellowship supported by the National Institute for Health Research while completing part of this work (DRF‐2014‐07‐050). The views expressed in this publication are those of the authors and not necessarily those of the National Health Service (NHS), the National Institute for Health Research or the Department of Health. JW also declares that publishing research is beneficial to his career.

Jori Leijdekkers received an unrestricted personal grant from Merck B.V.

Antonio La Marca received research funding to his institution from companies producing gonadotrophins (Merck Serono, Ferring, IBSA, MSD). He did not receive direct payment for consultancies or conference speaking in the last 3 years from any of these companies. Antonio La Marca is an investigator on a trial included in this review (Allegra 2017). To manage this potential conflict, review authors did not extract data or assess risk of bias for the studies they have been involved with.

Ben Mol has received consultancy fees from ObsEva, Guerbet and Merck; payment for review preparation from European Journal of Obstetrics and Gynecology and Reproductive Biology; and travel/accommodation/meeting expenses for various non‐commercial scientific meetings.

Jane Marjoribanks does not have any conflicts of interest to declare.

Helen Torrance has received travel grants from from Merck B.V.

Frank Broekmans has not consulted for any related companies in the last 3 years.

Frank Broekmans, Ben Mol and Helen Torrance are investigators in the OPTIMIST trial, which is included in this review (Oudshoorn 2017; Van Tilborg 2017). Frank Broekmans is an investigator on two other trials included in this review (Klinkert 2005; Olivennes 2015). To manage this potential conflict, review authors did not extract data or assess risk of bias for the studies they have been involved with.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
4
4
Forest plot of comparison: 1 Anticipated low responders: higher vs lower dose, outcome: 1.1 Live birth or ongoing pregnancy per woman randomised.
5
5
Forest plot of comparison: 2 Anticipated normal responders: higher vs lower dose, outcome: 2.1 Live birth or ongoing pregnancy.
6
6
Forest plot of comparison: 2 Anticipated normal responders: higher vs lower dose, outcome: 2.21 Dose‐response: live birth or ongoing pregnancy.
7
7
Forest plot of comparison: 3 Anticipated high‐responders: higher vs lower dose, outcome: 3.1 Live birth or ongoing pregnancy.
8
8
Forest plot of comparison: 3 Anticipated high‐responders: higher vs lower dose, outcome: 3.21 Dose‐response: live birth or ongoing pregnancy.
9
9
Forest plot of comparison: 4 ORT‐based algorithm vs standard dose or non‐ORT based algorithm, outcome: 4.1 Live birth or ongoing pregnancy per woman randomised.
10
10
Forest plot of comparison: 4 ORT‐based algorithm vs standard dose or non‐ORT based algorithm, outcome: 4.5 Moderate or severe OHSS.
11
11
Forest plot of comparison: 6 AMH + AFC‐based algorithm vs AFC‐based algorithm, outcome: 6.1 Live birth or ongoing pregnancy.
1.1
1.1. Analysis
Comparison 1 Anticipated low responders: higher vs lower dose, Outcome 1 Live birth or ongoing pregnancy.
1.2
1.2. Analysis
Comparison 1 Anticipated low responders: higher vs lower dose, Outcome 2 Severe OHSS.
1.3
1.3. Analysis
Comparison 1 Anticipated low responders: higher vs lower dose, Outcome 3 Clinical pregnancy.
1.5
1.5. Analysis
Comparison 1 Anticipated low responders: higher vs lower dose, Outcome 5 Moderate or severe OHSS.
1.6
1.6. Analysis
Comparison 1 Anticipated low responders: higher vs lower dose, Outcome 6 Multiple pregnancy in randomised women.
1.7
1.7. Analysis
Comparison 1 Anticipated low responders: higher vs lower dose, Outcome 7 Log(N oocytes retrieved); data presented on the log scale ‐ cannot interpret pooled estimates as N of oocytes.
1.8
1.8. Analysis
Comparison 1 Anticipated low responders: higher vs lower dose, Outcome 8 Poor response to stimulation.
1.9
1.9. Analysis
Comparison 1 Anticipated low responders: higher vs lower dose, Outcome 9 Normal response to stimulation.
1.10
1.10. Analysis
Comparison 1 Anticipated low responders: higher vs lower dose, Outcome 10 Hyper‐response to stimulation.
1.11
1.11. Analysis
Comparison 1 Anticipated low responders: higher vs lower dose, Outcome 11 Cycle cancellations for poor response.
1.12
1.12. Analysis
Comparison 1 Anticipated low responders: higher vs lower dose, Outcome 12 Cycle cancellations for hyper‐response.
1.13
1.13. Analysis
Comparison 1 Anticipated low responders: higher vs lower dose, Outcome 13 Cycle cancellations for poor or hyper‐response.
1.14
1.14. Analysis
Comparison 1 Anticipated low responders: higher vs lower dose, Outcome 14 Women with at least one transferable embryo.
1.15
1.15. Analysis
Comparison 1 Anticipated low responders: higher vs lower dose, Outcome 15 Total dose of FSH.
1.16
1.16. Analysis
Comparison 1 Anticipated low responders: higher vs lower dose, Outcome 16 Duration of FSH administration.
1.18
1.18. Analysis
Comparison 1 Anticipated low responders: higher vs lower dose, Outcome 18 Cumulative live birth: 1 cycle (fresh + frozen).
1.19
1.19. Analysis
Comparison 1 Anticipated low responders: higher vs lower dose, Outcome 19 Cumulative live birth: 18 months.
1.20
1.20. Analysis
Comparison 1 Anticipated low responders: higher vs lower dose, Outcome 20 Multiple pregnancy in women with clinical pregnancy.
2.1
2.1. Analysis
Comparison 2 Anticipated normal responders: higher vs lower dose, Outcome 1 Live birth or ongoing pregnancy.
2.2
2.2. Analysis
Comparison 2 Anticipated normal responders: higher vs lower dose, Outcome 2 Severe OHSS.
2.3
2.3. Analysis
Comparison 2 Anticipated normal responders: higher vs lower dose, Outcome 3 Clinical pregnancy.
2.5
2.5. Analysis
Comparison 2 Anticipated normal responders: higher vs lower dose, Outcome 5 Moderate or severe OHSS.
2.6
2.6. Analysis
Comparison 2 Anticipated normal responders: higher vs lower dose, Outcome 6 Multiple pregnancy in randomised women.
2.7
2.7. Analysis
Comparison 2 Anticipated normal responders: higher vs lower dose, Outcome 7 Log(N oocytes retrieved); data presented on the log scale ‐ cannot interpret pooled estimates as N of oocytes.
2.8
2.8. Analysis
Comparison 2 Anticipated normal responders: higher vs lower dose, Outcome 8 Poor response to stimulation.
2.9
2.9. Analysis
Comparison 2 Anticipated normal responders: higher vs lower dose, Outcome 9 Normal response to stimulation.
2.10
2.10. Analysis
Comparison 2 Anticipated normal responders: higher vs lower dose, Outcome 10 Hyper‐response to stimulation.
2.11
2.11. Analysis
Comparison 2 Anticipated normal responders: higher vs lower dose, Outcome 11 Cycle cancellations for poor response.
2.12
2.12. Analysis
Comparison 2 Anticipated normal responders: higher vs lower dose, Outcome 12 Cycle cancellations for hyper‐response.
2.13
2.13. Analysis
Comparison 2 Anticipated normal responders: higher vs lower dose, Outcome 13 Cycle cancellations for poor or hyper‐response.
2.14
2.14. Analysis
Comparison 2 Anticipated normal responders: higher vs lower dose, Outcome 14 Women with at least one transferable embryo.
2.15
2.15. Analysis
Comparison 2 Anticipated normal responders: higher vs lower dose, Outcome 15 Total dose of FSH.
2.16
2.16. Analysis
Comparison 2 Anticipated normal responders: higher vs lower dose, Outcome 16 Duration of FSH administration.
2.18
2.18. Analysis
Comparison 2 Anticipated normal responders: higher vs lower dose, Outcome 18 Cumulative live birth: 1 cycle (fresh + frozen).
2.19
2.19. Analysis
Comparison 2 Anticipated normal responders: higher vs lower dose, Outcome 19 Cumulative live birth: 18 months.
2.20
2.20. Analysis
Comparison 2 Anticipated normal responders: higher vs lower dose, Outcome 20 Multiple pregnancy in women with clinical pregnancy.
2.21
2.21. Analysis
Comparison 2 Anticipated normal responders: higher vs lower dose, Outcome 21 Dose‐response: live birth or ongoing pregnancy.
2.22
2.22. Analysis
Comparison 2 Anticipated normal responders: higher vs lower dose, Outcome 22 Dose‐response: cumulative live birth: 1 cycle (fresh + frozen).
2.23
2.23. Analysis
Comparison 2 Anticipated normal responders: higher vs lower dose, Outcome 23 Dose‐response: clinical pregnancy.
2.24
2.24. Analysis
Comparison 2 Anticipated normal responders: higher vs lower dose, Outcome 24 Dose‐response: log(N oocytes retrieved); data presented on the log scale ‐ cannot interpret pooled estimates as N of oocytes.
2.25
2.25. Analysis
Comparison 2 Anticipated normal responders: higher vs lower dose, Outcome 25 Dose‐response: poor response to stimulation.
2.26
2.26. Analysis
Comparison 2 Anticipated normal responders: higher vs lower dose, Outcome 26 Dose‐response: normal response to stimulation.
2.27
2.27. Analysis
Comparison 2 Anticipated normal responders: higher vs lower dose, Outcome 27 Dose‐response: hyper‐response to stimulation.
2.28
2.28. Analysis
Comparison 2 Anticipated normal responders: higher vs lower dose, Outcome 28 Dose‐response: cycle cancellations for poor response.
2.29
2.29. Analysis
Comparison 2 Anticipated normal responders: higher vs lower dose, Outcome 29 Dose‐response: women with at least one transferable embryo.
2.30
2.30. Analysis
Comparison 2 Anticipated normal responders: higher vs lower dose, Outcome 30 Dose‐response: total dose of FSH.
2.31
2.31. Analysis
Comparison 2 Anticipated normal responders: higher vs lower dose, Outcome 31 Dose‐response: duration of FSH administration.
3.1
3.1. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 1 Live birth or ongoing pregnancy.
3.2
3.2. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 2 Severe OHSS.
3.3
3.3. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 3 Clinical pregnancy.
3.5
3.5. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 5 Moderate or severe OHSS.
3.6
3.6. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 6 Multiple pregnancy in randomised women.
3.7
3.7. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 7 Log(N oocytes retrieved); data presented on the log scale ‐ cannot interpret pooled estimates as N of oocytes.
3.8
3.8. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 8 Poor response to stimulation.
3.9
3.9. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 9 Normal response to stimulation.
3.10
3.10. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 10 Hyper‐response to stimulation.
3.11
3.11. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 11 Cycle cancellations for poor response.
3.12
3.12. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 12 Cycle cancellations for hyper‐response.
3.13
3.13. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 13 Cycle cancellations for poor or hyper‐response.
3.14
3.14. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 14 Women with at least one transferable embryo.
3.15
3.15. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 15 Total dose of FSH.
3.16
3.16. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 16 Duration of FSH administration.
3.17
3.17. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 17 Cost per woman randomised.
3.18
3.18. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 18 Cumulative live birth: 1 cycle (fresh + frozen).
3.19
3.19. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 19 Cumulative live birth: 18 months.
3.20
3.20. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 20 Multiple pregnancy in women with clinical pregnancy.
3.21
3.21. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 21 Dose‐response: live birth or ongoing pregnancy.
3.22
3.22. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 22 Dose‐response: clinical pregnancy.
3.23
3.23. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 23 Dose‐response: cumulative live birth:1 cycle (fresh + frozen).
3.24
3.24. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 24 Dose‐response: severe OHSS.
3.25
3.25. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 25 Dose‐response: moderate or severe OHSS.
3.26
3.26. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 26 Dose‐response: log(N oocytes retrieved); data presented on the log scale ‐ cannot interpret pooled estimates as N of oocytes.
3.27
3.27. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 27 Dose‐response: poor response to stimulation.
3.28
3.28. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 28 Dose‐response: normal response to stimulation.
3.29
3.29. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 29 Dose‐response: hyper‐response to stimulation.
3.30
3.30. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 30 Dose‐response: cycle cancellations for poor response.
3.31
3.31. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 31 Dose‐response: cycle cancellations for hyper‐response.
3.32
3.32. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 32 Dose‐response: cycle cancellations for poor or hyper‐response.
3.33
3.33. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 33 Dose‐response: women with at least one transferable embryo.
3.34
3.34. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 34 Dose‐response: total dose of FSH.
3.35
3.35. Analysis
Comparison 3 Anticipated high‐responders: higher vs lower dose, Outcome 35 Dose‐response: duration of FSH administration.
4.1
4.1. Analysis
Comparison 4 ORT‐based algorithm vs standard dose or non‐ORT based algorithm, Outcome 1 Live birth or ongoing pregnancy.
4.2
4.2. Analysis
Comparison 4 ORT‐based algorithm vs standard dose or non‐ORT based algorithm, Outcome 2 Severe OHSS.
4.3
4.3. Analysis
Comparison 4 ORT‐based algorithm vs standard dose or non‐ORT based algorithm, Outcome 3 Clinical pregnancy.
4.5
4.5. Analysis
Comparison 4 ORT‐based algorithm vs standard dose or non‐ORT based algorithm, Outcome 5 Moderate or severe OHSS.
4.6
4.6. Analysis
Comparison 4 ORT‐based algorithm vs standard dose or non‐ORT based algorithm, Outcome 6 Multiple pregnancy in randomised women.
4.7
4.7. Analysis
Comparison 4 ORT‐based algorithm vs standard dose or non‐ORT based algorithm, Outcome 7 Log(N oocytes retrieved); data presented on the log scale ‐ cannot interpret pooled estimates as N of oocytes.
4.8
4.8. Analysis
Comparison 4 ORT‐based algorithm vs standard dose or non‐ORT based algorithm, Outcome 8 Poor response to stimulation.
4.9
4.9. Analysis
Comparison 4 ORT‐based algorithm vs standard dose or non‐ORT based algorithm, Outcome 9 Normal response to stimulation.
4.10
4.10. Analysis
Comparison 4 ORT‐based algorithm vs standard dose or non‐ORT based algorithm, Outcome 10 Hyper‐response to stimulation.
4.11
4.11. Analysis
Comparison 4 ORT‐based algorithm vs standard dose or non‐ORT based algorithm, Outcome 11 Cycle cancellations for poor response.
4.12
4.12. Analysis
Comparison 4 ORT‐based algorithm vs standard dose or non‐ORT based algorithm, Outcome 12 Cycle cancellations for hyper‐response.
4.13
4.13. Analysis
Comparison 4 ORT‐based algorithm vs standard dose or non‐ORT based algorithm, Outcome 13 Cycle cancellations for poor or hyper‐response.
4.14
4.14. Analysis
Comparison 4 ORT‐based algorithm vs standard dose or non‐ORT based algorithm, Outcome 14 Women with at least one transferable embryo.
4.15
4.15. Analysis
Comparison 4 ORT‐based algorithm vs standard dose or non‐ORT based algorithm, Outcome 15 Total dose of FSH.
4.16
4.16. Analysis
Comparison 4 ORT‐based algorithm vs standard dose or non‐ORT based algorithm, Outcome 16 Duration of FSH administration.
4.18
4.18. Analysis
Comparison 4 ORT‐based algorithm vs standard dose or non‐ORT based algorithm, Outcome 18 Cumulative live birth: 1 cycle (fresh + frozen).
4.19
4.19. Analysis
Comparison 4 ORT‐based algorithm vs standard dose or non‐ORT based algorithm, Outcome 19 Cumulative live birth: 18 months.
4.20
4.20. Analysis
Comparison 4 ORT‐based algorithm vs standard dose or non‐ORT based algorithm, Outcome 20 Multiple pregnancy in women with clinical pregnancy.
5.2
5.2. Analysis
Comparison 5 AMH‐based algorithm vs AFC‐based algorithm, Outcome 2 Severe OHSS.
5.3
5.3. Analysis
Comparison 5 AMH‐based algorithm vs AFC‐based algorithm, Outcome 3 Clinical pregnancy.
5.5
5.5. Analysis
Comparison 5 AMH‐based algorithm vs AFC‐based algorithm, Outcome 5 Moderate or severe OHSS.
5.6
5.6. Analysis
Comparison 5 AMH‐based algorithm vs AFC‐based algorithm, Outcome 6 Multiple pregnancy in randomised women.
5.7
5.7. Analysis
Comparison 5 AMH‐based algorithm vs AFC‐based algorithm, Outcome 7 Log(N oocytes retrieved); data presented on the log scale ‐ cannot interpret pooled estimates as N of oocytes.
5.8
5.8. Analysis
Comparison 5 AMH‐based algorithm vs AFC‐based algorithm, Outcome 8 Poor response to stimulation.
5.9
5.9. Analysis
Comparison 5 AMH‐based algorithm vs AFC‐based algorithm, Outcome 9 Normal response to stimulation.
5.10
5.10. Analysis
Comparison 5 AMH‐based algorithm vs AFC‐based algorithm, Outcome 10 Hyper‐response to stimulation.
5.11
5.11. Analysis
Comparison 5 AMH‐based algorithm vs AFC‐based algorithm, Outcome 11 Cycle cancellations for poor response.
5.12
5.12. Analysis
Comparison 5 AMH‐based algorithm vs AFC‐based algorithm, Outcome 12 Cycle cancellations for hyper‐response.
5.13
5.13. Analysis
Comparison 5 AMH‐based algorithm vs AFC‐based algorithm, Outcome 13 Cycle cancellations for poor or hyper‐response.
5.14
5.14. Analysis
Comparison 5 AMH‐based algorithm vs AFC‐based algorithm, Outcome 14 Women with at least one transferable embryo.
5.15
5.15. Analysis
Comparison 5 AMH‐based algorithm vs AFC‐based algorithm, Outcome 15 Total dose of FSH.
5.16
5.16. Analysis
Comparison 5 AMH‐based algorithm vs AFC‐based algorithm, Outcome 16 Duration of FSH administration.
5.19
5.19. Analysis
Comparison 5 AMH‐based algorithm vs AFC‐based algorithm, Outcome 19 Multiple pregnancy in women with clinical pregnancy.
6.1
6.1. Analysis
Comparison 6 AMH + AFC‐based algorithm vs AFC‐based algorithm, Outcome 1 Live birth or ongoing pregnancy.
6.2
6.2. Analysis
Comparison 6 AMH + AFC‐based algorithm vs AFC‐based algorithm, Outcome 2 Severe OHSS.
6.3
6.3. Analysis
Comparison 6 AMH + AFC‐based algorithm vs AFC‐based algorithm, Outcome 3 Clinical pregnancy.
6.5
6.5. Analysis
Comparison 6 AMH + AFC‐based algorithm vs AFC‐based algorithm, Outcome 5 Moderate or severe OHSS.
6.6
6.6. Analysis
Comparison 6 AMH + AFC‐based algorithm vs AFC‐based algorithm, Outcome 6 Multiple pregnancy in randomised women.
6.7
6.7. Analysis
Comparison 6 AMH + AFC‐based algorithm vs AFC‐based algorithm, Outcome 7 Log(N oocytes retrieved); data presented on the log scale ‐ cannot interpret pooled estimates as N of oocytes.
6.8
6.8. Analysis
Comparison 6 AMH + AFC‐based algorithm vs AFC‐based algorithm, Outcome 8 Poor response to stimulation.
6.9
6.9. Analysis
Comparison 6 AMH + AFC‐based algorithm vs AFC‐based algorithm, Outcome 9 Normal response to stimulation.
6.10
6.10. Analysis
Comparison 6 AMH + AFC‐based algorithm vs AFC‐based algorithm, Outcome 10 Hyper‐response to stimulation.
6.11
6.11. Analysis
Comparison 6 AMH + AFC‐based algorithm vs AFC‐based algorithm, Outcome 11 Cycle cancellations for poor response.
6.12
6.12. Analysis
Comparison 6 AMH + AFC‐based algorithm vs AFC‐based algorithm, Outcome 12 Cycle cancellations for hyper‐response.
6.13
6.13. Analysis
Comparison 6 AMH + AFC‐based algorithm vs AFC‐based algorithm, Outcome 13 Cycle cancellations for poor or hyper‐response.
6.14
6.14. Analysis
Comparison 6 AMH + AFC‐based algorithm vs AFC‐based algorithm, Outcome 14 Women with at least one transferable embryo.
6.15
6.15. Analysis
Comparison 6 AMH + AFC‐based algorithm vs AFC‐based algorithm, Outcome 15 Total dose of FSH.
6.16
6.16. Analysis
Comparison 6 AMH + AFC‐based algorithm vs AFC‐based algorithm, Outcome 16 Duration of FSH administration.
6.18
6.18. Analysis
Comparison 6 AMH + AFC‐based algorithm vs AFC‐based algorithm, Outcome 18 Live birth or ongoing pregnancy (including FET for freeze‐all).
6.19
6.19. Analysis
Comparison 6 AMH + AFC‐based algorithm vs AFC‐based algorithm, Outcome 19 Multiple pregnancy in women with clinical pregnancy.
7.1
7.1. Analysis
Comparison 7 AMH + AFC + bFSH‐based algorithm vs bFSH‐based algorithm, Outcome 1 Live birth or ongoing pregnancy.
7.3
7.3. Analysis
Comparison 7 AMH + AFC + bFSH‐based algorithm vs bFSH‐based algorithm, Outcome 3 Clinical pregnancy.
7.7
7.7. Analysis
Comparison 7 AMH + AFC + bFSH‐based algorithm vs bFSH‐based algorithm, Outcome 7 Log(N oocytes retrieved); data presented on the log scale ‐ cannot interpret pooled estimates as N of oocytes.
7.8
7.8. Analysis
Comparison 7 AMH + AFC + bFSH‐based algorithm vs bFSH‐based algorithm, Outcome 8 Poor response to stimulation.
7.9
7.9. Analysis
Comparison 7 AMH + AFC + bFSH‐based algorithm vs bFSH‐based algorithm, Outcome 9 Normal response to stimulation.
7.10
7.10. Analysis
Comparison 7 AMH + AFC + bFSH‐based algorithm vs bFSH‐based algorithm, Outcome 10 Hyper‐response to stimulation.
7.15
7.15. Analysis
Comparison 7 AMH + AFC + bFSH‐based algorithm vs bFSH‐based algorithm, Outcome 15 Total dose of FSH.
7.16
7.16. Analysis
Comparison 7 AMH + AFC + bFSH‐based algorithm vs bFSH‐based algorithm, Outcome 16 Duration of FSH administration.
See this image and copyright information in PMC

References

References to studies included in this review

Allegra 2017 {published and unpublished data}
    1. Allegra A, Marino A, Volpes A, Coffaro F, Scaglione P, Gullo A, et al. A randomized controlled trial investigating the use of a predictive nomogram for the selection of the FSH starting dose in IVF/ICSI cycles. Reproductive Biomedicine Online 2017;34(4):429‐38. - PubMed
Arce 2014 {published data only}
    1. Arce JC, Andersen AN, Fernandez‐Sanchez M, Visnova H, Bosch E, Garcia‐Velasco JA, et al. Ovarian response to recombinant human follicle‐stimulating hormone: a randomized, antimullerian hormone‐stratified, dose response trial in women undergoing in vitro fertilization/ intracytoplasmic sperm injection. Fertility and Sterility 2014;102(6):1633‐40. - PubMed
Bastu 2016 {published and unpublished data}
    1. Bastu E, Buyru F, Ozsurmeli M, Demiral I, Dogan M, Yeh J. A randomized, single‐blind, prospective trial comparing three different gonadotropin doses with or without addition of letrozole during ovulation stimulation in patients with poor ovarian response. European Journal of Obstetrics & Gynecology and Reproductive Biology 2016;203:30‐4. - PubMed
Cavagna 2006 {published data only}
    1. Cavagna M, Dzik A, Freitas GC, Soares JB, Pawn K, Sales ALM, et al. Comparison of 150 IU and 225 IU of follitropin‐beta in a fixed‐dose regimen for ovarian stimulation using a depot formulation of GnRH agonist: a prospective randomized clinical trial. Jornal Brasileiro de Reproducao Assistida 2006;10(2):21‐4.
Harrison 2001 {published data only}
    1. Harrison RF, Jacob S, Spillane H, Mallon E, Hennelly B. A prospective randomized clinical trial of differing starter doses of recombinant follicle‐stimulating hormone (follitropin‐β) for first time in vitro fertilization and intracytoplasmic sperm injection treatment cycles. Fertility and Sterility 2001;75(1):23‐31. - PubMed
Hoomans 2002 {published data only}
    1. Hoomans EHM, Mulder BB, on behalf of the Asian Puregon Study Group. A group‐comparative, randomized, double‐blind comparison of the efficacy and efficiency of two fixed daily dose regimens (100‐ and 200‐IU) of recombinant follicle stimulating hormone (rFSH, Puregon) in Asian women undergoing ovarian stimulation for IVF/ICSI. Journal of Assisted Reproduction and Genetics 2002;19(10):470‐6. - PMC - PubMed
Jayaprakasan 2010 {published and unpublished data}
    1. Jayaprakasan K, Hopkisson J, Campbell B, Johnson I, Thornton J, Raine‐Fenning N. A randomised controlled trial of 300 versus225 IU recombinant FSH for ovarian stimulation in predicted normal responders by antral follicle count. British Journal of Obstetrics and Gynaecology 2010;117:853‐62. - PubMed
Klinkert 2005 {published and unpublished data}
    1. Klinkert ER, Broekmans FJM, Looman CWN, Habbema JDF, Velde ER. Expected poor responders on the basis of an antral follicle count do not benefit from a higher starting dose of gonadotrophins in IVF treatment: a randomized controlled trial. Human Reproduction 2005;20(3):611‐5. - PubMed
​Lan 2013 {published and unpublished data}
    1. Lan VTN, Linh NK, Tuong HM, Wong PC, Howles CM. Anti‐Mullerian hormone versus antral follicle count for defining the starting dose of FSH. Reproductive BioMedicine Online 2013;27(4):390‐9. - PubMed
Lefebrve 2015 {published and unpublished data}
    1. Lefebvre J, Antaki R, Kadoch IJ, Dean NL, Sylvestre C, Bissonnette F, et al. 450 IU versus 600 IU gonadotropin for controlled ovarian stimulation in poor responders: a randomized controlled trial. Fertility and Sterility 2015;104(6):1419‐25. - PubMed
Magnusson 2017 {published and unpublished data}
    1. Magnusson Å, Nilsson L, Oleröd G, Thurin‐Kjellberg1 A, Bergh C. The addition of anti‐Müllerian hormone in an algorithm for individualized hormone dosage did not improve the prediction of ovarian response—a randomized, controlled trial. Human Reproduction 2017;32(4):811‐9. - PubMed
Nyboe Andersen 2017 {published and unpublished data}
    1. Nyboe Andersen A, Nelson SM, Fauser BCJM, García‐Velasco JA, Klein BM, Arce JC, ESTHER‐1 study group. Individualized versus conventional ovarian stimulation for in vitro fertilization: a multicenter, randomized, controlled, assessor‐blinded, phase3 noninferiority trial. Fertility and Sterility 2017;107(2):387‐96. - PubMed
Olivennes 2015 {published data only (unpublished sought but not used)}
    1. Olivennes F, Trew G, Borini A, Broekmans F, Arriagada P, Warne DW, Howles CM. Randomized, controlled, open‐label, noninferiority study of the CONSORT algorithm for individualized dosing of follitropin alfa. Reproductive BioMedicine Online 2015;30:248‐57. - PubMed
Oudshoorn 2017 {published data only}
    1. Oudshoorn SC, Tilborg TC, Eijkemans MJC, Oosterhuis GJE, Friederich J, Hooff HA, et al. Individualized versus standard FSH dosing in women starting IVF/ICSI: an RCT. Part 2: the predicted hyper responder. Human Reproduction 2017;32(12):2506‐14. - PubMed
Out 2004 {published data only}
    1. Out HJ, Rutherford A, Fleming R, Tay CCK, Trew G, Ledger W, et al. A randomized, double‐blind, multicentre clinical trial comparing starting doses of 150 and 200 IU of recombinant FSH in women treated with the GnRH antagonist ganirelix for assisted reproduction. Human Reproduction 2004;19(1):90‐5. - PubMed
Popovic‐Todorovic 2003 {published and unpublished data}
    1. Popovic‐Todorovic B, Loft A, Bredkjñer HE, Bangsbùll S, Nielsen IK, Nyboe Andersen A. A prospective randomized clinical trial comparing an individual dose of recombinant FSH based on predictive factors versus a 'standard' dose of 150 IU/day in 'standard' patients undergoing IVF/ICSI treatment. Human Reproduction 2003;18(11):2275‐82. - PubMed
Tan 2005 {published data only}
    1. Tan SL, Child TJ, Cheung AP, Fluker MR, Yuzpe A, Casper R, et al. A randomized, double‐blind, multicenter study comparing a starting dose of 100 IU or 200 IU of recombinant follicle stimulating hormone (Puregon R) in women undergoing controlled ovarian hyperstimulation for IVF treatment. Journal of Assisted Reproduction and Genetics 2005;22(2):81‐8. - PMC - PubMed
Tasker 2010 {published and unpublished data}
    1. Tasker F, Hamoda H, Wilner H, Grace J, Khalaf Y. A randomised controlled trial comparing cycle outcome of individualised versus standard dosage of recombinant FSH with IVF/ICSI treatment. Human Reproduction 2010;25(Suppl 1):i170‐210.
Van Tilborg 2017 {published data only}
    1. Tilborg TC, Torrance HL, Oudshoorn SC, Eijkemans MJC, Koks CAM, Verhoeve HRV, et al. Individualized versus standard FSH dosing in women starting IVF/ICSI: anRCT. Part 1: the predicted poor responder. Human Reproduction 2017;32(12):2496‐2505. - PubMed
YongPYK 2003 {published data only}
    1. Yong PYK, Brett S, Baird DT, Thong KJ. A prospective randomized clinical trial comparing 150 IU and 225 IU of recombinant follicle‐stimulating hormone(Gonal‐F*) in a fixed‐dose regimen for controlled ovarian stimulation in in vitro fertilization treatment. Fertility and Sterility 2003;79(2):308‐15. - PubMed

References to studies excluded from this review

Berkkanoglu 2010 {published data only}
    1. Berkkanoglu M, Ozgur K. What is the optimum maximal gonadotropin dosage used in microdose flare‐up cycles in poor responders?. Fertility and Sterility 2010;94(2):662‐5. - PubMed
Camier 1999 {published data only}
    1. Camier B. A multicentre, prospective, randomised study to compare low dose protocol versus conventional administration of Rh‐FSH (GONAL‐F®) in normo‐responders undergoing ART. Congress of controversies in Obstestrics, Gynaecology and Infertility 1999;1:7.
Cavagna 2009 {published data only}
    1. Cavagna M, Dzik A, Freitas GC, Soares JB, Donadio N, Cavagna F, et al. A prospective and randomized trial comparing 225IU and 300 IU follitropin‐alpha; in a fixed‐dose regimen for controlled ovarian stimulation. Jornal Brasileiro de Reproducao Assistida 2009;24(2):66‐70.
DeJong 2000 {published data only}
    1. Jong D, Macklon NS, Fauser BCJM. A pilot study involving minimal ovarian stimulation for in vitro fertilization: extending the "follicle‐stimulating hormone window" combined with the gonadotropin‐releasing hormone antagonist cetrorelix. Fertility and Sterility 2000;73(5):1051‐4. - PubMed
Fluker 2000 {published data only}
    1. Fluker MR, Copeland JE, Yuzpe AA. A prospective randomized clinical trial of four fixed starting doses of recombinant FSH in women undergoing ovarian stimulation for IVF. Human Reproduction 2000;15:26.
Latin‐American Puregon IVF Study Group 2001 {published data only}
    1. Latin‐American Puregon IVF Study Group. A double‐blind clinical trial comparing a fixed daily dose of 150 and 250 IU of recombinant follicle‐stimulating hormone in women undergoing in vitro fertilization. Fertility and Sterility 2001;76(5):950‐6. - PubMed
NCT02915900 {unpublished data only}
    1. NCT02915900. Optimising FSH dosage during in vitro fertilization (IVF) [Method for Determining Optimal FSH Dosage During in Vitro Fertilization (IVF)]. clinicaltrials.gov/ct2/show/NCT02915900 First received 27 September 2016.
Out 1999 {published data only}
    1. Out HJ, Lindenberg S, Mikkelsen AL, Eldar‐Geva T, Healy DL, Leader A, et al. A prospective, randomized, double‐blind clinical trial to study the efficacy and efficiency of a fixed dose of recombinant follicle stimulating hormone (Puregon) in women undergoing ovarian stimulation. Human Reproduction 1999;14(3):622‐7. - PubMed
Out 2000 {published data only}
    1. Out HJ, Braat DDM, Lintsen BME, Gurgan T, Bukulmez O, Gökmen O, et al. Increasing the daily dose of recombinant follicle stimulating hormone (Puregon) does not compensate for the age‐related decline in retrievable oocytes are ovarian stimulation. 2000 Human Reproduction;15(1):29‐35. - PubMed
Out 2001 {published data only}
    1. Out HJ, David I, Ron‐El R, Friedler S, Shalev E, Geslevich J, et al. A randomized, double‐blind clinical trial using fixed daily doses of 100 IU or 200 IU of recombinant FSH in ICSI cycles. Human Reproduction 2001;16(6):1104‐9. - PubMed
Pruksananonda 2004 {published data only}
    1. Pruksananonda K, Suwajanakorn S, Sereepapong W, Virutamasen P. Comparison of two different fixed doses of follitropin‐β in controlled ovarian hyperstimulation: a prospective randomized, double blind clinical trial. Journal of the Medical Association of Thailand 2004;87(10):1151‐5. - PubMed
Simberg 2000 {published data only}
    1. Simberg N, Rova K, Gudmundsson J, Lundkvist Ö, Lundqvist M, Bekuretsion M, et al. A randomized study comparing Puregon 100 IU or 150 IU as starting dose in IVF treatment. Human Reproduction 2000;Abstract book 1:125.
Tsagareishvili 2005​ {published data only}
    1. Tsagareishvili G, Khonelidze N, Lazarev A. Results of application of high daily doses of recombinant follicle stimulating hormone in different age groups of women in IVF program. Georgian Medical News. 2005; Vol. 6:11. - PubMed
Wikland 2001 {published data only}
    1. Wikland M, Bergh C, Borg K, Hillensjö T, Howles CM, Knutsson A, et al. A prospective, randomized comparison of two starting doses of recombinant FSH in combination with cetrorelix in women undergoing ovarian stimulation for IVF/ICSI. Human Reproduction 2001;16(8):1676‐81. - PubMed

References to studies awaiting assessment

NCT02309671 {published data only}
    1. NCT02309671. A Dose‐response Trial Using FE 999049 in Japanese Women Undergoing in Vitro Fertilisation (IVF) / Intracytoplasmic Sperm Injection (ICSI) Treatment. https://clinicaltrials.gov/ct2/show/NCT02309671 First received 5th December 2014.

References to ongoing studies

CTRI/2016/10/007367 {unpublished data only}
    1. CTRI/2016/10/007367. Phase III Study to Evaluate the Efficacy and Safety of Recombinant Human FSH of Cadila Healthcare Limited, India as compared to Gonal‐F Administered Subcutaneously in Female Patients Undergoing Assisted Reproductive Technology. http://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=16431&EncHid... First received 14th October 2016.
EUCT2012‐004969‐40 {unpublished data only}
    1. EUCT2012‐004969‐40. An AMH based individualised controlled ovarian stimulation regiment using Corifollitrophin Alphs or graded doses of rFSH versus a standard protocol. A randomised controlled trial. www.clinicaltrialsregister.eu/ctr‐search/trial/2012‐004969‐40/DK First received 23rd November 2012.
NCT01794208 {unpublished data only}
    1. NCT01794208. Efficacy and Safety of FSH‐GEX™ in Comparison With 150 IU Gonal‐f®. https://clinicaltrials.gov/ct2/show/NCT01794208 First received 18th February 2013.
NCT02430740 {unpublished data only}
    1. NCT02430740. Tailored Ovarian Stimulation Based on BMI, AMH, AFC. https://clinicaltrials.gov/ct2/show/NCT02430740 First received 30th April 2015.
NCT02739269 {published data only}
    1. NCT02739269. Antimullerian Hormone Versus Antral Follicle Count for Determination of Gonadotrophin Dosing in IVF. https://clinicaltrials.gov/ct2/show/NCT02739269 First received 15th April 2016.
Singh 2015 {published data only}
    1. Singh M, Singh R, Jindal A, Jindal PC. A prospective randomised controlled trial (RCT) on the role of AMH tailored stimulation protocols (Agonist or Antagonist), in improving IVF outcome in previous failed cycles. Human Reproduction. 2015; Vol. 30:i419‐20, P‐699.

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References to other published versions of this review

Lensen
    1. Lensen SF, Wilkinson J, Mol BWJ, Marca A, Torrance H, Broekmans FJ. Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing IVF/ICSI. Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing IVF/ICSI. Cochrane Database of Systematic Reviews 2017, Issue 6. [DOI: 10.1002/14651858.CD012693] - DOI - PubMed

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