Scolaris Content Display Scolaris Content Display

Cochrane Database of Systematic Reviews Review - Intervention

Luteal phase support for assisted reproduction cycles

Authors' declarations of interest

Version published: 07 July 2015 Version history

https://doi.org/10.1002/14651858.CD009154.pub3
Collapse all Expand all

Abstract

available in

Background

Progesterone prepares the endometrium for pregnancy by stimulating proliferation in response to human chorionic gonadotropin (hCG) produced by the corpus luteum in the luteal phase of the menstrual cycle. In assisted reproduction techniques (ART), progesterone and/or hCG levels are low, so the luteal phase is supported with progesterone, hCG or gonadotropin‐releasing hormone (GnRH) agonists to improve implantation and pregnancy rates.

Objectives

To determine the relative effectiveness and safety of methods of luteal phase support provided to subfertile women undergoing assisted reproduction.

Search methods

We searched databases including the Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO and trial registers up to November 2014. Further searches were undertaken in August 2015.

Selection criteria

Randomised controlled trials (RCTs) of luteal phase support using progesterone, hCG or GnRH agonist supplementation in ART cycles.

Data collection and analysis

We used standard methodological procedures expected by Cochrane. Our primary outcome was live birth or ongoing pregnancy. The overall quality of the evidence was assessed using GRADE methods.

Main results

Ninety‐four RCTs (26,198 women) were included. Most studies had unclear or high risk of bias in most domains. The main limitations in the evidence were poor reporting of study methods and imprecision due to small sample sizes.

1. hCG vs placebo/no treatment (five RCTs, 746 women)

Findings suggested benefit for the hCG group in live birth or ongoing pregnancy rates when data were analysed with a fixed‐effect model (OR 1.76, 95% CI 1.08 to 2.86, three RCTs, 527 women, I2 = 24%, very low‐quality evidence) but there was no clear evidence of a difference using a random‐effects model (OR 1.67, 95% CI 0.90 to 3.12). hCG may increase ovarian hyperstimulation syndrome (OHSS) rates (OR 4.28, 95% CI 1.91 to 9.6, one RCT, 387 women, low‐quality evidence).

2. Progesterone vs placebo/no treatment (eight RCTs, 875 women)

Findings suggested benefit for the progesterone group in live birth or ongoing pregnancy rates when data were analysed with a fixed‐effect model (OR 1.77, 95% CI 1.09 to 2.86, five RCTs, 642 women, I2 = 35%, very low‐quality evidence) but there was no clear evidence of a difference using a random‐effects model (OR 1.77, 95% CI 0.96 to 3.26). OHSS was not reported.

3. Progesterone vs hCG regimens (16 RCTs, 2162 women)

hCG regimens included hCG alone and hCG with progesterone. There was no evidence of a difference between progesterone and hCG regimens in live birth or ongoing pregnancy rates (OR 0.95, 95% CI 0.65 to 1.38, five RCTs, 833 women, I2 = 0%, low‐quality evidence). Progesterone was associated with lower OHSS rates than hCG regimens (OR 0.46, 95% CI 0.30 to 0.71, 5 RCTs, 1293 women , I2=48%).

4. Progesterone vs progesterone with oestrogen (16 RCTs, 2577 women)

There was no evidence of a difference between the groups in rates of live birth or ongoing pregnancy (OR 1.12, 95% CI 0.91 to 1.38, nine RCTs, 1651 women, I2 = 0%, low‐quality evidence) or OHSS (OR 0.56, 95% CI 0.2 to 1.63, two RCTs, 461 women, I2 = 0%, low‐quality evidence).

5. Progesterone vs progesterone + GnRH agonist (seven RCTs, 1708 women)

Live birth or ongoing pregnancy rates were lower in the progesterone‐only group than the progesterone plus GnRH agonist group (OR 0.62, 95% CI 0.48 to 0.81, nine RCTs, 2861 women, I2 = 55%, random effects, low‐quality evidence). Statistical heterogeneity was high but the direction of effect was consistent across studies. OHSS was reported in one study only; there was no evidence of a difference between the groups (OR 1.00, 95% CI 0.33 to 3.01, one RCT, 300 women, very low quality evidence).

6. Progesterone regimens (45 RCTs, 13,814 women)

There were nine different comparisons between progesterone regimens. Findings for live birth or ongoing pregnancy were as follows: intramuscular (IM) versus oral: OR 0.71, 95% CI 0.14 to 3.66 (one RCT, 40 women, very low‐quality evidence); IM versus vaginal/rectal: OR 1.37, 95% CI 0.94 to 1.99 (seven RCTs, 2309 women, I2 = 71%, random effects, very low‐quality evidence); vaginal/rectal versus oral: OR 1.19, 95% CI 0.83 to 1.69 (four RCTs, 857 women, I2 = 32%, low‐quality evidence); low‐dose versus high‐dose vaginal: OR 0.97, 95% CI 0.84 to 1.11 (five RCTs, 3720 women, I2 = 0%, moderate‐quality evidence); short versus long protocol: OR 1.04, 95% CI 0.79 to 1.36 (five RCTs, 1205 women, I2 = 0%, low‐quality evidence); micronised versus synthetic: OR 0.9, 95% CI 0.53 to 1.55 (two RCTs, 470 women, I2 = 0%, low‐quality evidence); vaginal ring versus gel: OR 1.09, 95% CI 0.88 to 1.36 (one RCT, 1271 women, low‐quality evidence); subcutaneous versus vaginal gel: OR 0.92, 95% CI 0.74 to 1.14 (two RCTs, 1465 women, I2 = 0%, low‐quality evidence); vaginal versus rectal: OR 1.28, 95% CI 0.64 to 2.54 (one RCT, 147 women, very low‐quality evidence). OHSS rates were reported for only two comparisons: IM versus oral, and low versus high‐dose vaginal; there was no evidence of a difference between the groups.

7. Progesterone and oestrogen regimens (two RCTs, 1195 women)

The included studies compared two different oestrogen protocols. There was no evidence of a difference in live birth or ongoing pregnancy rates between a short or long protocol (OR 1.08, 95% CI 0.81 to 1.43, one RCT, 910 women, low‐quality evidence) or between a low or high dose of oestrogen (OR 0.65, 95% CI 0.37 to 1.13, one RCT, 285 women, very low‐quality evidence). Neither study reported OHSS.

Authors' conclusions

hCG or progesterone given during the luteal phase may be associated with higher rates of live birth or ongoing pregnancy than placebo or no treatment, but the evidence is not conclusive. The addition of GnRHa to progesterone appears to improve outcomes. hCG may increase the risk of OHSS compared to placebo. Moreover hCG, with or without progesterone, is associated with higher rates of OHSS than progesterone alone. Neither the addition of oestrogen nor the route of progesterone administration appears to be associated with an improvement in outcomes.

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Plain language summary

available in

Luteal phase support for assisted reproduction

Review question

Many different interventions, dosages and administration routes of luteal phase support have been investigated. We made seven different comparisons to prepare a complete overview of this topic.

Background

After ovulation, the luteal phase of the menstrual cycle starts, and continues until the next menstruation. Remnants of the ovulated egg in the ovary are known as 'corpus luteum', or yellow body. The yellow body produces hormones, including progesterone. Progesterone stimulates proliferation of the lining of the uterus to prepare for implantation.

During assisted reproduction, the woman's pituitary gland is desensitised with medications so that the ovaries can be stimulated in a controlled manner. This results in more mature eggs, which can be harvested and fertilised outside the woman's body. Hyperstimulation of the ovaries causes a luteal phase defect, as the corpus luteum is unable to produce sufficient progesterone.

As a low progesterone level may lower the chance of implantation, the luteal phase needs to be supported. This may involve oral, vaginal or intramuscular progesterone, human chorionic gonadotropin (hCG) (which stimulates progesterone production) or gonadotropin‐releasing hormone (GnRH) agonists. GnRH agonists stimulate the production of GnRH, a hormone responsible for follicle‐stimulating hormone (FSH), and luteinising hormone (LH), which triggers ovulation and develops the yellow body. GnRH agonists are thought to restore LH levels and support the luteal phase naturally.

Study characteristics

We found 94 randomised controlled trials comparing different luteal phase support regimens in a total of 26,198 women. Our primary outcome was live birth or ongoing pregnancy. Other outcomes were clinical pregnancy, ovarian hyperstimulation syndrome (OHSS), miscarriage and multiple pregnancy. The evidence is current to August 2015.

Key results

hCG or progesterone given during the luteal phase may be associated with higher rates of live birth or ongoing pregnancy than placebo or no treatment, but the evidence is not conclusive. The addition of GnRHa to progesterone appears to improve outcomes. hCG may increase the risk of OHSS compared to placebo. Moreover hCG, with or without progesterone, is associated with higher rates of OHSS than progesterone alone. Neither the addition of oestrogen nor the route of progesterone administration appears to be associated with an improvement in outcomes.

Quality of the evidence

Evidence for most comparisons was of low or very low quality. The main limitations in the evidence were poor reporting of study methods and imprecision due to small sample sizes.

Authors' conclusions

Implications for practice

hCG or progesterone given during the luteal phase may be associated with higher rates of live birth or ongoing pregnancy than placebo or no treatment, but the evidence is not conclusive. The addition of GnRHa to progesterone appears to improve outcomes. hCG may increase the risk of OHSS compared to placebo. Moreover hCG, with or without progesterone, is associated with higher rates of OHSS than progesterone alone. Neither the addition of oestrogen nor the route of progesterone administration appears to be associated with an improvement in outcomes.

Implications for research

Of the 94 included studies, only 10 used blinding. The method of blinding used and specification of who was blinded were poorly reported. If high‐quality evidence is to be gained, studies should be properly blinded and should use a double‐dummy design.

Only 31 studies reported live birth as an outcome. We believe this outcome is more valuable than short‐term outcomes such as clinical pregnancy rate. Therefore researchers should use live birth as the main outcome of their study.

Early studies were placebo controlled. As research has shown that luteal phase support has a positive effect on pregnancy outcomes, it is unethical to not use luteal phase support. Therefore we support the trend in more recent studies to compare different kinds of support, doses or routes of administration. GnRH agonist is relatively new as a method of providing luteal phase support, but it shows promising results. Therefore, high‐quality randomised double‐blind controlled trials should be conducted to compare GnRH agonist support versus progesterone.

Summary of findings

Open in table viewer
Summary of findings for the main comparison. hCG compared with placebo/no treatment for assisted reproduction cycles

hCG compared with placebo/no treatment for assisted reproduction cycles

Population: subfertile women
Setting: assisted reproduction
Intervention: hCG
Comparison: placebo/no treatment

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo/No treatment

hCG

Live birth or ongoing pregnancy

120 per 1000

194 per 1000
(128 to 281)

OR 1.76
(1.08 to 2.86)

527
(3 RCTs)

⊕⊝⊝⊝
Very lowa,b,c,f

Clinical pregnancy

155 per 1000

192 per 1000
(141 to 256)

OR 1.3
(0.9 to 1.88)

746
(5 RCTs)

⊕⊕⊝⊝
Very lowa,b,c,d

OHSS

41 per 1000

155 per 1000
(76 to 292)

OR 4.28
(1.91 to 9.6)

387
(1 RCT)

⊕⊕⊝⊝
Lowa,c,e

*The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

aSerious risk of bias due to inadequate reporting of study methods. Risk of bias unclear in most domains of most studies.

bSerious imprecision with low event rate.

cNumber of studies was not sufficient for assessment of publication bias.

dFindings compatible with meaningful benefit for hCG group, or with no effect.

eSerious imprecision; single study with low event rate.

fFindings not statistically significant when random‐effects model was used (OR 1.67, 95% CI 0.90 to 3.12), or when analysis was restricted to studies reporting live birth.

Open in table viewer
Summary of findings 2. Progesterone compared with placebo/no treatment for assisted reproduction cycles

Progesterone compared with placebo/no treatment for assisted reproduction cycles

Population: subfertile women
Setting: assisted reproduction
Intervention: progesterone
Comparison: placebo/no treatment

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo/no treatment

Progesterone

Live birth or ongoing pregnancy

39 per 1000

66 per 1000
(42 to 103)

OR 1.77
(1.09 to 2.86)

642
(5 RCTs)

⊕⊝⊝⊝
Very lowa,b,c,d

Clinical pregnancy

100 per 1000

174 per 1000
(126 to 234)

OR 1.89
(1.3 to 2.75)

841
(7 RCTs)

⊕⊕⊝⊝
Lowa,b,c

OHSS

Not reported in any included studies

*The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

aSerious risk of bias due to inadequate reporting of study methods. Risk of bias unclear in most domains of most studies.

bSerious imprecision with low event rate.

cNumber of studies was not sufficient for assessment of publication bias.

d Findings not statistically significant when random‐effects model was used (OR 1.77, 95% CI 0.96 to 3.26), or when analysis was restricted to studies reporting live birth.

Open in table viewer
Summary of findings 3. Progesterone compared with hCG regimens for assisted reproduction cycles

Progesterone compared with hCG regimens for assisted reproduction cycles

Population: subfertile women
Setting: assisted reproduction
Intervention: progesterone
Comparison: hCG (alone or with progesterone)

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

hCG (alone or with progesterone)

Progesterone

Live birth or ongoing pregnancy

198 per 1000

190 per 1000
(138 to 254)

OR 0.95
(0.65 to 1.38)

833
(5 RCTs)

⊕⊕⊝⊝
Lowa,b,c,d

Clinical pregnancy

284 per 1000

300 per 1000
(263 to 340)

OR 1.08
(0.9 to 1.3)

2355
(16 RCTs)

⊕⊕⊕⊝
Moderatea

OHSS

118 per 1000

58 per 1000

(39 to 87)

OR 0.46

(0.30 to 0.71)

1293

(5 studies)

⊕⊕⊝⊝
Lowa,c,e

*The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

aSerious risk of bias due to inadequate reporting of study methods. Risk of bias unclear in most domains of most studies.

bSerious imprecision with low event rate.

cNumber of studies was not sufficient for assessment of publication bias.

dFindings compatible with meaningful benefit for either group, or with no effect

e Some inconsistency: I2=48% overall, I2=60% in progesterone vs hCG subgroup

Open in table viewer
Summary of findings 4. Progesterone compared with progesterone + oestrogen for assisted reproduction cycles

Progesterone compared with progesterone + oestrogen for assisted reproduction cycles

Population: subfertile women
Setting: assisted reproduction
Intervention: progesterone
Comparison: progesterone + oestrogen (route of oestrogen: oral, transdermal, vaginal or oral + transdermal)

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Progesterone + oestrogen

Progesterone

Live birth or ongoing pregnancy

367 per 1000

393 per 1000
(345 to 444)

OR 1.12
(0.91 to 1.38)

1651
(9 RCTs)

⊕⊕⊝⊝
Lowa, b, c

Clinical pregnancy

433 per 1000

397 per 1000
(355 to 443)

OR 0.86
(0.72 to 1.04)

2169
(14 RCTs)

⊕⊕⊝⊝
Lowa, d, f

OHSS

51 per 1000

30 per 1000
(11 to 82)

OR 0.58
(0.2 to 1.68)

461
(2 RCTs)

⊕⊕⊝⊝
Lowb, c, e

*The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

aSerious risk of bias due to inadequate reporting of study methods. Risk of bias unclear in most domains of most studies.

bSerious imprecision with low event rate.

cNumber of studies was not sufficient for assessment of publication bias.

dSerious inconsistency with substantial statistical heterogeneity (I2 = 56%). Limiting analysis to the 9 studies using oral oestrogen yielded OR of 1.01 (95% CI 0.80 to 1.27) and reduced heterogeneity (I2 = 16%).

eSerious risk of bias due to inadequate reporting of study methods. Risk of bias both 'high risk' and 'low risk'

fTwo studies with an outlying result.

Open in table viewer
Summary of findings 5. Progesterone compared with progesterone + GnRH agonist for assisted reproduction cycles

Progesterone compared with progesterone + GnRH agonist for assisted reproduction cycles

Population: women who had undergone IVF/ICSI
Setting: clinic
Intervention: progesterone luteal support
Comparison: progesterone + GnRH agonist

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Progesterone + GnRH agonist

Progesterone luteal support

Live birth or ongoing pregnancy

356 per 1000

255 per 1000
(209 to 309)

OR 0.62
(0.48 to 0.81)

2861
(9 RCTs)

⊕⊝⊝⊝
Very lowa,b

Clinical pregnancy

405 per 1000

310 per 1000
(258 to 367)

OR 0.66
(0.51 to 0.85)

2435
(8 RCTs)

⊕⊕⊝⊝
Lowc,d

OHSS

50 per 1000

50 per 1000
(17 to 137)

OR 1.00

(0.33 to 3.01)

300
(1 study)

⊕⊝⊝⊝

Very lowe,f,

*The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

a Evidence of significant heterogeneity I2 = 69%

b Only three of the studies reported on live birth as an outcome

c Evidence of heterogeneity I2=47%

d Some studies used multiple doses and some used single doses. We have used subgroup analysis to explore this further

e Lack of detail to make a judgement of risk of bias

f Evidence based on a single trial

Open in table viewer
Summary of findings 6. Progesterone regimens for assisted reproduction cycles

Progesterone regimens for assisted reproduction cycles

Population: subfertile women
Setting: assisted reproduction
Comparisons of progesterone regimens

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Comparison

Intervention

Live birth or ongoing pregnancy

IM vs oral

200 per 1000

151 per 1000
(34 to 478)

OR 0.71
(0.14 to 3.66)

40
(1 RCT)

⊕⊝⊝⊝
Very lowa,b,c

Live birth or ongoing pregnancy

IM vs vaginal/rectal

266 per 1000

310 per 1000
(272 to 353)

OR 1.24
(1.03 to 1.5)

2309
(7 RCTs)

⊕⊝⊝⊝
Very lowa,c,d

Live birth or ongoing pregnancy

Vaginal/rectal vs oral

205 per 1000

235 per 1000
(176 to 303)

OR 1.19
(0.83 to 1.69)

857
(4 RCTs)

⊕⊕⊝⊝
Lowa,c,e

Live birth or ongoing pregnancy

Low dose vaginal vs high dose vaginal

301 per 1000

295 per 1000
(266 to 324)

OR 0.97
(0.84 to 1.11)

3720
(5 RCTs)

⊕⊕⊕⊝
Moderatea,c

Live birth or ongoing pregnancy

Short protocol vs long protocol

664 per 1000

672 per 1000
(609 to 728)

OR 1.04
(0.79 to 1.36)

1205
(5 RCTs)

⊕⊕⊕⊝
Lowa,c,e

Live birth or ongoing pregnancy

Micronised vs synthetic

220 per 1000

203 per 1000
(130 to 305)

OR 0.9
(0.53 to 1.55)

470
(2 RCTs)

⊕⊕⊝⊝
Lowb,c,e

Live birth or ongoing pregnancy

Vaginal ring vs vaginal gel

441 per 1000

462 per 1000
(409 to 517)

OR 1.09
(0.88 to 1.36)

1271
(1 RCT)

⊕⊕⊝⊝
Lowc,f,g

Live birth or ongoing pregnancy

Subcutaneous vs vaginal gel

358 per 1000

339 per 1000
(292 to 388)

OR 0.92
(0.74 to 1.14)

1465
(2 RCTs)

⊕⊕⊝⊝
Lowc,g,h

Live birth or ongoing pregnancy

Vaginal vs rectal

306 per 1000

360 per 1000

(220 to 528)

OR 1.28

(0.64 to 2.54)

147

(1 RCT)

⊕⊝⊝⊝
Very lowa,b,c

OHSS

IM vs oral

50 per 1000

50 per 1000

(3 to 475)

OR 1.00

(0.06 to 17.18)

40

(1 RCT)

⊕⊝⊝⊝
Very lowa,b,c

OHSS

Low dose vaginal vs high dose vaginal

60 per 1000

55 per 1000

(35 to 86)

OR 0.91 (0.57 to 1.46)

1251

(2 RCTs)

⊕⊕⊕⊝
Lowb,c,g

OHSS rates not reported for other comparisons.

*The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

aSerious risk of bias due to inadequate reporting of study methods. Risk of bias unclear in most study domains.

bVery serious imprecision with low event rate; findings compatible with meaningful benefit in either arm or with no effect.

cNumber of studies was not sufficient for assessment of publication bias.

dVery serious inconsistency with varying directions of effect (I2 = 71%). Findings not statistically significant when random‐effects model was used, or when analysis was restricted to studies reporting live births.

eSerious imprecision with low event rate; findings compatible with meaningful benefit in the oral arm or with no effect.

fSerious imprecision; findings compatible with meaningful benefit in the gel arm or with no effect.

gSerious risk of bias due to inadequate reporting of study methods in 1 or more studies.

hSerious imprecision; findings compatible with meaningful benefit in the subcutaneous arm or with no effect.

Open in table viewer
Summary of findings 7. Progesterone + oestrogen regimens for assisted reproduction cycles

Progesterone + oestrogen regimens for assisted reproduction cycles

Population: subfertile women
Setting: assisted reproduction
Comparisons of progesterone and oestrogen regimens

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Comparison

Progesterone regimens

Live birth/ongoing pregnancy ‐ short vs long protocol

293 per 1000

309 per 1000
(251 to 372)

OR 1.08

(0.81 to 1.43)

910

(1 RCT)

⊕⊕⊝⊝
Lowa,b,c

Live birth/ongoing pregnancy ‐ low vs high dose protocol

342 per 1000

253 per 1000
(161 to 370)

OR 0.65

(0.37 to 1.13)

285

(1 RCT)

⊕⊝⊝⊝
Very lowa,c,d

OHSS ‐ short vs long protocol

Not reported in any studies

OHSS ‐ low vs high dose protocol

Not reported in any studies

*The basis for the assumed risk is the risk in the control group. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: odds ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

aSerious risk of bias due to inadequate reporting of study methods. Risk of bias unclear in most study domains.

bSerious imprecision; findings compatible with meaningful benefit in either arm or with no effect.

cNumber of studies was not sufficient for assessment of publication bias.

dVery serious imprecision with low event rate; findings compatible with meaningful benefit in either arm or with no effect.

Background

Description of the condition

Assisted reproductive technology (ART), such as in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI), is used increasingly to assist couples to have a family. In cases of fertility treatment during which one or more embryos were transferred, less than one‐third of cases resulted in a live birth (CDC 2009; de Mouzon 2010; Macaldowie 2014). These figures suggest that implantation failure is an important limiting factor in the outcomes of ART.

The endometrium, which lines the uterus, prepares for implantation of the embryo. This process starts in the proliferative phase (from menstruation to ovulation) and extends throughout the luteal phase (from ovulation until menstruation). The luteal phase begins on the day of the luteinising hormone (LH) surge, which causes ovulation. The luteal phase ends at the onset of the next menstruation and usually lasts 12 to 16 days. During the luteal phase, the corpus luteum undergoes morphological and biochemical changes known as 'luteinisation'. Under the influence of LH, specific cells called granulosa cells produce progesterone. This in turn induces the secretory transformation of the endometrium, preparing it for implantation by thickening and increasing vascularisation to facilitate implantation (Farquhar 2010). Implantation occurs six days after fertilisation in natural cycles.

After implantation, trophoblastic tissue of the placenta secretes human chorionic gonadotropin (hCG), which acts on the ovary. hCG maintains and stimulates the corpus luteum, the remnant of the follicle, to produce oestradiol and progesterone (Pabuccu 2005). This is important in maintaining the pregnancy until the placenta takes over steroid hormone production at approximately seven weeks.

From the early phase of assisted reproduction, it has been clear that the luteal phase in ART is not sufficient, although the underlying mechanism is unclear (Edwards 1980). Several theories have been proposed to explain the deficient luteal phase in ART. In ART cycles, the corpus luteum is formed from the remnants of aspirated follicles under the influence of LH and produces progesterone and oestradiol (Messinis 2009). It was first thought that oocyte retrieval caused a luteal phase defect and, in particular, steroid secretion, but this theory was rejected when Kerin (Kerin 1981) demonstrated that aspiration of a single follicle did not lead to impaired steroid function. Another theory was that gonadotropin‐releasing hormone (GnRH) agonist co‐treatment caused prolonged pituitary recovery, which resulted in lack of LH; thus the corpus luteum did not develop fully (Smitz 1992a). Lack of LH was thought to be caused by a short‐loop negative feedback mechanism after hCG administration for oocyte maturation. This theory was also rejected, as long‐loop negative feedback by ovarian oestrogens has a greater effect on LH levels (Miyake 1979), and hCG does not lower LH secretion in non‐stimulated, normal ovulating women (Tavaniotou 2003). Currently it is thought that LH levels are lowered by high steroid levels (Fatemi 2009). Steroid levels are high because of the multiple corpora lutea, which produce more steroids than are produced in a natural cycle. This causes negative feedback on the pituitary gland and lowers LH levels. In this way, the luteal phase is shortened (known as premature luteolysis), and chances of pregnancy are reduced. In summary, premature luteolysis results from high concentrations of steroids caused by higher numbers of corpora lutea (secondary to controlled ovarian stimulation) during the early luteal phase, which in turn inhibit LH release directly by negative feedback.

In 2005, GnRH was introduced as a new means of providing luteal phase support. GnRH blocks the LH surge, and it was assumed that GnRH agonists might maintain their stimulatory effect throughout the luteal phase and restore LH levels ‐ a process that would support the luteal phase (Pirard 2006a). In 2004, Tesarik reported on the use of GnRH agonists six days after ICSI amongst oocyte donors. This study showed that single‐dose agonist administration increased the implantation rate without affecting miscarriage and abortion rates, resulting in an improved birth rate. However the multiple pregnancy rate was also increased (Tesarik 2004).

Adequate luteal phase support is therefore essential during IVF and ICSI for improving implantation and pregnancy rates. This can be achieved by substituting deficient LH with GnRH agonists or hCG, which has a longer half‐life, or directly by using progesterone with or without oestrogen. The ideal method of luteal phase supplementation remains a matter of debate and is the focus of this review.

Description of the intervention

The following agents can be used during the luteal phase.

  1. Progesterone (including micronised progesterone or synthetic progestogens such as dydrogesterone, which have higher bioavailability (Schindler 2009)), administered by the following routes.

    1. Intramuscular (IM).

    2. Oral.

    3. Vaginal ‐ an oral progesterone supplement administered by the vaginal route can lead to higher serum progesterone concentrations (Choavaratana 2004). Progesterone can also be administered vaginally by a gel or cream, which can generate high concentrations by bypassing the first‐pass effect through the liver (Geber 2007a).

    4. Rectal.

  2. Human chorionic gonadotropin (hCG) is similar to LH in its mode of action and physiological effects. Molecular structure is also similar. However hCG differs from LH in that elevated sialic acid residues are responsible for the longer serum half‐life and potency (Balasch 2004). Two types of hCG have been used: human derived and recombinant (Mochtar 2007). hCG is administered by the following routes.

    1. Intramuscular (IM).

    2. Subcutaneous (SC). It has been suggested that the bioavailability of hCG is lower after SC injections than after IM injections, but this remains unclear (Chan 2003;Mannaerts 1998; Saal 1991; Wikland 1995).

  3. Oestrogen: oral, transdermal or vaginal administration in combination with progesterone.

  4. GnRH agonists.

    1. Intranasal.

    2. Intramuscular (IM).

    3. Subcutaneous (SC).

How the intervention might work

In ART, levels of progesterone in the luteal phase are insufficient (see above); therefore the levels of progesterone need to be increased. The progesterone level can be increased directly by giving progesterone, or progesterone and oestrogen in combination, or indirectly by giving hCG, which in turn stimulates progesterone secretion. Addition of a GnRH agonist is thought to restore LH levels during the luteal phase.

Why it is important to do this review

Less than one‐third of all cases involving an embryo result in a live birth. Luteal phase support has a positive effect on the outcome of ART compared with no treatment (van der Linden 2011). Many randomised trials have compared different methods of administration and different preparations to identify the best method of providing luteal phase support. This updated Cochrane review examines all currently available evidence on hCG, progesterone, oestrogen and GnRH analogues as agents for luteal phase support in ART.

Objectives

To determine the relative effectiveness and safety of methods of luteal phase support provided to subfertile women undergoing assisted reproduction.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs) comparing any of the agents used for luteal phase support during the luteal phase of an ART cycle. We included cross‐over trials in the review for completeness but used only first phase data in the analysis. We did not include quasi‐RCTs. We excluded studies investigating luteal phase support involving intrauterine insemination (IUI).

Types of participants

We included all subfertile women undergoing treatment with ART, including IVF or ICSI. We did not take the cause of subfertility into account. We excluded studies including women who had cycles of gamete intrafallopian transfer (GIFT) or zygote intrafallopian transfer (ZIFT), unless these treatments took place in less than 20% of cycles, as pregnancy outcomes with GIFT and ZIFT are less than with IVF. This 20% threshold was arbitrary.

Types of interventions

We included trials if they investigated or included:

  1. any type, dose or route of progesterone, provided at least five doses were given during the luteal phase, to ensure the inclusion of true luteal phase support studies;

  2. any type, dose or route of hCG, provided at least two doses were given during the luteal phase, to ensure the inclusion of true luteal phase support studies;

  3. progesterone combined with oestrogen;

  4. progesterone combined with hCG; or

  5. GnRH agonist during the luteal phase.

We considered all ovarian stimulation protocols.

We excluded trials if they investigated or included:

  1. luteal phase support after frozen embryo transfer;

  2. luteal phase support after embryo transfer from donated oocytes;

  3. luteal phase support after embryo transfer from frozen oocytes or frozen ovarian tissue;

  4. luteal phase support after in vitro maturation (IVM) cycles; or

  5. luteal phase support after intrauterine insemination (IUI) cycles.

Types of outcome measures

Primary outcomes

1. Live birth rate (LBR) or ongoing pregnancy per woman ('live birth' defined as the delivery of one or more living infants; 'ongoing pregnancy' defined as a pregnancy beyond 12 weeks' gestation).

Secondary outcomes

2. Clinical pregnancy rate (CPR) per woman (defined as the presence of a gestational sac, with or without a foetal heartbeat, on ultrasonography).

3. Miscarriage rate (MR) per woman.

4. Ovarian hyperstimulation syndrome (OHSS) per woman.

5. Multiple pregnancy rate per woman (counted as one).

Search methods for identification of studies

This review used information provided in the Cochrane Menstrual Disorder and Subfertility Group (MDSG) module regarding search strategies (www.mrw.interscience.wiley.com/cochrane/clabout/articles/MENSTR/frame.html). We sought all published and unpublished RCTs that described progesterone or hCG, or both, for luteal support in women undergoing ART. We used indexed and free‐text terms. We designed search strategies in consultation with the MDSG Trials Search Co‐ordinator. All searches were run from inception until 05.08.15

Electronic searches

We searched the following databases.

  1. MDSG Specialised Register (see Appendix 1).

  2. Cochrane Central Register of Controlled Trials (CENTRAL) (see Appendix 2).

  3. MEDLINE (see Appendix 3).

  4. EMBASE (see Appendix 4).

  5. PsycINFO (see Appendix 5).

  6. Cumulative Index to Nursing and Allied Health Literature (CINAHL) (see Appendix 6).

  7. Database of Abstracts of Reviews of Effects (DARE) (see Appendix 7).

The MDSG Specialised Register has been prepared through handsearching.

We combined the MEDLINE search with the Cochrane highly sensitive search strategy for identifying randomised trials, which appears in the Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0, Chapter 6, 6.4.11 (Higgins 2011).

We combined the EMBASE search with trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN) (www.sign.ac.uk/mehodology/filters.html#random).

We imposed no language restrictions on the searches.

Searching other resources

We searched the following.

  1. ClinicalTrials.gov (http://clinicaltrials.gov/ct2/home) for ongoing and registered trials (Appendix 8)

  2. The World Health Organization International Trials Registry Platform (www.who.int/trialsearch/Default.aspx) for ongoing and registered trials (Appendix 8)

  3. Conference abstracts on the Web of Science (http://wokinfo.com) (see Appendix 9).

  4. OpenSigle for grey literature from Europe (http://opensigle.inist.fr), using the search string "((chorionic gonadotropin) OR (progesterone)) AND (luteal phase)".

  5. Latin American Caribbean Health Sciences Literature (LILACS) (http://regional.bvsalud.org/php/index.php?lang=en), using the keywords "luteal phase support".

Data collection and analysis

Selection of studies

Two review authors (MvdL, MM) independently screened titles and abstracts to exclude studies that were clearly irrelevant. We retrieved the full texts of potentially eligible studies for further independent scrutiny by two review authors (MvdL, MM) and checked compliance with the inclusion criteria by using the study eligibility form (see Appendix 10). We provided reasons for exclusion in the 'Characteristics of excluded trials' table. When it was unclear whether a study was eligible, we contacted the original study authors. We resolved disagreements through consultation with a third review author (CF).

Data extraction and management

We extracted data using a data extraction form (see Appendix 11) that was designed and pilot‐tested by the review authors. In the case of multiple publications, we referenced studies by their main trial report and linked the references. We contacted the original study authors if further information was required. Three review authors (MvdL, MM, KB) independently extracted data and resolved disagreements through consultation with the other review authors.

Assessment of risk of bias in included studies

We assessed risk of bias with regard to sequence generation, allocation, blinding of participants and personnel, blinding of outcome assessment, completeness of outcome data, selective reporting and other potential sources of bias. We summarised conclusions in a 'Risk of bias' table (see Appendix 12). Review authors judged all six domains as at 'low risk', 'high risk' or 'unclear risk' of bias and described in the table the methods used. When information was missing, we contacted study authors.

  1. Random sequence generation (selection bias).

    1. Proper methods included use of a computer random number generator, coin tossing, dice throwing and shuffling of cards or envelopes.

    2. Allocation by judgement of clinician, preference of participant, lab tests, date of birth, record number and inadequate sequence generation such as day of the week was not sufficient.

  2. Allocation concealment (selection bias).

    1. Proper methods required sequentially numbered drug containers of identical appearance, numbered opaque sealed envelopes or secure third party randomisation such as by telephone or computer allocation.

    2. Prior knowledge of the allocation because of an open random allocation schedule or alternation, rotation, etc, was not sufficient.

  3. Blinding of participants and personnel (performance bias).

    1. Review authors assigned low risk of bias when blinding of clinicians and participants (when possible) was ensured, or when incomplete blinding had no effect on the outcome measurement.

    2. When no blinding was provided and this had an influence on the outcome measurement, review authors identified the study as having risk of bias.

  4. Blinding of outcome assessment (detection bias).

    1. Review authors assigned low risk of bias when blinding of researchers (when possible) was ensured, or when incomplete blinding had no effect on the outcome measurement.

    2. When no blinding was provided and this had an influence on the outcome measurement, review authors identified the study as having risk of bias.

  5. Incomplete outcome data (attrition bias).

    1. Review authors assigned low risk of bias when missing outcome data were unlikely to be related to true outcomes, or when all outcome data were complete.

    2. High risk of bias indicated that missing outcome data were likely to be related to true outcomes, or that the proportion of missing outcome results compared with observed event risk was sufficient to induce clinically relevant bias in observed effect size.

  6. Selective reporting (reporting bias).

    1. Review authors assigned low risk of bias when all prespecified outcomes that were of interest or described in the protocol were reported.

    2. High risk of bias indicated that not all prespecified outcomes were mentioned, reported outcomes were not prespecified or a key outcome that would be expected was not reported.

  7. Free of other bias.

    1. Risk of other bias (e.g. embryo transfer policies different in different arms of the study) showed extreme baseline imbalance.

When risk of bias tables had been completed, we generated a risk of bias summary figure (Higgins 2011).

Measures of treatment effect

We retrieved only dichotomous data for this review; thus we calculated Peto odds ratios (ORs) with 95% confidence intervals (CIs).

Unit of analysis issues

The primary analysis was per woman randomly assigned. We counted multiple live births as one live birth and included cross‐over data from the first phase of the study. When information were missing, we contacted the study authors.

Dealing with missing data

To obtain complete data, as much as possible, we contacted the original study authors. In case data could not be obtained, we undertook imputation for the primary outcome and assumed that no live birth occurred when this was not reported. When data for secondary outcomes were missing, we analysed only available data.

Assessment of heterogeneity

We assessed heterogeneity by examining a forest plot and the I2 statistic according to guidelines set forth in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). If we detected substantial heterogeneity, that is, I2 ≥ 50%, we performed a sensitivity analysis to explore possible explanations.

Assessment of reporting biases

We assessed publication bias by examining a funnel plot if more than 10 studies were included. An asymmetrical funnel plot indicates possible publication bias, although the asymmetry may have other causes. We assessed within‐study reporting bias if study protocols were available, and if we noted differences between outcomes in the protocol and in the subsequent publication.

Data synthesis

We combined the data from primary studies by using a fixed‐effect model in the following comparisons.

  1. hCG versus placebo or no treatment.

  2. Progesterone versus placebo or no treatment.

  3. Progesterone versus hCG regimens.

    1. Progesterone versus hCG.

    2. Progesterone versus progesterone and hCG.

  4. Progesterone versus progesterone and oestrogen.

    1. Oral oestrogen.

    2. Transdermal oestrogen.

    3. Vaginal oestrogen.

    4. Oral and transdermal oestrogen.

  5. Progesterone versus progesterone and GnRH agonist.

    1. Single dose.

    2. Multiple dose.

  6. Progesterone regimens.

    1. IM progesterone versus oral progesterone.

    2. IM progesterone versus vaginal or rectal progesterone.

    3. Vaginal or rectal progesterone versus oral progesterone.

    4. Low‐dose vaginal progesterone (≤ 100 mg) versus high‐dose vaginal progesterone (> 100 mg).

    5. Short protocol versus long protocol.

    6. Micronised progesterone versus synthetic progesterone.

    7. Vaginal ring versus vaginal gel.

    8. Subcutaneous versus vaginal gel.

    9. Vaginal progesterone versus rectal progesterone.

  7. Progesterone + oestrogen regimens.

    1. Short protocol versus long protocol.

    2. Low‐dose oestrogen (≤ 2 mg) versus high‐dose oestrogen (> 2 mg).

When studies contributed to more than one comparison in a pooled analysis, we split as equally as possible comparisons data from the group that appeared in both comparisons. When data were split in this way, we provided details in a footnote in the forest plot.

Subgroup analysis and investigation of heterogeneity

We analysed data in the following subgroups as well.

  1. Ovarian stimulation protocols including:

    1. clomiphene citrate alone without GnRH agonists;

    2. human gonadotropins with clomiphene citrate without GnRH agonists;

    3. human gonadotropins with or without GnRH agonists; and

    4. human gonadotropins with or without GnRH antagonists.

  2. Participants with previously failed cycles.

    1. ≤ 2 failed ART cycles.

    2. > 2 failed ART cycles.

  3. Duration of progesterone.

    1. Stop at day of positive pregnancy test.

    2. Given up to 12 weeks for women who conceive.

  4. Number of embryos transferred.

    1. Single embryo transfer.

    2. > one embryo transferred.

Sensitivity analysis

We performed a sensitivity analysis for the primary outcome to determine differences in results caused by:

  1. eligibility restricted to studies without high risk of bias;

  2. alternative imputation strategies that had been adopted;

  3. use of risk ratio rather than odds ratio as the effect estimate; or

  4. use of a random‐effects rather than a fixed‐effect analysis.

Overall quality of the body of evidence: 'Summary of findings' table

We prepared 'Summary of findings' tables using GRADEPRO software. These tables evaluate the overall quality of the body of evidence for the primary review outcomes, using GRADE (Grades of Recommendation, Assessment, Development and Evaluation) criteria (study limitations (i.e. risk of bias), consistency of effect, imprecision, indirectness and publication bias). We have justified, documented and incorporated into reporting of results for each outcome judgements about evidence quality (high, moderate or low).

Results

Description of studies

See Characteristics of included studies and Characteristics of excluded studies.

Results of the search

We conducted our searches on 05 August 2015 (using the strings reported in the appendices (Appendix 2; Appendix 3; Appendix 4; Appendix 5; Appendix 1; Appendix 6; Appendix 7; Appendix 8; Appendix 9), and in Open System for Information on Grey Literature in Europe (OpenSigle) and Latin American Caribbean Health Sciences Literature (LILACS). We identified 2441 studies and found six studies by using other methods such as handsearching.

On the website ClinicalTrials.gov in November 2014, we found 10 ongoing studies after using the keywords "luteal phase support". One study did not provide sufficient contact details. Five study authors did not reply (NCT01178931, NCT00828191, NCT00656201, NCT00708539, NCT01850030). One study author replied, and this study turned out to be already published (NCT00827983 as Baker 2014). Three studies were already published (NCT01147770 as Kyrou 2011, NCT01367912 as Tonguc 2011 and NCT01177904 as Kohls 2012). The World Health Organization International Trials Registry Platform (ICTRP), when searched with the keywords "luteal phase support", brought up eight new studies. Three studies did not provide sufficient contact details. Three studies were already published (ISRCTN88722916 as Aboulghar 2008, ICTR2013050713265N1 as Salehpour 2013, and ICTR138807192568N1 as Aghsa 2012). One study author did reply but had no data ready (EUCTR2013‐001105‐81‐HU). One study author did not reply (NCT01237535). From both these sites there were 11 ongoing studies.

Further database searches on 4 August 2015 identified two new studies eligible for inclusion and we have incorporated their data in the abstract, results and discussion sections of the review. Two studies requiring additional information before we could assess eligibility await classification for inclusion or exclusion at the next update of this review.

A further search of the ICTRP and clinicaltrials.gov (Appendix 8) sites on 4 August 2015 found another 17 ongoing studies. After de‐duplication a total of 22 ongoing studies remained. For full details of all ongoing studies see Characteristics of ongoing studies.

After duplicates were removed, 578 studies were left for screening. We excluded 352 clearly irrelevant studies. We obtained and fully reviewed the full‐text articles for the other 226 studies. We excluded all quasi‐randomised trials, together with articles that did not meet our inclusion criteria. We excluded another 31 articles from the review and included in the meta‐analysis a total of 94 studies (see Figure 1 for a study flow diagram). Three trials are awaiting assessment (Pirard 2015; Tomic 2015; Zafardoust 2015) .

Figure 1
Study flow diagram.

Study flow diagram.

Included studies

Study design

We included 94 studies, all of which were randomised controlled trials. We found no cross‐over trials for inclusion. In total, included studies consisted of 25,471 women with a mean age of 32.4 years. Inclusion and exclusion criteria varied among studies. Some studies included women with polycystic ovarian syndrome (PCOS), but this was an exclusion criterion in other studies. A few studies included women undergoing their first cycle, but most studies included women who had already undergone ART. Overall a mean of 2.43 embryos per woman were transferred, most with a maximum of three or four embryos.

For 24 studies, only the abstract was published (Albert 1991; Ata 2010; Beltsos 2011; Brigante 2013; Caligara 2007; Colakoglu 2011; Dunstone 1999; Erdem 2013; Geber 2007; Geusa 2001; Kably Ambe 2005; Loh 1996; Macrolin 1993; Miller 2010; Nallapeta 2013; Porcu 2003; Rodriguez‐Pezino 2004; Salehpour 2013; Saucedo 2000; Saucedo 2003; Serour 2012; Strehler 1999; Sumita 2003; Ugur 2001); the other studies were full‐text journal publications. Only 13 were multi‐centre studies (Baker 2014; Belaisch‐Allart 1990; Beltsos 2011; Bergh 2012; Doody 2009; Elgindy 2010; Kleinstein 2005; Lockwood 2014; Miller 2010; Nyboe Andersen 2002; Pouly 1996; Stadtmauer 2013; Zegers‐Hochschild 2000).

Thirteen of our included studies were carried out in the United States of America (Albert 1991; Baker 2014; Beltsos 2011; Doody 2009; Engmann 2008; Goudge 2010; Hurd 1996; Licciardi 1999; Miller 2010; Propst 2001; Stadtmauer 2013; Williams 2001; Yanushpolsky 2010). Ten studies were reported from Turkey (Ata 2008; Ata 2010; Ceyhan 2008; Colakoglu 2011; Erdem 2013; Gorkemli 2004; Isik 2009; Isikoglu 2007; Tonguc 2011; Ugur 2001; Yildiz 2014) and eight from Italy (Abate 1999; Abate 1999a; Artini 1995; Brigante 2013; Dal Prato 2008; Geusa 2001; Perino 1997; Porcu 2003). Twenty‐seven studies were conducted in other European countries: Austria (Feichtinger 2011), Belgium (Fatemi 2006), Denmark (Humaidan 2006; Nyboe Andersen 2002), Finland (Vimpeli 2001), France (Belaisch‐Allart 1987; Belaisch‐Allart 1990; Macrolin 1993; Pouly 1996), Germany (Kleinstein 2005; Ludwig 2001; Ludwig 2002; Strehler 1999), Greece (Drakakis 2007; Kyrou 2011), the Netherlands (Beckers 2000; Mochtar 2006), Spain (Caligara 2007; Kably Ambe 2005; Kohls 2012; Martinez 2000; Serna 2008; Tesarik 2006) and the UK (Dunstone 1999; Nallapeta 2013; Tay 2005). Thirteen were carried out in Asia: China (Lam 2008; Lin 2013; Ng 2003; Ng 2007; Wong 1990), India (Chakravarty 2005; Ganesh 2011; Inamdar 2012; Patki 2007; Sumita 2003), Japan (Fujimoto 2002; Iwase 2008) and Singapore (Loh 1996). We also found studies from Australia (Torode 1987), Brasil (Geber 2007; Geber 2007a), Canada (Colwell 1991), Egypt (Aboulghar 2008; Elgindy 2010; Serour 2012; Aboulghar 2015), Israel (Friedler 1999; Golan 1993; Kupferminc 1990; Lewin 1994), Iran (Aghahosseini 2011; Aghsa 2012; Moini 2011; Salehpour 2013), Jordan (Qublan 2008) and Mexico (Rodriguez‐Pezino 2004; Saucedo 2000; Saucedo 2003), and we found three multi‐centre, multi‐national studies: one from Chile, Colombia and Brazil (Zegers‐Hochschild 2000), one from Denmark and Sweden (Bergh 2012) and one from Hungary, Germany, Italy, Switzerland and the UK (Lockwood 2014).

Participants

Participants were women undergoing ART for a large variety of indications, including (low‐grade) endometriosis, polycystic ovarian syndrome or an unknown or unspecified cause of infertility.

Interventions

Thirteen studies investigated down‐regulation using GnRH antagonists (Baker 2014; Ceyhan 2008; Engmann 2008; Fatemi 2006; Geber 2007; Humaidan 2006; Isik 2009; Kohls 2012; Kyrou 2011; Nyboe Andersen 2002; Rodriguez‐Pezino 2004; Serna 2008; Tesarik 2006), and six studies did not use down‐regulation with GnRH analogues (Colwell 1991; Hurd 1996; Kupferminc 1990; Lewin 1994; Torode 1987; Wong 1990); clomiphene citrate, human menopausal gonadotropin (hMG) or both were used in most of those studies. Fifty‐three studies investigated GnRH agonists, and two studies investigated both GnRH agonists and antagonists (Kably Ambe 2005; Lockwood 2014). The other studies did not define the down‐regulation protocol used.

Outcomes

Live birth was reported in only 28 studies (Abate 1999; Abate 1999a; Ata 2010; Baker 2014; Beckers 2000; Bergh 2012; Chakravarty 2005; Dal Prato 2008; Doody 2009; Golan 1993; Goudge 2010; Isik 2009; Isikoglu 2007; Iwase 2008; Lewin 1994; Lin 2013; Lockwood 2014; Ludwig 2001; Mochtar 2006; Nyboe Andersen 2002; Pouly 1996; Propst 2001; Qublan 2008; Stadtmauer 2013; Tay 2005; Tesarik 2006; Yanushpolsky 2010; Zegers‐Hochschild 2000).

Fifty‐five studies reported ongoing pregnancy (Abate 1999a; Aghahosseini 2011; Aghsa 2012; Ata 2010; Aboulghar 2015Baker 2014; Beckers 2000; Belaisch‐Allart 1987; Belaisch‐Allart 1990; Beltsos 2011; Bergh 2012; Brigante 2013; Ceyhan 2008; Chakravarty 2005; Colwell 1991; Dal Prato 2008; Doody 2009; Engmann 2008; Fatemi 2006; Feichtinger 2011; Friedler 1999; Ganesh 2011; Golan 1993; Gorkemli 2004; Goudge 2010; Hurd 1996; Inamdar 2012; Isik 2009; Isikoglu 2007; Iwase 2008; Kleinstein 2005; Kohls 2012; Kupferminc 1990; Kyrou 2011; Lewin 1994; Lin 2013; Lockwood 2014; Ludwig 2001; Ludwig 2002; Macrolin 1993; Miller 2010; Mochtar 2006; Ng 2007; Nyboe Andersen 2002; Perino 1997; Pouly 1996; Propst 2001; Qublan 2008; Salehpour 2013; Serna 2008; Stadtmauer 2013; Tay 2005; Tesarik 2006; Tonguc 2011; Yanushpolsky 2010; Yildiz 2014Zegers‐Hochschild 2000).

All studies reported (clinical) pregnancy, except for seven studies, which used miscarriage rate (Nallapeta 2013) or ongoing pregnancy as the main outcome (Beltsos 2011; Colwell 1991; Fatemi 2006; Feichtinger 2011; Serna 2008; Tay 2005).

Miscarriage is reported in 45 studies (Aghahosseini 2011; Aghsa 2012; Ata 2008; Baker 2014; Beckers 2000; Belaisch‐Allart 1987; Bergh 2012; Chakravarty 2005; Colwell 1991; Dal Prato 2008; Drakakis 2007; Elgindy 2010; Engmann 2008; Fatemi 2006; Friedler 1999; Ganesh 2011; Geber 2007a; Golan 1993; Iwase 2008; Kably Ambe 2005; Kleinstein 2005; Kohls 2012; Kupferminc 1990; Kyrou 2011; Lam 2008; Licciardi 1999; Lin 2013; Lockwood 2014; Ludwig 2001; Ludwig 2002; Martinez 2000; Miller 2010; Nallapeta 2013; Ng 2007; Nyboe Andersen 2002; Perino 1997; Pouly 1996; Qublan 2008; Rodriguez‐Pezino 2004; Salehpour 2013; Saucedo 2000; Serna 2008; Strehler 1999; Tonguc 2011; Yanushpolsky 2010), OHSS in 10 studies (Albert 1991; Belaisch‐Allart 1990; Ceyhan 2008; Doody 2009; Iwase 2008; Lin 2013; Ludwig 2001; Macrolin 1993; Martinez 2000; Ugur 2001) and multiple pregnancy in 20 studies (Aghsa 2012; Ata 2008; Bergh 2012; Colwell 1991; Geber 2007a; Goudge 2010; Inamdar 2012; Isik 2009; Iwase 2008; Kleinstein 2005; Kohls 2012; Kyrou 2011; Licciardi 1999; Ludwig 2001; Ng 2007; Nyboe Andersen 2002; Pouly 1996; Strehler 1999; Tonguc 2011; Zegers‐Hochschild 2000).

Excluded studies

We excluded from the review 129 studies that did not meet our inclusion criteria. In accordance with the guidelines of the MDSG, we excluded all quasi‐randomised trials (Anserini 2001; Anthony 1993; Buvat 1988; Buvat 1990; Herman 1990; Herman 1996; Leeton 1985; Mahadevan 1985; McBain 1987; Polson 1992; Smith 1989; Smitz 1993; Yovich 1984; Yovich 1985; Yovich 1991), which had been included in an older version of this review (Daya 2004). We excluded all studies that included GIFT or ZIFT in more than 20% of cycles, or that did not mention the percentage of GIFT or ZIFT cycles used (Allen 2004; Araujo 1994; Araujo Filho 1996; Smitz 1988; Smitz 1992; van Steirteghem 1988).

Risk of bias in included studies

See the 'Summary of findings' tables for an overall assessment of the quality of evidence for each comparison. We prepared a table for each comparison (summary of findings Table for the main comparison; summary of findings Table 2; summary of findings Table 3; summary of findings Table 4; summary of findings Table 5; summary of findings Table 6; summary of findings Table 7). See also the risk of bias graph (see Figure 2) and the risk of bias summary (see Figure 3) for an overview.

Figure 2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Forty eight studies did not report the method of randomisation used. Most of those that did report the randomisation method used computerised randomisation (Aghahosseini 2011; Aghsa 2012; Ata 2008; Ata 2010; Aboulghar 2015; Baker 2014; Bergh 2012; Caligara 2007; Ceyhan 2008; Engmann 2008; Fatemi 2006; Feichtinger 2011; Gorkemli 2004; Humaidan 2006; Inamdar 2012; Isik 2009; Isikoglu 2007; Iwase 2008; Kleinstein 2005; Kohls 2012; Kyrou 2011; Lam 2008; Lin 2013; Lockwood 2014; Ludwig 2002; Martinez 2000; Ng 2003; Ng 2007; Pouly 1996; Serna 2008; Tesarik 2006; Yanushpolsky 2010; Yildiz 2014; Zegers‐Hochschild 2000). Randomisation lists or tables were often used (Belaisch‐Allart 1987; Belaisch‐Allart 1990; Ludwig 2001; Qublan 2008), as was a third party or study investigator (Aboulghar 2008; Dal Prato 2008; Ganesh 2011; Stadtmauer 2013). Doody 2009 used a telephone‐based electronic interactive voice response system, and Elgindy 2010 and Propst 2001 used permuted block randomisation.

Fifty studies did not report the method of allocation concealment used. Numbered, sealed envelopes were used most of the time (Aboulghar 2008; Ata 2008; Baker 2014; Beckers 2000; Dal Prato 2008; Elgindy 2010; Engmann 2008; Ganesh 2011; Geber 2007; Geber 2007a; Goudge 2010; Humaidan 2006; Hurd 1996; Kleinstein 2005; Kohls 2012; Kyrou 2011; Lam 2008; Lockwood 2014; Mochtar 2006; Ng 2003; Ng 2007; Nyboe Andersen 2002; Propst 2001; Qublan 2008; Salehpour 2013; Serna 2008; Serour 2012; Tesarik 2006; Tonguc 2011; Williams 2001). Caligara 2007 used a phone call to an unrelated department, Ceyhan 2008 central consultation, Doody 2009 a telephone‐based electronic interactive voice response system and Feichtinger 2011; Inamdar 2012 and Isik 2009 a third party nurse. Ata 2010, Isikoglu 2007, Lam 2008 and Yanushpolsky 2010 concealed allocation via an onsite computer system by utilising locked files.

Fatemi 2006 and Ludwig 2002 were the only studies that reported using a non‐concealed randomisation list.

Blinding

Fourteen studies mentioned that they used blinding (Aghsa 2012; Ata 2008; Belaisch‐Allart 1990; Bergh 2012; Colwell 1991; Doody 2009; Ganesh 2011; Geber 2007; Geber 2007a; Inamdar 2012; Isik 2009; Isikoglu 2007; Tesarik 2006; Tonguc 2011). The other studies did not blind personnel, researchers or participants (Aboulghar 2008; Aghahosseini 2011; Ata 2010; Caligara 2007; Ceyhan 2008; Dal Prato 2008; Doody 2009; Engmann 2008; Fatemi 2006; Ganesh 2011; Kleinstein 2005; Kohls 2012; Lam 2008; Lin 2013; Lockwood 2014; Miller 2010; Ng 2003; Ng 2007; Nyboe Andersen 2002; Propst 2001; Salehpour 2013; Serna 2008; Yanushpolsky 2010) or did not mention blinding. The studies of Moini 2011, Patki 2007 and Qublan 2008 were placebo controlled but did not specify the use of blinding. The main reason reported (in the paper or after contact with the original authors) for not blinding was that the study authors believed blinding would be difficult because of the different routes of administration used. We believe it is possible to use proper blinding with a double‐dummy design.

Incomplete outcome data

Fifty‐two studies reported the numbers of and reasons for withdrawal, or reported no drop‐outs. Qublan 2008 reported that more participants were recruited than analysed but did not report the reasons, and Brigante 2013 reported more outcomes than included patients.

Selective reporting

As stated before, only an abstract was available for 14 studies, which suggested high risk of selective reporting. Most studies reported planned outcomes, except for 18 (Abate 1999; Artini 1995; Beckers 2000; Belaisch‐Allart 1987; Belaisch‐Allart 1990; Drakakis 2007; Feichtinger 2011; Friedler 1999; Golan 1993; Goudge 2010; Hurd 1996; Kupferminc 1990; Lewin 1994; Licciardi 1999; Perino 1997; Tay 2005; Torode 1987; Vimpeli 2001). Aghahosseini 2011, Aghsa 2012, Ganesh 2011 and Wong 1990 reported outcomes in the Results section that were different from those reported in the Methods section.

Other potential sources of bias

Eight studies were supported by the pharmaceutical companies that had supplied the investigated interventions (Baker 2014; Beltsos 2011; Bergh 2012; Doody 2009; Lockwood 2014; Miller 2010; Propst 2001; Stadtmauer 2013). Two were supported by a grant from a pharmaceutical company (Ludwig 2002; Vimpeli 2001), and Kleinstein 2005 was supported by a pharmaceutical company, but this company does not supply the investigated products. One study (Ludwig 2001) reported a relatively large number of miscarriages, which were not consistent with reported rates of live birth, clinical pregnancy and ongoing pregnancy. This study was rated as having high risk of bias in this domain.

Assessment for publication bias

We looked at the following comparisons: 3.2 Progesterone versus hCG regimens, outcome clinical pregnancy rate (CPR); 4.2 Progesterone versus progesterone + oestrogen (CPR); 6.2.2 Progesterone regimens, outcome CPR: IM progesterone versus vaginal or rectal progesterone; and 6.2.4 Progesterone regimens, outcome CPR: low‐dose vaginal progesterone versus high‐dose vaginal progesterone for publication bias, as these four comparisons involved more than 10 included studies. We did this by making three funnel plots, combining comparisons 6.2.2 Progesterone regimens, outcome CPR: IM progesterone versus vaginal or rectal progesterone; and 6.2.4 Progesterone regimens, outcome CPR: low‐dose vaginal progesterone versus high‐dose vaginal progesterone (see Figure 4; Figure 5; Figure 6). Figure 4 shows most of the studies around the pooled estimate, suggesting that different sizes of studies were included. Although one study (Golan 1993) seemed to be out of the expected pattern, we did not see asymmetry; therefore this funnel plot indicated a small risk of publication bias. Figure 5 shows most of the studies around the pooled estimate with the studies reasonably equally divided on both sides. A large space at the lower side of the graph means that small studies may not be published. Overall the funnel plot revealed a small risk of publication bias. Figure 6 shows most of the studies around the pooled estimate with all studies reasonably equally divided on both sides. This funnel plot also showed that small studies may not be published. Overall it indicated a small risk of publication bias.

Figure 4
Funnel plot of comparison: 2 Progesterone vs hCG, outcome: 2.2 Clinical pregnancy rate.

Funnel plot of comparison: 2 Progesterone vs hCG, outcome: 2.2 Clinical pregnancy rate.

Figure 5
Funnel plot of comparison: 4 [NEW] Progesterone vs progesterone + oestrogen, outcome: 4.2 Clinical pregnancy rate.

Funnel plot of comparison: 4 [NEW] Progesterone vs progesterone + oestrogen, outcome: 4.2 Clinical pregnancy rate.

Figure 6
Funnel plot of comparison: 6 [NEW] Progesterone regimens, outcome: 6.2 Clinical pregnancy rate.

Funnel plot of comparison: 6 [NEW] Progesterone regimens, outcome: 6.2 Clinical pregnancy rate.

Effects of interventions

See: Summary of findings for the main comparison hCG compared with placebo/no treatment for assisted reproduction cycles; Summary of findings 2 Progesterone compared with placebo/no treatment for assisted reproduction cycles; Summary of findings 3 Progesterone compared with hCG regimens for assisted reproduction cycles; Summary of findings 4 Progesterone compared with progesterone + oestrogen for assisted reproduction cycles; Summary of findings 5 Progesterone compared with progesterone + GnRH agonist for assisted reproduction cycles; Summary of findings 6 Progesterone regimens for assisted reproduction cycles; Summary of findings 7 Progesterone + oestrogen regimens for assisted reproduction cycles

1. hCG versus placebo or no treatment

Primary outcome
1.1 Live birth/ongoing pregnancy rate

Three studies reported live birth (Beckers 2000) or ongoing pregnancy (Belaisch‐Allart 1990; Kupferminc 1990). See Figure 7 for details of this comparison.

Figure 7
Forest plot of comparison: 1 Human chorionic gonadotropin (hCG) vs placebo or no treatment, outcome: 1.1 Live birth/ongoing pregnancy rate.

Forest plot of comparison: 1 Human chorionic gonadotropin (hCG) vs placebo or no treatment, outcome: 1.1 Live birth/ongoing pregnancy rate.

Live birth and pregnancy rates were higher in the hCG group (OR 1.76, 95% CI 1.08 to 2.86, three RCTs, 527 women, I2 = 24%, very low‐quality evidence).

However this findings was sensitive to choice of statistical model, and when a random‐effects model was used there was no longer evidence of a difference between the groups (OR 1.67, 95% CI 0.90 to 3.12).

When the analysis was restricted to live birth, only 38 women were included and again there was no evidence of a difference between the groups (OR 2.20, 95% CI 0.38 to 12.87).

Secondary outcomes
1.2 Clinical pregnancy rate (CPR)

Five studies (Artini 1995; Beckers 2000; Belaisch‐Allart 1990; Kupferminc 1990; Torode 1987) reported this outcome.
Evidence suggested no differences between groups (OR 1.30, 95% CI 0.90 to 1.88, five RCTs, 746 women, I2 = 0%, very low quality evidence). See Analysis 1.2 for details of this comparison.

Subgroup analysesfor clinical pregnancy rate

1.2.1 Ovarian stimulation protocol

Five studies were included in subgroups. Researchers utilised hCG with clomiphene citrate without GnRH agonists (Torode 1987), hCG with or without GnRH agonists (Artini 1995; Beckers 2000; Belaisch‐Allart 1990) or hCG with or without GnRH agonists (Kupferminc 1990). Evidence suggested no substantial differences from the main analysis in any of the subgroups. See Analysis 1.3 for details.

1.2.2 Women with previously failed cycles

No data were available for this subgroup analysis.

1.2.3 Duration of treatment

Not applicable.

1.2.4Number of embryos transferred

No data were available for this subgroup analysis.

1.3 Miscarriage rate

Two studies (Beckers 2000; Kupferminc 1990) reported this outcome.
Evidence suggested no differences between groups (OR 1.51, 95% CI 0.37 to 6.21, two RCTs, 140 women, I2 = 0%). See Analysis 1.4 for details of this comparison.

1.4 Ovarian hyperstimulation syndrome (OHSS)

One study (Belaisch‐Allart 1990) reported this outcome.

This result showed benefit for the placebo group (OR 4.28, 95% CI 1.91 to 9.60, one RCT, 387 women, low quality evidence). As this result was based on a single study, it should be interpreted with caution. See Analysis 1.5 for details of this comparison.

1.5 Multiple pregnancy

No studies reported this outcome.

2. Progesterone versus placebo or no treatment

Primary outcome
2.1 Live birth/ongoing pregnancy rate

Five studies reported live birth (Abate 1999a) or ongoing pregnancy (Belaisch‐Allart 1987; Colwell 1991; Hurd 1996; Kupferminc 1990).

Rates of live birth or ongoing pregnancy were higher in the progesterone group (OR 1.77, 95% CI 1.09 to 2.86, five RCTs, 642 women, I2 = 19%, very low quality evidence).

Findings require cautious interpretation, as when the analysis was restricted to live birth, evidence suggested no differences between groups (OR 4.21, 95% CI 0.93 to 19.18, one RCT, 156 women). Heterogeneity was high in the studies of ongoing pregnancy (I2 = 68%).

See Figure 8 for details of this comparison.

Figure 8
Forest plot of comparison: 2 Progesterone vs placebo or no treatment, outcome: 2.1 Live birth/ongoing pregnancy rate.

Forest plot of comparison: 2 Progesterone vs placebo or no treatment, outcome: 2.1 Live birth/ongoing pregnancy rate.

Sensitivity analyses

Pooled findings for live birth/ongoing pregnancy were no longer statistically significant when a random‐effects model was used (OR 1.77, 95% CI 0.96 to 3.26); this underlines the need for caution in interpreting these findings. Other sensitivity analyses did not materially affect the findings.

Secondary outcomes
2.2 Clinical pregnancy rate

Seven studies (Abate 1999; Abate 1999a; Artini 1995; Belaisch‐Allart 1987; Hurd 1996; Kupferminc 1990; Wong 1990) reported this outcome.
Pregnancy rates were higher in the progesterone group (OR 1.89, 95% CI 1.30 to 2.75, seven RCTs, 841 women, I2 = 0%, low quality evidence). See Analysis 2.2 for details of this comparison.

Subgroup analysesfor clinical pregnancy rate

2.2.1 Ovarian stimulation protocol

Findings of the subgroup of four studies (Abate 1999; Abate 1999a; Artini 1995; Kupferminc 1990) that administered human gonadotropins with or without GnRH agonists were consistent with the main findings, showing benefit for the progesterone group. Benefit was stronger when the study without GnRH agonists was excluded. Studies that administered clomiphene citrate alone without GnRH agonists (Hurd 1996) or human gonadotropins with clomiphene citrate without GnRH agonists (Belaisch‐Allart 1987; Wong 1990) did not clearly show benefit for the progesterone group. However results of the test for subgroup differences were not statistically significant.

See Analysis 2.3 for details.

2.2.2 Women with previously failed cycles

No data were available for this subgroup analysis.

2.2.3 Duration of progesterone

Findings of the subgroup of four studies (Abate 1999; Abate 1999a; Belaisch‐Allart 1987; Hurd 1996) that administered progesterone for up to 12 weeks were consistent with the main findings, showing benefit for the progesterone group. The subgroup of three studies (Artini 1995; Kupferminc 1990; Wong 1990) that stopped progesterone at the time of the pregnancy test did not clearly show benefit for the progesterone group. However results of the test for subgroup differences were not statistically significant.

See Analysis 2.4 for details.

2.2.4 Number of embryos transferred

No data were available for this subgroup analysis.

2.3 Miscarriage rate

Three studies (Belaisch‐Allart 1987; Colwell 1991; Kupferminc 1990) reported this outcome.
No evidence suggested differences between groups (OR 1.22, 95% CI 0.49 to 3.03, three RCTs, 425 women, I2 = 0%). See Analysis 2.5 for details of this comparison.

2.4 Ovarian hyperstimulation syndrome (OHSS)

No studies reported this outcome.

2.5 Multiple pregnancy

One study (Colwell 1991) reported this outcome.

Evidence suggested no differences between groups (OR 5.87, 95% CI 0.22 to 155.76, one RCT, 34 women). See Analysis 2.6 for details of this comparison.

3. Progesterone versus hCG regimens

Primary outcome
3.1 Live birth/ongoing pregnancy rate

Five studies reported live birth (Golan 1993; Ludwig 2001) or ongoing pregnancy (Kupferminc 1990; Macrolin 1993; Tay 2005). Researchers compared progesterone versus hCG (four RCTs, 434 women) or versus progesterone plus hCG (two RCTs, 399 women).

Evidence suggested no differences between groups in rates of live birth or ongoing pregnancy (OR 0.95, 95% CI 0.65 to 1.38, five RCTs, 833 women, I2 = 0%, low quality evidence).

Findings were similar, regardless of whether the comparison group received hCG only or hCG plus progesterone. See Figure 9 for details of this comparison.

Figure 9
Forest plot of comparison: 3 Progesterone vs hCG regimens, outcome: 3.1 Live birth or ongoing pregnancy rate.

Forest plot of comparison: 3 Progesterone vs hCG regimens, outcome: 3.1 Live birth or ongoing pregnancy rate.

Restriction of the analysis to studies reporting live birth also showed no evidence of differences between groups.

Secondary outcomes
3.2 Clinical pregnancy rate

Eighteen studies reported this outcome. Researchers compared progesterone versus hCG (11 RCTs, 1378 women) or versus progesterone plus hCG (seven RCTs, 977 women).

Evidence suggested no differences between groups in rates of clinical pregnancy (OR 1.08, 95% CI 0.90 to 1.30, 16 RCTs, 2355 women, I2 = 0%, moderate quality evidence).

Findings did not differ substantially, regardless of whether the comparison group received hCG only or hCG plus progesterone. See Analysis 3.2 for details.

Because this comparison included more than 10 studies, we prepared a funnel plot to determine the risk of publication bias (see Figure 4), which is assessed in the section Selective reporting (reporting bias). We concluded that this study showed a small risk of publication bias.

Subgroup analyses for clinical pregnancy rate

3.2.1 Ovarian stimulation method

Four studies of progesterone versus progesterone plus hCG were subgrouped by method of ovarian stimulation. One (Wong 1990) utilised hCG with clomiphene citrate without GnRH agonists, and three utilised hCG with or without GnRH agonists (Fujimoto 2002; Ludwig 2001; Macrolin 1993). Findings did not differ substantially from those of the main analysis in either subgroup (see Analysis 3.3). No studies of progesterone versus hCG alone were available for this subgroup analysis.

3.2.2 Women with previously failed cycles

No data were available for this subgroup analysis.

3.2.3 Duration of progesterone

Seven studies of progesterone versus progesterone plus hCG were subgrouped by duration of progesterone treatment. Six stopped treatment at the pregnancy test (Artini 1995; Golan 1993; Humaidan 2006; Kupferminc 1990; Ludwig 2001; Martinez 2000), and one administered progesterone for up to 12 weeks when pregnant (Vimpeli 2001). Findings did not differ substantially from those of the main analysis in either subgroup. No studies of progesterone versus hCG alone were available for this subgroup analysis. See Analysis 3.4 for details of this comparison.

3.2.4 Number of embryos transferred

No data were available for this subgroup analysis.

3.3 Miscarriage rate

Five studies reported this outcome. Researchers compared progesterone versus hCG (five RCTs, 735 women) or versus progesterone plus hCG (one RCT, 97 women).

Evidence suggested no differences between groups in rates of miscarriage (OR 1.24, 95% CI 0.66 to 12.31, five RCTs, 832 women, I2 = 0%). Findings did not differ substantially, regardless of whether the hCG group received progesterone as well. See Analysis 3.6 for details.

3.4 Ovarian hyperstimulation syndrome (OHSS)

Five studies reported this outcome. They compared progesterone versus hCG (four RCTs, 671 women) or versus progesterone plus hCG (three RCTs, 678 women). Figure 10

Figure 10
Forest plot of comparison: 3 Progesterone vs hCG regimens, outcome: 3.5 OHSS.

Forest plot of comparison: 3 Progesterone vs hCG regimens, outcome: 3.5 OHSS.

Progesterone was associated with lower rates of OHSS rates than hCG with or without progesterone (OR 0.46, 95% CI 0.30 to 0.71, 5 RCTs, 1293 women , I2=48%) .

Findings differed according to whether the hCG group received progesterone as well, though the statistical test for subgroup differences suggested no significant difference between the groups (p=0.30). When progesterone was compared with hCG alone, there was no clear evidence of a difference between the groups (OR 0.57, 95% CI 0.32 to 1.00, 4 studies I2=41%). When progesterone alone was compared with hCG plus progesterone, rates were lower in the progesterone alone group, though with substantial statistical heterogeneity (OR 0.36, 95% CI 0.18 to 0.69, 3 RCTs, 678 women ,l2=61%).

3.5 Multiple pregnancy

One study reported this outcome. Researchers compared progesterone versus hCG (112 women) or versus progesterone plus hCG (97 women).

Evidence suggested no differences between groups for this outcome (OR 0.44, 95% CI 0.07 to 2.65, one RCT, 209 women). See Analysis 3.7 for details of this comparison.

4. Progesterone versus progesterone + oestrogen

After data extraction, we found that different routes of oestrogen administration were used as well as different dosages of oestrogen. Therefore we decided to stratify the analysis on the basis of route of administration.

Primary outcome
4.1 Live birth/ongoing pregnancy rate

Nine studies reported live birth (Ata 2010; Lewin 1994; Lin 2013) or ongoing pregnancy (Aghahosseini 2011; Ceyhan 2008; Engmann 2008; Fatemi 2006; Serna 2008; Yanushpolsky 2010). Routes of oestrogen administration were oral (six RCTs, 1266 women), transdermal (two RCTs, 219 women) and vaginal (one RCT, 166 women). See Figure 11 for details of this comparison.

Figure 11
Forest plot of comparison: 4 Progesterone vs progesterone + oestrogen, outcome: 4.1 Live birth/ongoing pregnancy rate.

Forest plot of comparison: 4 Progesterone vs progesterone + oestrogen, outcome: 4.1 Live birth/ongoing pregnancy rate.

Evidence suggested no differences between groups in rates of live birth or ongoing pregnancy (OR 1.12, 95% CI 0.91 to 1.38, nine RCTs, 1651 women, I2 = 0%, low quality evidence).

Findings were similar when the analysis was restricted to studies reporting live birth (OR 1.32, 95% CI 0.93 to 1.86, three RCTs, 562 women, I2 = 0%).

When data were considered by route of oestrogen administration, findings did not differ substantially from those of the main analysis.

Secondary outcomes
4.2 Clinical pregnancy rate

Fourteen studies reported this outcome (Aghahosseini 2011; Ata 2010; Ceyhan 2008; Colakoglu 2011; Drakakis 2007; Elgindy 2010; Engmann 2008; Erdem 2013; Gorkemli 2004; Kably Ambe 2005; Lewin 1994; Lin 2013; Moini 2011; Yanushpolsky 2010).

Routes of oestrogen administration were oral (nine RCTs, 1427 women), transdermal (three RCTs, 364 women), vaginal (two RCTs, 301 women) and oral/transdermal (one RCT, 77 women). Elgindy 2010 was a three‐arm study comparing progesterone, progesterone + oral oestrogen and progesterone + vaginal oestrogen. To make sure we did not duplicate data, we divided data from the progesterone‐only arm by two, so half of the progesterone‐only events and participants were reported under the subgroup 'oral', and the other half of the progesterone‐only events and participants were reported under the subgroup 'vaginal'.

When studies were pooled, no evidence suggested differences between groups (OR 0.86, 95% CI 0.72 to 1.04, 14 RCTs, 4169 women, I2 = 56%, low quality evidence). However substantial heterogeneity was noted for this analysis (56%), and results of the test for subgroup differences were statistically significant (P value = 0.004).

When the data were considered by route of oestrogen administration, heterogeneity in the comparison using oral oestrogen was relatively low (I2 = 16%), and evidence suggested no differences between groups. However heterogeneity in comparisons using other routes of administration was high (I2 = 56% to 82%), and in studies using transdermal oestrogen, a higher pregnancy rate was reported in the progesterone + oestrogen groups. These findings should be regarded with caution because of the inconsistency observed between studies and the small quantity of data provided.

Because this comparison included more than 10 studies, we prepared a funnel plot to determine the risk of publication bias (see Figure 5), which is discussed in the section Selective reporting (reporting bias). We concluded that the study showed a small risk of publication bias.

Subgroup analysesfor clinical pregnancy rate

4.2.1 Ovarian stimulation protocol

Eight studies were subgrouped by method of ovarian stimulation. Seven utilised hCG with or without GnRH agonists (Aghahosseini 2011; Drakakis 2007; Elgindy 2010; Engmann 2008; Lewin 1994; Moini 2011; Yanushpolsky 2010), and two utilised hCG with or without GnRH antagonists (Ceyhan 2008; Engmann 2008). Findings did not differ substantially from those of the main analysis in either subgroup. See Analysis 4.3.

4.2.2 Women with previously failed cycles

No data were available for this subgroup analysis.

4.2.3 Duration of progesterone

Ten studies were subgrouped by duration of progesterone. Two stopped treatment at the pregnancy test (Drakakis 2007; Lewin 1994), and eight administered progesterone for up to 12 weeks when pregnant (Aghahosseini 2011; Ceyhan 2008; Elgindy 2010; Engmann 2008; Gorkemli 2004; Lin 2013; Moini 2011; Yanushpolsky 2010). Studies in the subgroups were not pooled because of marked heterogeneity (I2 = 63% to 67%), possibly related to the differing methods of oestrogen administration described within each subgroup. See Analysis 4.4.

4.2.4 Number of embryos transferred

No data were available for this subgroup analysis.

4.3 Miscarriage rate

Ten studies reported this outcome (Aghahosseini 2011; Ata 2008; Drakakis 2007; Elgindy 2010; Engmann 2008; Fatemi 2006; Kably Ambe 2005; Lin 2013; Serna 2008; Yanushpolsky 2010). Routes of oestrogen administration were oral (seven RCTs, 1370 women), transdermal (one RCT, 160 women), vaginal (two RCTs, 301 women) and oral/transdermal (one RCT, 77 women).

When studies were pooled, no evidence suggested differences between groups (OR 0.98, 95% CI 0.72 to 1.35, 10 RCTs, 1908 women, I2 = 15%).

When data were considered by route of oestrogen administration, findings did not differ substantially from those of the main analysis. However heterogeneity was high in the comparison using vaginal oestrogen (I2 = 59%).

4.4 Ovarian hyperstimulation syndrome (OHSS)

Two studies reported this outcome (Ceyhan 2008;Lin 2013). Routes of oestrogen administration were oral (one RCT, 461 women) and transdermal (one RCT, 59 women).

When these studies were pooled, evidence suggested no differences between groups (OR 0.58, 95% CI 0.20 to 1.68, two RCTs, 461 women, I2 = 0%, low quality evidence).

When the data were considered by route of oestrogen administration, findings did not differ substantially. See Analysis 4.6 for details of this comparison.

4.5 Multiple pregnancy

No studies reported this outcome.

5. Progesterone versus progesterone + GnRH agonist

Primary outcome
5.1 Live birth/ongoing pregnancy rate

Nine studies reported live birth (Isik 2009; Isikoglu 2007; Qublan 2008) or ongoing pregnancy (Aboulghar 2015; Ata 2008; Brigante 2013; Inamdar 2012; Tesarik 2006; Yildiz 2014). Researchers administered the GnRH agonist as a single dose (five RCTs, 1536 women) or in multiple doses (five RCTs, 1325 women). See Figure 12 for details of this comparison.

Figure 12
Forest plot of comparison: 5 Progesterone vs progesterone + GnRH agonist, outcome: 5.1 Live birth or ongoing pregnancy rate.

Forest plot of comparison: 5 Progesterone vs progesterone + GnRH agonist, outcome: 5.1 Live birth or ongoing pregnancy rate.

The live birth/ongoing pregnancy rate was lower in the progesterone‐only group than the progesterone + GnRHa group (OR 0.62, 95% CI 0.48 to 0.81, nine RCTs, 2861 women, I2 = 55%, random effects, low quality evidence). The high statistical heterogeneity in this analysis was due to wide variation between studies in size of the effect, although the direction of the effect was consistent.

Findings were similar when the analysis was restricted to studies reporting live birth only (OR 0.34, 95% CI 0.15 to 0.59, three RCTs, 455 women, I2 = 66%).

When the data were considered by number of doses of GnRH agonist, findings did not differ substantially. See Analysis 5.1 for details of this comparison.

Secondary outcomes
5.2 Clinical pregnancy rate

Eight studies reported this outcome (Ata 2008; Aboulghar 2015; Brigante 2013; Isik 2009; Isikoglu 2007; Qublan 2008; Tesarik 2006; Yildiz 2014). Researchers administered the GnRH agonist as a single dose (five RCTs, 1536 women) or in multiple doses (four RCTs, 899 women); One trial had two intervention arms of single and multiple doses (Yildiz 2014).

Pregnancy rates were lower in the progesterone‐only group (OR 0.66, 95% CI 0.51 to 0.85, eight RCTs, 2435 women, I2 = 47%, random effects, low quality evidence). High statistical heterogeneity in this analysis appeared to be largely due to wide variation between studies in the size of the effect. See Analysis 5.2 for details.

When data were considered by number of doses of GnRH agonist, findings were consistent with those of the analysis of live birth/ongoing pregnancy in the single‐dose progesterone group but were not statistically significant in the multiple‐dose group. Results of the statistical test for subgroup differences were not significant. See Analysis 5.1 for details.

Subgroup analyses for clinical pregnancy rate

5.2.1 Ovarian stimulation protocol

In subgroup analyses, findings were consistent with those of the main analysis in the subgroup that received hCG with or without GnRH antagonists (Isik 2009; Porcu 2003; Tesarik 2006;Yildiz 2014) and the subgroup that received hCG with or without GnRH agonists (Aboulghar 2015Ata 2008; Isikoglu 2007; Qublan 2008; Tesarik 2006). Results of the statistical test for subgroup differences were not significant. See Analysis 5.3 for details.

5.2.2 Women with previously failed cycles

No data were available for this subgroup analysis.

5.2.3 Duration of progesterone (clinical pregnancy rate)

In subgroup analyses, findings were consistent with those of the main analysis in the subgroup that stopped treatment at the time of the pregnancy test (Aboulghar 2015; Isik 2009; Isikoglu 2007; Tesarik 2006; Yildiz 2014). Random effects model. Evidence suggested no differences between groups in the subgroup of women who were treated for up to 12 weeks when pregnant (Ata 2008). However results of the statistical test for subgroup differences were not significant. See Analysis 5.4 for details of this comparison.

5.2.4 Number of embryos transferred (clinical pregnancy rate)

No data were available for this subgroup analysis.

5.3 Miscarriage rate

Two studies reported this outcome (Qublan 2008;Yildiz 2014). The GnRH agonist was mostly administered in multiple doses. Evidence suggested no differences between groups (OR 1.37, 95% CI 0.53 to 3.52, 2 RCTs, 420 women). See Analysis 5.5 for details.

5.4 Multiple pregnancy

Four studies reported this outcome (Ata 2008; Inamdar 2012; Isik 2009;Yildiz 2014). Researchers administered the GnRH agonist as a single dose (two RCTs, 724 women) or in multiple doses (one RCT, 426 women) and one study both single and multiple doses.

Evidence suggested no differences between groups. When the data were considered by number of doses of GnRH agonist, findings did not differ substantially. See Analysis 5.6 for details.

5.5 Ovarian hyperstimulation syndrome (OHSS)

One study reported OHSS and showed no evidence of a difference between the groups (OR 1.00, 95% CI 0.33 to 3.01, 1 RCT, 300 women, very low quality evidence). See Analysis 5.7 for details.

6. Progesterone regimens

Primary outcome
6.1 Live birth/ongoing pregnancy rate

Twenty‐five studies compared progesterone regimens and reported live birth (Abate 1999a; Baker 2014; Bergh 2012; Chakravarty 2005; Dal Prato 2008; Doody 2009; Goudge 2010; Iwase 2008; Lockwood 2014; Mochtar 2006; Nyboe Andersen 2002; Pouly 1996; Propst 2001; Stadtmauer 2013; Zegers‐Hochschild 2000) or ongoing pregnancy (Aghsa 2012; Beltsos 2011; Friedler 1999; Kohls 2012; Kyrou 2011; Ludwig 2002; Perino 1997; Salehpour 2013; Tay 2005; Yanushpolsky 2010).

See Figure 13 for details of this comparison.

Figure 13
Forest plot of comparison: 6 Progesterone regimens, outcome: 6.1 Live birth or ongoing pregnancy rate.

Forest plot of comparison: 6 Progesterone regimens, outcome: 6.1 Live birth or ongoing pregnancy rate.

6.1.1 Intramuscular (IM) vs oral

One study made this comparison and reported live birth (Iwase 2008). No evidence suggested differences between groups (OR 0.71, 95% CI 0.14 to 3.66, one RCT, 40 women, very low quality evidence).

6.1.2 IM vs vaginal or rectal

Seven studies made this comparison and reported live birth (Abate 1999a; Dal Prato 2008; Propst 2001; Zegers‐Hochschild 2000) or ongoing pregnancy (Beltsos 2011; Perino 1997; Yanushpolsky 2010;). Dal Prato 2008 was a three‐arm study investigating IM progesterone versus vaginal gel 90 mg daily versus vaginal gel 90 mg twice daily. We combined both vaginal arms and compared them with the IM arm.

Live birth and ongoing pregnancy rates were higher in the vaginal/rectal group (OR 1.24, 95% CI 1.03 to 1.50, seven RCTs, 2039 women, I2 = 71%, very low quality evidence). However, statistical heterogeneity was high, and when a random‐effects model was used, no evidence suggested differences between groups (OR 1.37, 95% CI 0.94 to 1.99).

When analysis was restricted to studies reporting live birth, no evidence suggested differences between groups (OR 1.31, 95% CI 0.84 to 2.05, four RCTs, 1222 women, I2 = 59%, random‐effects model).

6.1.3 Vaginal or rectal vs oral

Four studies made this comparison and reported live birth (Chakravarty 2005; Pouly 1996) or ongoing pregnancy (Friedler 1999; Salehpour 2013).
Evidence suggested no differences between groups (OR 1.19, 95% CI 0.83 to 1.69, four RCTs, 857 women, I2 = 32%, low quality evidence).

Findings did not differ substantially when analysis was restricted to studies reporting live birth.

6.1.4 Low dose vaginal (≤ 100 mg) vs high dose vaginal (> 100 mg)

Five studies made this comparison and reported live birth (Bergh 2012; Dal Prato 2008; Doody 2009) or ongoing pregnancy (Ludwig 2002; Tay 2005). Doody 2009 was a three‐arm study comparing micronised progesterone vaginal gel 90 mg versus vaginal progesterone 100 mg twice daily versus vaginal progesterone 100 mg three times daily. We combined the two high‐dose arms in this comparison.

Evidence suggested no differences between groups (OR 0.97, 95% CI 0.84 to 1.11, five RCTs, 3720 women, I2 = 0%, moderate quality evidence).

Findings did not differ substantially when analysis was restricted to studies reporting live birth.

6.1.5 Short protocol vs long protocol

FIve studies made this comparison and reported live birth (Goudge 2010; Mochtar 2006; Nyboe Andersen 2002) or ongoing pregnancy (Kohls 2012; Kyrou 2011). Mochtar 2006 was a three‐arm study comparing micronised vaginal progesterone 200 mg twice daily starting at the evening of hCG administration for final oocyte maturation versus starting at the evening after oocyte retrieval versus starting at the evening after ET. We combined the first two arms.

No evidence suggested differences between groups (OR 1.04, 95% CI 0.79 to 1.36, five RCTs, 1205 women, I2 = 0%, low quality evidence).

Findings did not differ substantially when analysis was restricted to studies reporting live birth.

6.1.6 Micronised progesterone vs synthetic progesterone

Two studies made this comparison (Chakravarty 2005; Iwase 2008). Both reported live birth.
Evidence suggested no differences between groups (OR 0.90, 95% CI 0.53 to 1.55, two RCTs, 470 women, I2 = 0%, low quality evidence).

6.1.7 Vaginal ring vs vaginal gel

One study made this comparison (Stadtmauer 2013) and reported live birth.

Evidence suggested no differences between groups (OR 1.09, 95% CI 0.88 to 1.36, one RCT, 1271 women, low quality evidence).

6.1.8 Subcutaneous vs vaginal gel

Two studies made this comparison (Baker 2014; Lockwood 2014). Both reported live births.

Evidence suggested no differences between groups (OR 0.92, 95% CI 0.74 to 1.14, two RCTs, 1465 women, I2 = 0%, low quality evidence).

6.1.9 Vaginal vs rectal

One study made this comparison (Aghsa 2012) and reported ongoing pregnancy.

Evidence suggested no differences between groups (OR 1.28, 95% CI 0.64 to 2.54, one RCT, 147 women, very low quality evidence).

Secondary outcomes
6.2 Clinical pregnancy rate

Forty‐one studies compared progesterone regimens and reported clinical pregnancy. See Analysis 6.2 for details of this comparison.

6.2.1 IM vs oral

Three studies made this comparison (Iwase 2008; Licciardi 1999; Saucedo 2000).
Evidence suggested no differences between groups (OR 1.96, 95% CI 0.89 to 4.32, three RCTs, 123 women, I2 = 0%).

Subgroup analyses for clinical pregnancy rate

No data were available for subgroup analyses.

6.2.2 IM vs vaginalor rectal

Thirteen studies made this comparison (Abate 1999a; Artini 1995; Dal Prato 2008; Geusa 2001; Miller 2010; Perino 1997; Porcu 2003; Propst 2001; Saucedo 2000; Saucedo 2003; Sumita 2003; Yanushpolsky 2010; Zegers‐Hochschild 2000). Dal Prato 2008 was a three‐arm study investigating IM progesterone versus vaginal gel 90 mg daily versus vaginal gel 90 mg twice daily. We combined both vaginal arms and compared them with the IM arm.
Evidence suggested no differences between groups (OR 1.14, 95% CI 0.97 to 1.33, 13 RCTs, 2932 women, I2 = 43%).

Because this comparison included more than 10 studies, we prepared a funnel plot to determine the risk of publication bias (see Figure 5). This was discussed in the section Selective reporting (reporting bias). We concluded that the study showed a small risk of publication bias.

Subgroup analyses for clinical pregnancy rate

6.2.2.1 Ovarian stimulation protocol

Eleven studies were subgrouped by method of ovarian stimulation. Ten utilised hCG with or without GnRH agonists (Abate 1999a; Artini 1995; Dal Prato 2008; Geusa 2001; Perino 1997; Porcu 2003; Saucedo 2003; Sumita 2003; Yanushpolsky 2010; Zegers‐Hochschild 2000). Studies in this subgroup were not pooled because of marked heterogeneity (I2 = 65%). A single study utilised hCG with or without GnRH agonists (Miller 2010) and reported findings similar to those of the main analysis. See Analysis 6.6 for details.

6.2.2.2 Women with previously failed cycles

No data were available for this subgroup analysis.

6.2.2.3 Duration of progesterone

Seven studies were subgrouped by duration of progesterone. Two stopped treatment at the pregnancy test (Artini 1995;Perino 1997), and five administered progesterone for up to 12 weeks when pregnant (Abate 1999a; Dal Prato 2008; Propst 2001; Sumita 2003; Yanushpolsky 2010). Studies in these subgroups were not pooled because of statistical heterogeneity (I2 = 68%), and inconsistency was noted in the directions of effect. See Analysis 6.7 for details of this comparison.

6.2.2.4 Number of embryos transferred

No data were available for this subgroup analysis.

6.2.3 Vaginal or rectal vs oral

Seven studies made this comparison (Chakravarty 2005; Friedler 1999; Ganesh 2011; Patki 2007; Pouly 1996; Salehpour 2013; Saucedo 2000).

Evidence suggested no differences between groups (OR 0.89, 95% CI 0.75 to 1.05, seven RCTs, 2815 women, I2 = 52%).

Heterogeneity was substantial, in part because of the findings of Patki 2007. This study compared vaginal progesterone versus vaginal progesterone + oral progesterone, and the two different routes may have played a role in creating heterogeneity. When this study was omitted from the analysis, the I2 value was reduced to 25%.

Subgroup analyses for clinical pregnancy rate

6.2.3.1 Ovarian stimulation protocol

No data were available for this subgroup analysis.

6.2.3.2 Women with previously failed cycles

No data were available for this subgroup analysis.

6.2.3.3 Duration of progesterone

Five studies were subgrouped by duration of progesterone treatment. Two studies stopped treatment at the pregnancy test (Friedler 1999; Patki 2007), and four administered progesterone for up to 12 weeks when pregnant (Chakravarty 2005; Ganesh 2011; Pouly 1996; Salehpour 2013). Findings in the subgroup that stopped at the pregnancy test suggested benefit for the oral group, but inconsistency and very high heterogeneity were noted for the subgroup (I2 = 82%), which indicates that this finding should be regarded very cautiously. Findings in the group that administered progesterone for up to 12 weeks did not differ substantially from those of the main analysis. Results of the test for subgroup differences were not statistically significant. See Analysis 6.8 for details of this comparison.

6.2.3.4 Number of embryos transferred

No data were available for this subgroup analysis.

6.2.4 Low dose vaginal (≤ 100 mg) vs high dose vaginal (> 100 mg)

Twelve studies made this comparison (Bergh 2012; Dal Prato 2008; Doody 2009; Dunstone 1999; Ganesh 2011; Geber 2007a; Kleinstein 2005; Ludwig 2002; Ng 2003; Ng 2007; Rodriguez‐Pezino 2004; Strehler 1999). Doody 2009 was a three‐arm study comparing micronised progesterone vaginal gel 90 mg versus vaginal progesterone 100 mg twice daily versus vaginal progesterone 100 mg three times daily. We combined the two high‐dose arms in this comparison.

Evidence suggested no differences between groups (OR 0.98, 95% CI 0.87 to 1.09, 12 RCTs, 5659 women, I2 = 30%).

Because this comparison included more than 10 studies, we prepared a funnel plot to determine the risk of publication bias (see Figure 5). This was discussed in the section Selective reporting (reporting bias); we concluded that the study showed a small risk of publication bias.

Subgroup analyses for clinical pregnancy rate

6.2.4.1 Ovarian stimulation protocol

Nine studies were subgrouped by method of ovarian stimulation. Eight utilised hCG with or without GnRH agonists (Dal Prato 2008; Doody 2009; Ganesh 2011; Geber 2007a; Kleinstein 2005; Ng 2003; Ng 2007; Strehler 1999), and one utilised hCG with or without GnRH agonists (Rodriguez‐Pezino 2004). For both subgroups, findings were similar to those of the main analysis. See Analysis 6.9 for details.

6.2.4.2 Women with previously failed cycles

No data were available for this subgroup analysis.

6.2.4.3 Duration of progesterone

Nine studies were subgrouped by duration of progesterone. Three stopped treatment at the pregnancy test (Ludwig 2002; Ng 2003; Ng 2007), and six administered progesterone for up to 12 weeks when pregnant ((Dal Prato 2008; Doody 2009; Ganesh 2011; Geber 2007a; Kleinstein 2005; Strehler 1999). In both subgroups, findings were similar to those of the main analysis. See Analysis 6.10 for details.

6.2.4.4 Number of embryos transferred

No data were available for this subgroup analysis.

6.2.5 Short protocol vs long protocol

Six studies made this comparison (Goudge 2010; Kohls 2012; Kyrou 2011; Mochtar 2006; Serour 2012; Williams 2001). Mochtar 2006 was a three‐arm study comparing micronised vaginal progesterone 200 mg twice daily starting at the evening of hCG administration for final oocyte maturation versus starting at the evening after oocyte retrieval versus starting at the evening after embryo transfer (ET). We combined the first two arms.
Evidence suggested no differences between groups (OR 1.14, 95% CI 0.87 to 1.50, six RCTs, 1128 women, I2 = 5%).

Subgroup analyses for clinical pregnancy rate

6.2.5.1 Ovarian stimulation protocol

Four studies were subgrouped by method of ovarian stimulation. Two utilised hCG with or without GnRH agonists (Goudge 2010; Mochtar 2006), and two utilised hCG with or without GnRH antagonists (Kohls 2012; Kyrou 2011). In both subgroups, findings were similar to those of the main analysis. See Analysis 6.11 for details.

6.2.5.2 Women with previously failed cycles

No data were available for this subgroup analysis.

6.2.5.3 Duration of progesterone

No data were available for this subgroup analysis.

6.2.5.4 Number of embryos transferred

No data were available for this subgroup analysis.

6.2.6 Micronised progesterone vs synthetic progesterone

Four studies made this comparison (Chakravarty 2005; Ganesh 2011; Iwase 2008; Patki 2007).

Clinical pregnancy rates were lower in the micronised progesterone group (OR 0.79, 95% CI 0.66 to 0.96, four RCTs, 2388 women, I2 = 19%), suggesting benefit for the synthetic progesterone group.

Subgroup analyses for clinical pregnancy rate

No data were available for subgroup analyses.

6.2.7 Vaginal ring vs vaginal gel

One study made this comparison (Stadtmauer 2013).

Evidence suggested no differences between groups (OR 1.05, 95% CI 0.84 to 1.31, one RCT, 1271 women).

6.2.8 Subcutaneous vs vaginal gel

Two studies made this comparison (Baker 2014; Lockwood 2014).
Evidence suggested no differences between groups (OR 0.88, 95% CI 0.71 to 1.08, two RCTs, 1465 women, I2 = 0%).

Subgroup analyses for clinical pregnancy rate

No data were available for subgroup analyses.

6.2.9 Vaginal vs rectal

One study made this comparison (Aghsa 2012).

Evidence suggested no differences between groups (OR 1.32, 95% CI 0.68 to 2.56, one RCT, 147 women).

6.3 Miscarriage rate

Twenty‐six studies compared progesterone regimens and reported miscarriage. See Analysis 6.3 for details of this comparison.

6.3.1 IM vs oral

Three studies made this comparison (Iwase 2008; Licciardi 1999; Saucedo 2000).
Evidence suggested no differences between groups (OR 1.43, 95% CI 0.34 to 6.11, three RCTs, 123 women, I2 = 13%).

6.3.2 IM vs vaginal or rectal

Six studies made this comparison (Dal Prato 2008; Miller 2010; Nallapeta 2013; Perino 1997; Saucedo 2000; Yanushpolsky 2010).
Evidence suggested no differences between groups (OR 0.79, 95% CI 0.56 to 1.13, six RCTs, 1468 women, I2 = 0%).

6.3.3 Vaginalor rectal vs oral

Five studies made this comparison (Chakravarty 2005; Friedler 1999; Ganesh 2011; Pouly 1996; Salehpour 2013). Dal Prato 2008 was a three‐arm study investigating IM progesterone versus vaginal gel 90 mg daily versus vaginal gel 90 mg twice daily. We combined both vaginal arms and compared them with the IM arm.
Evidence suggested no differences between groups (OR 1.18, 95% CI 0.76 to 1.82, five RCTs, 2220 women, I2 = 0%).

6.3.4 Low dose vaginal (≤ 100 mg) vs high dose vaginal (> 100 mg)

Nine studies made this comparison (Bergh 2012; Dal Prato 2008; Ganesh 2011; Geber 2007a; Kleinstein 2005; Ludwig 2002; Ng 2007; Rodriguez‐Pezino 2004; Strehler 1999).

Miscarriage rates were lower in the low‐dose group (OR 0.73, 95% CI 0.55 to 0.98, nine RCTs, 4333 women, I2 = 0%), suggesting benefit for this group.

6.3.5 Short protocol vs long protocol

Three studies made this comparison (Kohls 2012; Kyrou 2011; Nyboe Andersen 2002).
Evidence suggested no differences between groups (OR 0.96, 95% CI 0.61 to 1.50, three RCTs, 662 women, I2 = 0%).

6.3.6 Micronised progesterone vs synthetic progesterone

Two studies made this comparison (Chakravarty 2005; Ganesh 2011).
Evidence suggested no differences between groups (OR 1.16, 95% CI 0.69 to 1.95, two RCTs, 1793 women, I2 = 0%).

6.3.7 Vaginal ring vs vaginal gel

No studies reported this outcome.

6.3.8 Subcutaneous vs vaginal gel

Two studies made this comparison (Baker 2014; Lockwood 2014).
Evidence suggested no differences between groups (OR 0.82, 95% CI 0.44 to 1.54, two RCTs, 1465 women, I2 = 0%).

6.3.9 Vaginal vs rectal

One study made this comparison (Aghsa 2012).

Evidence suggested no differences between groups (OR 1.21, 95% CI 0.31 to 4.71, one RCT, 147 women).

6.4 Ovarian hyperstimulation syndrome (OHSS)

Two studies compared progesterone regimens and reported OHSS. See Analysis 6.4 for details of this comparison.

6.4.1 IM vs oral

One study made this comparison (Iwase 2008).

Evidence suggested no differences between groups (OR 1.00, 95% CI 0.06 to 17.18, one RCT, 40 women, very low quality evidence).

6.4.2 IM vs vaginal or rectal

No studies made this comparison.

6.4.3 Vaginal or rectal vs oral

No studies made this comparison.

6.4.4 Low dose vaginal (≤ 100 mg) vs high dose vaginal (> 100 mg)

Two studies made this comparison (Doody 2009; Iwase 2008). Doody 2009 was a three‐arm study comparing micronised progesterone vaginal gel 90 mg versus vaginal progesterone 100 mg twice daily versus vaginal progesterone 100 mg three times daily. We combined the two high‐dose arms in this comparison.
Evidence suggested no differences between groups (OR 0.91, 95% CI 0.57 to 1.46, two RCTs, 1251 women, I2 = 0%, low quality evidence).

6.4.5 Short protocol vs long protocol

No studies made this comparison.

6.4.6 Micronised progesterone vs synthetic progesterone

No studies made this comparison.

6.4.7 Vaginal ring vs vaginal gel

No studies made this comparison.

6.4.8 Subcutaneous vs vaginal gel

No studies made this comparison.

6.4.9 Vaginal vs rectal

No studies made this comparison.

6.5 Multiple pregnancy

Fourteen studies compared progesterone regimens and reported multiple pregnancy. See Analysis 6.5 for details of this comparison.

6.5.1 IM vs oral

Two studies made this comparison (Iwase 2008; Licciardi 1999).

More multiple pregnancies were reported in the IM arm (OR 4.23, 95% CI 1.16 to 15.40, two RCTs, 83 women, I2 = 0%), suggesting benefit for the oral arm. This analysis included only 14 events and 80 women, so this finding should be interpreted with caution.

6.5.2 IM vs vaginalor rectal

One study made this comparison (Zegers‐Hochschild 2000).

Evidence suggested no differences between groups (OR 0.97, 95% CI 0.60 to 1.59, one RCT, 505 women).

6.5.3 Vaginalor rectal vs oral

One study made this comparison (Pouly 1996).

Evidence suggested no differences between groups (OR 1.13, 95% CI 0.50 to 2.58, one RCT, 283 women).

6.5.4 Low dose vaginal (≤ 100 mg) vs high dose vaginal (> 100 mg)

Five studies made this comparison (Bergh 2012; Geber 2007a; Kleinstein 2005; Ng 2007; Strehler 1999).
Evidence suggested no differences between groups (OR 1.24, 95% CI 0.85 to 1.80, five RCTs, 2888 women, I2 = 0%).

6.5.5 Short protocol vs long protocol

Four studies made this comparison (Goudge 2010; Kohls 2012; Kyrou 2011; Nyboe Andersen 2002).
Evidence suggested no differences between groups (OR 1.13, 95% CI 0.80 to 1.60, four RCTs, 820 women, I2 = 15%).

6.5.6 Micronised progesterone vs synthetic progesterone

No studies reported this outcome.

6.5.7 Vaginal ring vs vaginal gel

No studies reported this outcome.

6.5.8 Subcutaneous vs vaginal gel

No studies reported this outcome.

6.5.9 Vaginal vs rectal

One study made this comparison (Aghsa 2012).

Evidence suggested no differences between groups (OR 0.96, 95% CI 0.19 to 4.91, one RCT, 147 women).

7. Progesterone + oestrogen regimens

Primary outcome
7.1 Live birth/ongoing pregnancy rate

Two studies comparing progesterone and oestrogen regimens reported ongoing pregnancy. One compared short versus long protocol (Feichtinger 2011), and one compared low versus high dosage (Tonguc 2011).

Tonguc 2011 was a three‐arm study comparing 2 mg oestradiol versus 4 mg oestradiol versus 6 mg oestradiol. We combined the arms with 4 mg and 6 mg oestradiol supplementation.

7.1.1 Short protocol vs long protocol

No studies making this comparison reported live birth.

Evidence suggested no differences between groups (OR 1.08, 95 CI 0.81 to 1.43, one RCT, 910 women, low quality evidence).

7.1.2 Low dosage vs high dosage

Evidence suggested no differences between groups (OR 0.65, 95% CI 0.37 to 1.13, one RCT, 285 women, very low quality evidence).

Secondary outcomes
7.2 Clinical pregnancy rate

7.2.1 Short protocol vs long protocol

No reported studies made this comparison.

7.2.2 Low dosage vs high dosage

One study (Tonguc 2011) made this comparison.

Evidence suggested no differences between groups (OR 0.81, 95% CI 0.48 to 1.37, one RCT, 285 women). See Analysis 7.2 for details.

7.3 Miscarriage rate

7.3.1 Short protocol vs long protocol

No studies reported this outcome.

7.3.2 Low dosage vs high dosage

One study made this comparison (Tonguc 2011) .

Evidence suggested no differences between groups (OR 3.13, 95% CI 0.86 to 11.39, one RCT, 285 women).

See Analysis 7.3 for details of this comparison.

7.4 OHSS

No studies reported this outcome.

7.5 Multiple pregnancy rates

7.5.1 Short protocol vs long protocol

No studies reported this outcome.

7.5.2 Low dosage vs high dosage

One study made this comparison (Tonguc 2011).

Evidence suggested no differences between groups (OR 0.25, 95% CI 0.06 to 1.12, one RCT, 285 women). See Analysis 7.4 for details,

8. Funnel plots

For comparisons with more than 10 included studies, we constructed a funnel plot. None of the funnel plots (Figure 4; Figure 5; Figure 6) suggested publication bias.

Discussion

Summary of main results

This systematic review of all randomised controlled trials (RCTs) of luteal phase support from 1987 to 2015 had a broad range of subjects. We had seven comparisons to ensure we included as many studies as possible. Because we did not include quasi‐RCTs, we had to exclude quite a few older studies; therefore we have sparse evidence regarding current standard luteal phase protocols. For an overview of the main findings, see the 'Summary of findings' tables (summary of findings Table for the main comparison; summary of findings Table 2; summary of findings Table 3; summary of findings Table 4; summary of findings Table 5; summary of findings Table 6; summary of findings Table 7).

We can summarise the following results based on our review.

Human chorionic gonadotropin (hCG) for luteal phase support

hCG given during the luteal phase may be associated with higher rates of live birth or ongoing pregnancy than placebo or no treatment, but the evidence is not conclusive. hCG increased the risk of ovarian hyperstimulation syndrome (OHSS) (1 RCT only).

Progesterone for luteal phase support

Progesterone given during the luteal phase may be associated with higher rates of live birth or ongoing pregnancy than placebo or no treatment, but the evidence is not conclusive. Progesterone was associated with lower rates of OHSS rates than hCG with or without progesterone.

Progesterone and oestrogen for luteal phase support

We found no conclusive evidence of differences between groups for any outcome. Supplementation of progesterone with oral oestrogen did not appear to influence live birth and ongoing pregnancy rates, but benefit from transdermal or oral + transdermal oestrogen supplementation is suggested. Findings for supplementation of progesterone with vaginal oestrogen were inconsistent.

Progesterone and GnRH agonists for luteal phase support

A relatively new method of luteal phase support involves use of GnRH agonists, which appeared to increase rates of live birth/ongoing pregnancy and clinical pregnancy compared with progesterone alone. There was no evidence of a difference between the groups for other outcomes, though OHSS was reported in only one study.

Different progesterone regimens

When we compared routes of progesterone administration, we gathered no conclusive findings. Vaginal progesterone is the most commonly used formulation in Europe according to a survey of 21 European centres (Aboulghar 2008). Sixteen centres used vaginal progesterone, three used IM progesterone, one used oral progesterone and one hCG.

We found several studies investigating Crinone 8% vaginal micronised progesterone gel. Therefore we conducted a comparison to investigate low‐dose (≤ 100 mg) versus high‐dose (> 100 mg) vaginal progesterone. The analysis for the miscarriage rate suggested benefit derived from low‐dose vaginal progesterone. No evidence revealed differences between low‐dose and high‐dose groups for the other outcomes. A new method consists of a weekly progesterone ring, for which we also conducted a comparison. No evidence favoured the vaginal ring or gel.

Comparisons of long versus short duration of progesterone administration showed no evidence of differences between groups in live birth and ongoing pregnancy rates. Findings for clinical pregnancy were inconsistent.

Comparisons of synthetic versus micronised progesterone yielded no evidence of differences between groups in live birth and ongoing pregnancy rates. However, evidence suggested that synthetic progesterone was associated with a higher clinical pregnancy rate than micronised progesterone. The only synthetic progesterone used was oral dydrogesterone.

With regard to multiple pregnancy, the only evidence of differences between groups was seen for the comparison of IM progesterone with oral progesterone, which suggested that IM progesterone is associated with multiple pregnancies to a greater extent than oral progesterone.

Overall completeness and applicability of evidence

Most studies provided 'implantation rate' as an outcome. For clinicians, this outcome is not useful, as they would rather know the pregnancy rate or the live birth rate.

For women the most important outcome is live birth, which was reported in only 31 studies. For the 2015 update of this review, we pooled live birth and ongoing pregnancy rates to increase the power of the analysis. Sensitivity analyses limited to studies reporting live birth yielded findings very similar to those obtained for the combined outcome, suggesting that ongoing pregnancy was a reasonable surrogate for live birth in this review. The outcome clinical pregnancy was reported in most studies and did provide a few significant results. To investigate the safety of luteal phase support, we also looked at the negative side effects, OHSS and multiple pregnancy. These outcomes were not reported in all studies; therefore this review might not give an accurate representation of these important factors in luteal phase support.

Adverse effects were reported poorly in most of the included studies.

Some of the studies that we found investigated procedures or interventions influencing the luteal phase but did not investigate an intervention used as luteal phase support. All of these studies are reported in the Characteristics of excluded studies.

We included only first cycle data, and four studies reported more cycles than included women (Erman Akar 2005; Lukaszuk 2005; Unfer 2004; Unfer 2004a). We contacted the authors but have not received a reply.

In our protocol, we stated that we would include two other comparisons: urinary hCG versus recombinant hCG and single‐dose GnRH agonist versus placebo. We found no studies that were conducted to investigate these comparisons. It is unlikely that these comparisons will be made in the future, as hCG is an older method of luteal phase support and is known for its high risk of OHSS. We do not expect new trials to investigate the differences between urinary and recombinant hCG. Nowadays, progesterone is an accepted method for luteal phase support, and it is considered unethical to not provide any form of luteal phase support. Therefore we do not expect any new trials to investigate the effects of GnRH agonists for luteal phase support versus placebo. For these reasons, we chose to remove these comparisons.

To make sure we were as thorough as possible, we came up with some additional comparisons: low‐dose vaginal progesterone versus high‐dose vaginal progesterone, short protocol progesterone versus long protocol progesterone, vaginal ring versus vaginal gel, subcutaneous versus vaginal gel, vaginal versus rectal progesterone and progesterone versus progesterone + multiple‐dose GnRH agonist.

The included studies used differing inclusion and exclusion criteria, but this was not a limitation for inclusion in our review.

In conclusion, we included all first cycles of randomised trials of luteal phase support. We changed our comparisons after we completed our search to ensure that we covered as much as possible on this topic.

Quality of the evidence

This review has a huge number of included studies ‐ 94 studies ‐ that investigated many different interventions for luteal phase support. The total number of included participants was 25,471, but because of the variety of included studies per comparison, the total sample size per comparison ranged from 30 to well over 5000 participants.

Only 25 studies (27%) reported methods of randomisation and allocation concealment in sufficient detail, and only half (48/93) were rated as having low risk of attrition bias. More than half were rated as having high risk of bias in one or more domains. Although sensitivity analyses limited to studies with clear description of allocation concealment did not substantially affect any of our findings, we rated down the quality of evidence for all comparisons in our 'Summary of findings' tables because of the high proportions of "unclear" and "high" risk of bias ratings in most studies (summary of findings Table for the main comparison; summary of findings Table 2; summary of findings Table 3; summary of findings Table 4; summary of findings Table 5; summary of findings Table 6; summary of findings Table 7).

Heterogeneity was low for most comparisons. For most cases in which substantial heterogeneity was detected, we were not able to find a clear reason, and for these analyses, our findings should be interpreted with caution.

The overall quality of the evidence ranged from very low to moderate. The main limitations were poor reporting of study methods and imprecision.

Potential biases in the review process

Two review authors extracted all data. MvdL extracted data from all studies, and MM and KB divided all studies between them; thus each extracted data from half of the studies. MvdL, who wrote the review, compared all results. In cases of disagreement, CF acted as a third review author and determined the final verdict. This usually happened after consultation with MvdL. This means that MvdL had a big influence on these decisions, and this might have introduced bias.

As a result of the large number of topics within the review, we might not have discussed all topics in depth.

We are quite sure that we found all relevant studies, but some studies might not have been published at the time of our search and are published now, at the time of publication. As discussed above, four studies did meet our inclusion criteria but reported more cycles than included women (Erman Akar 2005; Lukaszuk 2005; Unfer 2004; Unfer 2004a). We contacted these study authors but received no reply, so we did not include these studies.

In the 2015 update, we have made several changes and additions to the original protocol (see Differences between protocol and review). We believe that these changes are likely to have reduced rather than increased the potential for bias in the review, by ensuring that we consider all relevant comparisons and use the latest recommended Cochrane standards.

Agreements and disagreements with other studies or reviews

Upon comparing this review with a previous version (Daya 2004), we found a lot of similarities regarding the quality of included studies. Although this previous review included quasi‐randomised trials, the overall quality of the present review is still poor. As stated in the implications for research section of the previous versions of this review (Daya 2004, van der Linden 2011), improvement of the quality of studies, especially in terms of blinding, is important for further research. Among the more recent (after 2004) studies that we have included, the quality of studies does indeed seem to be better, although most of these researchers did not use blinding. In Daya 2004, it was discussed that live birth was not often reported as an outcome. This seems to be improved but in most cases, it still is not the main outcome.

We have noted some agreements and some disagreements between the findings of Daya 2004 and the results of this review. As no new studies have investigated hCG versus placebo, we found no new results. In all comparisons investigating hCG, we found that hCG involves higher risk of OHSS. This was significant for hCG versus placebo and progesterone versus progesterone + hCG.

In the previous versions of this review (Daya 2004 and van der Linden 2011), no evidence favoured a particular route of administration. Both versions of the review reported no differences in effect between different doses of vaginal progesterone.

Both reviews found higher pregnancy rates for progesterone in GnRH agonist‐stimulated cycles.

Study flow diagram.
Figures and Tables -
Figure 1

Study flow diagram.

Navigate to figure in ReviewOpen in new tab

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figures and Tables -
Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Navigate to figure in ReviewOpen in new tab

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Navigate to figure in ReviewOpen in new tab

Funnel plot of comparison: 2 Progesterone vs hCG, outcome: 2.2 Clinical pregnancy rate.
Figures and Tables -
Figure 4

Funnel plot of comparison: 2 Progesterone vs hCG, outcome: 2.2 Clinical pregnancy rate.

Navigate to figure in ReviewOpen in new tab

Funnel plot of comparison: 4 [NEW] Progesterone vs progesterone + oestrogen, outcome: 4.2 Clinical pregnancy rate.
Figures and Tables -
Figure 5

Funnel plot of comparison: 4 [NEW] Progesterone vs progesterone + oestrogen, outcome: 4.2 Clinical pregnancy rate.

Navigate to figure in ReviewOpen in new tab

Funnel plot of comparison: 6 [NEW] Progesterone regimens, outcome: 6.2 Clinical pregnancy rate.
Figures and Tables -
Figure 6

Funnel plot of comparison: 6 [NEW] Progesterone regimens, outcome: 6.2 Clinical pregnancy rate.

Navigate to figure in ReviewOpen in new tab

Forest plot of comparison: 1 Human chorionic gonadotropin (hCG) vs placebo or no treatment, outcome: 1.1 Live birth/ongoing pregnancy rate.
Figures and Tables -
Figure 7

Forest plot of comparison: 1 Human chorionic gonadotropin (hCG) vs placebo or no treatment, outcome: 1.1 Live birth/ongoing pregnancy rate.

Navigate to figure in ReviewOpen in new tab

Forest plot of comparison: 2 Progesterone vs placebo or no treatment, outcome: 2.1 Live birth/ongoing pregnancy rate.
Figures and Tables -
Figure 8

Forest plot of comparison: 2 Progesterone vs placebo or no treatment, outcome: 2.1 Live birth/ongoing pregnancy rate.

Navigate to figure in ReviewOpen in new tab

Forest plot of comparison: 3 Progesterone vs hCG regimens, outcome: 3.1 Live birth or ongoing pregnancy rate.
Figures and Tables -
Figure 9

Forest plot of comparison: 3 Progesterone vs hCG regimens, outcome: 3.1 Live birth or ongoing pregnancy rate.

Navigate to figure in ReviewOpen in new tab

Forest plot of comparison: 3 Progesterone vs hCG regimens, outcome: 3.5 OHSS.
Figures and Tables -
Figure 10

Forest plot of comparison: 3 Progesterone vs hCG regimens, outcome: 3.5 OHSS.

Navigate to figure in ReviewOpen in new tab

Forest plot of comparison: 4 Progesterone vs progesterone + oestrogen, outcome: 4.1 Live birth/ongoing pregnancy rate.
Figures and Tables -
Figure 11

Forest plot of comparison: 4 Progesterone vs progesterone + oestrogen, outcome: 4.1 Live birth/ongoing pregnancy rate.

Navigate to figure in ReviewOpen in new tab

Forest plot of comparison: 5 Progesterone vs progesterone + GnRH agonist, outcome: 5.1 Live birth or ongoing pregnancy rate.
Figures and Tables -
Figure 12

Forest plot of comparison: 5 Progesterone vs progesterone + GnRH agonist, outcome: 5.1 Live birth or ongoing pregnancy rate.

Navigate to figure in ReviewOpen in new tab

Forest plot of comparison: 6 Progesterone regimens, outcome: 6.1 Live birth or ongoing pregnancy rate.
Figures and Tables -
Figure 13

Forest plot of comparison: 6 Progesterone regimens, outcome: 6.1 Live birth or ongoing pregnancy rate.

Navigate to figure in ReviewOpen in new tab

Comparison 1 Human chorionic gonadotropin (hCG) vs placebo or no treatment, Outcome 1 Live birth/ongoing pregnancy rate.
Figures and Tables -
Analysis 1.1

Comparison 1 Human chorionic gonadotropin (hCG) vs placebo or no treatment, Outcome 1 Live birth/ongoing pregnancy rate.

Navigate to figure in ReviewOpen in new tab

Comparison 1 Human chorionic gonadotropin (hCG) vs placebo or no treatment, Outcome 2 Clinical pregnancy rate.
Figures and Tables -
Analysis 1.2

Comparison 1 Human chorionic gonadotropin (hCG) vs placebo or no treatment, Outcome 2 Clinical pregnancy rate.

Navigate to figure in ReviewOpen in new tab

Comparison 1 Human chorionic gonadotropin (hCG) vs placebo or no treatment, Outcome 3 Clinical pregnancy rate: subgroup analysis by COH method.
Figures and Tables -
Analysis 1.3

Comparison 1 Human chorionic gonadotropin (hCG) vs placebo or no treatment, Outcome 3 Clinical pregnancy rate: subgroup analysis by COH method.

Navigate to figure in ReviewOpen in new tab

Comparison 1 Human chorionic gonadotropin (hCG) vs placebo or no treatment, Outcome 4 Miscarriage rate.
Figures and Tables -
Analysis 1.4

Comparison 1 Human chorionic gonadotropin (hCG) vs placebo or no treatment, Outcome 4 Miscarriage rate.

Navigate to figure in ReviewOpen in new tab

Comparison 1 Human chorionic gonadotropin (hCG) vs placebo or no treatment, Outcome 5 OHSS.
Figures and Tables -
Analysis 1.5

Comparison 1 Human chorionic gonadotropin (hCG) vs placebo or no treatment, Outcome 5 OHSS.

Navigate to figure in ReviewOpen in new tab

Comparison 2 Progesterone vs placebo or no treatment, Outcome 1 Live birth/ongoing pregnancy rate.
Figures and Tables -
Analysis 2.1

Comparison 2 Progesterone vs placebo or no treatment, Outcome 1 Live birth/ongoing pregnancy rate.

Navigate to figure in ReviewOpen in new tab

Comparison 2 Progesterone vs placebo or no treatment, Outcome 2 Clinical pregnancy rate.
Figures and Tables -
Analysis 2.2

Comparison 2 Progesterone vs placebo or no treatment, Outcome 2 Clinical pregnancy rate.

Navigate to figure in ReviewOpen in new tab

Comparison 2 Progesterone vs placebo or no treatment, Outcome 3 Clinical pregnancy: subgroup analysis by COH method.
Figures and Tables -
Analysis 2.3

Comparison 2 Progesterone vs placebo or no treatment, Outcome 3 Clinical pregnancy: subgroup analysis by COH method.

Navigate to figure in ReviewOpen in new tab

Comparison 2 Progesterone vs placebo or no treatment, Outcome 4 Clinical pregnancy: subgroup analysis by treatment duration.
Figures and Tables -
Analysis 2.4

Comparison 2 Progesterone vs placebo or no treatment, Outcome 4 Clinical pregnancy: subgroup analysis by treatment duration.

Navigate to figure in ReviewOpen in new tab

Comparison 2 Progesterone vs placebo or no treatment, Outcome 5 Miscarriage rate.
Figures and Tables -
Analysis 2.5

Comparison 2 Progesterone vs placebo or no treatment, Outcome 5 Miscarriage rate.

Navigate to figure in ReviewOpen in new tab

Comparison 2 Progesterone vs placebo or no treatment, Outcome 6 Multiple pregnancy.
Figures and Tables -
Analysis 2.6

Comparison 2 Progesterone vs placebo or no treatment, Outcome 6 Multiple pregnancy.

Navigate to figure in ReviewOpen in new tab

Comparison 3 Progesterone vs hCG regimens, Outcome 1 Live birth or ongoing pregnancy rate.
Figures and Tables -
Analysis 3.1

Comparison 3 Progesterone vs hCG regimens, Outcome 1 Live birth or ongoing pregnancy rate.

Navigate to figure in ReviewOpen in new tab

Comparison 3 Progesterone vs hCG regimens, Outcome 2 Clinical pregnancy rate.
Figures and Tables -
Analysis 3.2

Comparison 3 Progesterone vs hCG regimens, Outcome 2 Clinical pregnancy rate.

Navigate to figure in ReviewOpen in new tab

Comparison 3 Progesterone vs hCG regimens, Outcome 3 Clinical pregnancy: progesterone vs progesterone + hCG: subgroup analysis by COH method.
Figures and Tables -
Analysis 3.3

Comparison 3 Progesterone vs hCG regimens, Outcome 3 Clinical pregnancy: progesterone vs progesterone + hCG: subgroup analysis by COH method.

Navigate to figure in ReviewOpen in new tab

Comparison 3 Progesterone vs hCG regimens, Outcome 4 Clinical pregnancy: progesterone vs hCG: subgroup analysis by treatment duration.
Figures and Tables -
Analysis 3.4

Comparison 3 Progesterone vs hCG regimens, Outcome 4 Clinical pregnancy: progesterone vs hCG: subgroup analysis by treatment duration.

Navigate to figure in ReviewOpen in new tab

Comparison 3 Progesterone vs hCG regimens, Outcome 5 OHSS.
Figures and Tables -
Analysis 3.5

Comparison 3 Progesterone vs hCG regimens, Outcome 5 OHSS.

Navigate to figure in ReviewOpen in new tab

Comparison 3 Progesterone vs hCG regimens, Outcome 6 Miscarriage rate.
Figures and Tables -
Analysis 3.6

Comparison 3 Progesterone vs hCG regimens, Outcome 6 Miscarriage rate.

Navigate to figure in ReviewOpen in new tab

Comparison 3 Progesterone vs hCG regimens, Outcome 7 Multiple pregnancy.
Figures and Tables -
Analysis 3.7

Comparison 3 Progesterone vs hCG regimens, Outcome 7 Multiple pregnancy.

Navigate to figure in ReviewOpen in new tab

Comparison 4 Progesterone vs progesterone + oestrogen, Outcome 1 Live birth/ongoing pregnancy rate.
Figures and Tables -
Analysis 4.1

Comparison 4 Progesterone vs progesterone + oestrogen, Outcome 1 Live birth/ongoing pregnancy rate.

Navigate to figure in ReviewOpen in new tab

Comparison 4 Progesterone vs progesterone + oestrogen, Outcome 2 Clinical pregnancy rate.
Figures and Tables -
Analysis 4.2

Comparison 4 Progesterone vs progesterone + oestrogen, Outcome 2 Clinical pregnancy rate.

Navigate to figure in ReviewOpen in new tab

Comparison 4 Progesterone vs progesterone + oestrogen, Outcome 3 Clinical pregnancy: subgroup analysis by COH method.
Figures and Tables -
Analysis 4.3

Comparison 4 Progesterone vs progesterone + oestrogen, Outcome 3 Clinical pregnancy: subgroup analysis by COH method.

Navigate to figure in ReviewOpen in new tab

Comparison 4 Progesterone vs progesterone + oestrogen, Outcome 4 Clinical pregnancy: subgroup analysis by treatment duration.
Figures and Tables -
Analysis 4.4

Comparison 4 Progesterone vs progesterone + oestrogen, Outcome 4 Clinical pregnancy: subgroup analysis by treatment duration.

Navigate to figure in ReviewOpen in new tab

Comparison 4 Progesterone vs progesterone + oestrogen, Outcome 5 Miscarriage rate.
Figures and Tables -
Analysis 4.5

Comparison 4 Progesterone vs progesterone + oestrogen, Outcome 5 Miscarriage rate.

Navigate to figure in ReviewOpen in new tab

Comparison 4 Progesterone vs progesterone + oestrogen, Outcome 6 OHSS.
Figures and Tables -
Analysis 4.6

Comparison 4 Progesterone vs progesterone + oestrogen, Outcome 6 OHSS.

Navigate to figure in ReviewOpen in new tab

Comparison 5 Progesterone vs progesterone + GnRH agonist, Outcome 1 Live birth or ongoing pregnancy rate.
Figures and Tables -
Analysis 5.1

Comparison 5 Progesterone vs progesterone + GnRH agonist, Outcome 1 Live birth or ongoing pregnancy rate.

Navigate to figure in ReviewOpen in new tab

Comparison 5 Progesterone vs progesterone + GnRH agonist, Outcome 2 Clinical pregnancy rate.
Figures and Tables -
Analysis 5.2

Comparison 5 Progesterone vs progesterone + GnRH agonist, Outcome 2 Clinical pregnancy rate.

Navigate to figure in ReviewOpen in new tab

Comparison 5 Progesterone vs progesterone + GnRH agonist, Outcome 3 Clinical pregnancy: subgroup analysis by COH method.
Figures and Tables -
Analysis 5.3

Comparison 5 Progesterone vs progesterone + GnRH agonist, Outcome 3 Clinical pregnancy: subgroup analysis by COH method.

Navigate to figure in ReviewOpen in new tab

Comparison 5 Progesterone vs progesterone + GnRH agonist, Outcome 4 Clinical pregnancy: subgroup analysis by treatment duration.
Figures and Tables -
Analysis 5.4

Comparison 5 Progesterone vs progesterone + GnRH agonist, Outcome 4 Clinical pregnancy: subgroup analysis by treatment duration.

Navigate to figure in ReviewOpen in new tab

Comparison 5 Progesterone vs progesterone + GnRH agonist, Outcome 5 Miscarriage rate.
Figures and Tables -
Analysis 5.5

Comparison 5 Progesterone vs progesterone + GnRH agonist, Outcome 5 Miscarriage rate.

Navigate to figure in ReviewOpen in new tab

Comparison 5 Progesterone vs progesterone + GnRH agonist, Outcome 6 Multiple pregnancy.
Figures and Tables -
Analysis 5.6

Comparison 5 Progesterone vs progesterone + GnRH agonist, Outcome 6 Multiple pregnancy.

Navigate to figure in ReviewOpen in new tab

Comparison 5 Progesterone vs progesterone + GnRH agonist, Outcome 7 OHSS.
Figures and Tables -
Analysis 5.7

Comparison 5 Progesterone vs progesterone + GnRH agonist, Outcome 7 OHSS.

Navigate to figure in ReviewOpen in new tab

Comparison 6 Progesterone regimens, Outcome 1 Live birth or ongoing pregnancy rate.
Figures and Tables -
Analysis 6.1

Comparison 6 Progesterone regimens, Outcome 1 Live birth or ongoing pregnancy rate.

Navigate to figure in ReviewOpen in new tab

Comparison 6 Progesterone regimens, Outcome 2 Clinical pregnancy rate.
Figures and Tables -
Analysis 6.2

Comparison 6 Progesterone regimens, Outcome 2 Clinical pregnancy rate.

Navigate to figure in ReviewOpen in new tab

Comparison 6 Progesterone regimens, Outcome 3 Miscarriage rate.
Figures and Tables -
Analysis 6.3

Comparison 6 Progesterone regimens, Outcome 3 Miscarriage rate.

Navigate to figure in ReviewOpen in new tab

Comparison 6 Progesterone regimens, Outcome 4 OHSS.
Figures and Tables -
Analysis 6.4

Comparison 6 Progesterone regimens, Outcome 4 OHSS.

Navigate to figure in ReviewOpen in new tab

Comparison 6 Progesterone regimens, Outcome 5 Multiple pregnancy.
Figures and Tables -
Analysis 6.5

Comparison 6 Progesterone regimens, Outcome 5 Multiple pregnancy.

Navigate to figure in ReviewOpen in new tab

Comparison 6 Progesterone regimens, Outcome 6 Clinical pregnancy: IM vs vaginal/rectal: subgroup analysis by COH method.
Figures and Tables -
Analysis 6.6

Comparison 6 Progesterone regimens, Outcome 6 Clinical pregnancy: IM vs vaginal/rectal: subgroup analysis by COH method.

Navigate to figure in ReviewOpen in new tab

Comparison 6 Progesterone regimens, Outcome 7 Clinical pregnancy: IM vs vaginal/rectal: subgroup analysis by treatment duration.
Figures and Tables -
Analysis 6.7

Comparison 6 Progesterone regimens, Outcome 7 Clinical pregnancy: IM vs vaginal/rectal: subgroup analysis by treatment duration.

Navigate to figure in ReviewOpen in new tab

Comparison 6 Progesterone regimens, Outcome 8 Clinical pregnancy: vaginal/rectal vs oral: subgroup analysis by treatment duration.
Figures and Tables -
Analysis 6.8

Comparison 6 Progesterone regimens, Outcome 8 Clinical pregnancy: vaginal/rectal vs oral: subgroup analysis by treatment duration.

Navigate to figure in ReviewOpen in new tab

Comparison 6 Progesterone regimens, Outcome 9 Clinical pregnancy: low vs high dose vaginal: subgroup analysis by COH method.
Figures and Tables -
Analysis 6.9

Comparison 6 Progesterone regimens, Outcome 9 Clinical pregnancy: low vs high dose vaginal: subgroup analysis by COH method.

Navigate to figure in ReviewOpen in new tab

Comparison 6 Progesterone regimens, Outcome 10 Clinical pregnancy: low vs high dose vaginal: subgroup analysis by duration of treatment.
Figures and Tables -
Analysis 6.10

Comparison 6 Progesterone regimens, Outcome 10 Clinical pregnancy: low vs high dose vaginal: subgroup analysis by duration of treatment.

Navigate to figure in ReviewOpen in new tab

Comparison 6 Progesterone regimens, Outcome 11 Clinical pregnancy: short vs long protocol: subgroup analysis by COH method.
Figures and Tables -
Analysis 6.11

Comparison 6 Progesterone regimens, Outcome 11 Clinical pregnancy: short vs long protocol: subgroup analysis by COH method.

Navigate to figure in ReviewOpen in new tab

Comparison 7 Progesterone + oestrogen regimens, Outcome 1 Live birth/ongoing pregnancy rate.
Figures and Tables -
Analysis 7.1

Comparison 7 Progesterone + oestrogen regimens, Outcome 1 Live birth/ongoing pregnancy rate.

Navigate to figure in ReviewOpen in new tab

Comparison 7 Progesterone + oestrogen regimens, Outcome 2 Clinical pregnancy rate.
Figures and Tables -
Analysis 7.2

Comparison 7 Progesterone + oestrogen regimens, Outcome 2 Clinical pregnancy rate.

Navigate to figure in ReviewOpen in new tab

Comparison 7 Progesterone + oestrogen regimens, Outcome 3 Miscarriage rate.
Figures and Tables -
Analysis 7.3

Comparison 7 Progesterone + oestrogen regimens, Outcome 3 Miscarriage rate.

Navigate to figure in ReviewOpen in new tab

Comparison 7 Progesterone + oestrogen regimens, Outcome 4 Multiple pregnancy.
Figures and Tables -
Analysis 7.4

Comparison 7 Progesterone + oestrogen regimens, Outcome 4 Multiple pregnancy.

Navigate to figure in ReviewOpen in new tab
Summary of findings for the main comparison. hCG compared with placebo/no treatment for assisted reproduction cycles

hCG compared with placebo/no treatment for assisted reproduction cycles

Population: subfertile women
Setting: assisted reproduction
Intervention: hCG
Comparison: placebo/no treatment

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo/No treatment

hCG

Live birth or ongoing pregnancy

120 per 1000

194 per 1000
(128 to 281)

OR 1.76
(1.08 to 2.86)

527
(3 RCTs)

⊕⊝⊝⊝
Very lowa,b,c,f

Clinical pregnancy

155 per 1000

192 per 1000
(141 to 256)

OR 1.3
(0.9 to 1.88)

746
(5 RCTs)

⊕⊕⊝⊝
Very lowa,b,c,d

OHSS

41 per 1000

155 per 1000
(76 to 292)

OR 4.28
(1.91 to 9.6)

387
(1 RCT)

⊕⊕⊝⊝
Lowa,c,e

*The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

aSerious risk of bias due to inadequate reporting of study methods. Risk of bias unclear in most domains of most studies.

bSerious imprecision with low event rate.

cNumber of studies was not sufficient for assessment of publication bias.

dFindings compatible with meaningful benefit for hCG group, or with no effect.

eSerious imprecision; single study with low event rate.

fFindings not statistically significant when random‐effects model was used (OR 1.67, 95% CI 0.90 to 3.12), or when analysis was restricted to studies reporting live birth.

Figures and Tables -
Summary of findings for the main comparison. hCG compared with placebo/no treatment for assisted reproduction cycles
Navigate to table in Review
Summary of findings 2. Progesterone compared with placebo/no treatment for assisted reproduction cycles

Progesterone compared with placebo/no treatment for assisted reproduction cycles

Population: subfertile women
Setting: assisted reproduction
Intervention: progesterone
Comparison: placebo/no treatment

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo/no treatment

Progesterone

Live birth or ongoing pregnancy

39 per 1000

66 per 1000
(42 to 103)

OR 1.77
(1.09 to 2.86)

642
(5 RCTs)

⊕⊝⊝⊝
Very lowa,b,c,d

Clinical pregnancy

100 per 1000

174 per 1000
(126 to 234)

OR 1.89
(1.3 to 2.75)

841
(7 RCTs)

⊕⊕⊝⊝
Lowa,b,c

OHSS

Not reported in any included studies

*The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

aSerious risk of bias due to inadequate reporting of study methods. Risk of bias unclear in most domains of most studies.

bSerious imprecision with low event rate.

cNumber of studies was not sufficient for assessment of publication bias.

d Findings not statistically significant when random‐effects model was used (OR 1.77, 95% CI 0.96 to 3.26), or when analysis was restricted to studies reporting live birth.

Figures and Tables -
Summary of findings 2. Progesterone compared with placebo/no treatment for assisted reproduction cycles
Navigate to table in Review
Summary of findings 3. Progesterone compared with hCG regimens for assisted reproduction cycles

Progesterone compared with hCG regimens for assisted reproduction cycles

Population: subfertile women
Setting: assisted reproduction
Intervention: progesterone
Comparison: hCG (alone or with progesterone)

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

hCG (alone or with progesterone)

Progesterone

Live birth or ongoing pregnancy

198 per 1000

190 per 1000
(138 to 254)

OR 0.95
(0.65 to 1.38)

833
(5 RCTs)

⊕⊕⊝⊝
Lowa,b,c,d

Clinical pregnancy

284 per 1000

300 per 1000
(263 to 340)

OR 1.08
(0.9 to 1.3)

2355
(16 RCTs)

⊕⊕⊕⊝
Moderatea

OHSS

118 per 1000

58 per 1000

(39 to 87)

OR 0.46

(0.30 to 0.71)

1293

(5 studies)

⊕⊕⊝⊝
Lowa,c,e

*The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

aSerious risk of bias due to inadequate reporting of study methods. Risk of bias unclear in most domains of most studies.

bSerious imprecision with low event rate.

cNumber of studies was not sufficient for assessment of publication bias.

dFindings compatible with meaningful benefit for either group, or with no effect

e Some inconsistency: I2=48% overall, I2=60% in progesterone vs hCG subgroup

Figures and Tables -
Summary of findings 3. Progesterone compared with hCG regimens for assisted reproduction cycles
Navigate to table in Review
Summary of findings 4. Progesterone compared with progesterone + oestrogen for assisted reproduction cycles

Progesterone compared with progesterone + oestrogen for assisted reproduction cycles

Population: subfertile women
Setting: assisted reproduction
Intervention: progesterone
Comparison: progesterone + oestrogen (route of oestrogen: oral, transdermal, vaginal or oral + transdermal)

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Progesterone + oestrogen

Progesterone

Live birth or ongoing pregnancy

367 per 1000

393 per 1000
(345 to 444)

OR 1.12
(0.91 to 1.38)

1651
(9 RCTs)

⊕⊕⊝⊝
Lowa, b, c

Clinical pregnancy

433 per 1000

397 per 1000
(355 to 443)

OR 0.86
(0.72 to 1.04)

2169
(14 RCTs)

⊕⊕⊝⊝
Lowa, d, f

OHSS

51 per 1000

30 per 1000
(11 to 82)

OR 0.58
(0.2 to 1.68)

461
(2 RCTs)

⊕⊕⊝⊝
Lowb, c, e

*The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

aSerious risk of bias due to inadequate reporting of study methods. Risk of bias unclear in most domains of most studies.

bSerious imprecision with low event rate.

cNumber of studies was not sufficient for assessment of publication bias.

dSerious inconsistency with substantial statistical heterogeneity (I2 = 56%). Limiting analysis to the 9 studies using oral oestrogen yielded OR of 1.01 (95% CI 0.80 to 1.27) and reduced heterogeneity (I2 = 16%).

eSerious risk of bias due to inadequate reporting of study methods. Risk of bias both 'high risk' and 'low risk'

fTwo studies with an outlying result.

Figures and Tables -
Summary of findings 4. Progesterone compared with progesterone + oestrogen for assisted reproduction cycles
Navigate to table in Review
Summary of findings 5. Progesterone compared with progesterone + GnRH agonist for assisted reproduction cycles

Progesterone compared with progesterone + GnRH agonist for assisted reproduction cycles

Population: women who had undergone IVF/ICSI
Setting: clinic
Intervention: progesterone luteal support
Comparison: progesterone + GnRH agonist

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Progesterone + GnRH agonist

Progesterone luteal support

Live birth or ongoing pregnancy

356 per 1000

255 per 1000
(209 to 309)

OR 0.62
(0.48 to 0.81)

2861
(9 RCTs)

⊕⊝⊝⊝
Very lowa,b

Clinical pregnancy

405 per 1000

310 per 1000
(258 to 367)

OR 0.66
(0.51 to 0.85)

2435
(8 RCTs)

⊕⊕⊝⊝
Lowc,d

OHSS

50 per 1000

50 per 1000
(17 to 137)

OR 1.00

(0.33 to 3.01)

300
(1 study)

⊕⊝⊝⊝

Very lowe,f,

*The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

a Evidence of significant heterogeneity I2 = 69%

b Only three of the studies reported on live birth as an outcome

c Evidence of heterogeneity I2=47%

d Some studies used multiple doses and some used single doses. We have used subgroup analysis to explore this further

e Lack of detail to make a judgement of risk of bias

f Evidence based on a single trial

Figures and Tables -
Summary of findings 5. Progesterone compared with progesterone + GnRH agonist for assisted reproduction cycles
Navigate to table in Review
Summary of findings 6. Progesterone regimens for assisted reproduction cycles

Progesterone regimens for assisted reproduction cycles

Population: subfertile women
Setting: assisted reproduction
Comparisons of progesterone regimens

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Comparison

Intervention

Live birth or ongoing pregnancy

IM vs oral

200 per 1000

151 per 1000
(34 to 478)

OR 0.71
(0.14 to 3.66)

40
(1 RCT)

⊕⊝⊝⊝
Very lowa,b,c

Live birth or ongoing pregnancy

IM vs vaginal/rectal

266 per 1000

310 per 1000
(272 to 353)

OR 1.24
(1.03 to 1.5)

2309
(7 RCTs)

⊕⊝⊝⊝
Very lowa,c,d

Live birth or ongoing pregnancy

Vaginal/rectal vs oral

205 per 1000

235 per 1000
(176 to 303)

OR 1.19
(0.83 to 1.69)

857
(4 RCTs)

⊕⊕⊝⊝
Lowa,c,e

Live birth or ongoing pregnancy

Low dose vaginal vs high dose vaginal

301 per 1000

295 per 1000
(266 to 324)

OR 0.97
(0.84 to 1.11)

3720
(5 RCTs)

⊕⊕⊕⊝
Moderatea,c

Live birth or ongoing pregnancy

Short protocol vs long protocol

664 per 1000

672 per 1000
(609 to 728)

OR 1.04
(0.79 to 1.36)

1205
(5 RCTs)

⊕⊕⊕⊝
Lowa,c,e

Live birth or ongoing pregnancy

Micronised vs synthetic

220 per 1000

203 per 1000
(130 to 305)

OR 0.9
(0.53 to 1.55)

470
(2 RCTs)

⊕⊕⊝⊝
Lowb,c,e

Live birth or ongoing pregnancy

Vaginal ring vs vaginal gel

441 per 1000

462 per 1000
(409 to 517)

OR 1.09
(0.88 to 1.36)

1271
(1 RCT)

⊕⊕⊝⊝
Lowc,f,g

Live birth or ongoing pregnancy

Subcutaneous vs vaginal gel

358 per 1000

339 per 1000
(292 to 388)

OR 0.92
(0.74 to 1.14)

1465
(2 RCTs)

⊕⊕⊝⊝
Lowc,g,h

Live birth or ongoing pregnancy

Vaginal vs rectal

306 per 1000

360 per 1000

(220 to 528)

OR 1.28

(0.64 to 2.54)

147

(1 RCT)

⊕⊝⊝⊝
Very lowa,b,c

OHSS

IM vs oral

50 per 1000

50 per 1000

(3 to 475)

OR 1.00

(0.06 to 17.18)

40

(1 RCT)

⊕⊝⊝⊝
Very lowa,b,c

OHSS

Low dose vaginal vs high dose vaginal

60 per 1000

55 per 1000

(35 to 86)

OR 0.91 (0.57 to 1.46)

1251

(2 RCTs)

⊕⊕⊕⊝
Lowb,c,g

OHSS rates not reported for other comparisons.

*The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

aSerious risk of bias due to inadequate reporting of study methods. Risk of bias unclear in most study domains.

bVery serious imprecision with low event rate; findings compatible with meaningful benefit in either arm or with no effect.

cNumber of studies was not sufficient for assessment of publication bias.

dVery serious inconsistency with varying directions of effect (I2 = 71%). Findings not statistically significant when random‐effects model was used, or when analysis was restricted to studies reporting live births.

eSerious imprecision with low event rate; findings compatible with meaningful benefit in the oral arm or with no effect.

fSerious imprecision; findings compatible with meaningful benefit in the gel arm or with no effect.

gSerious risk of bias due to inadequate reporting of study methods in 1 or more studies.

hSerious imprecision; findings compatible with meaningful benefit in the subcutaneous arm or with no effect.

Figures and Tables -
Summary of findings 6. Progesterone regimens for assisted reproduction cycles
Navigate to table in Review
Summary of findings 7. Progesterone + oestrogen regimens for assisted reproduction cycles

Progesterone + oestrogen regimens for assisted reproduction cycles

Population: subfertile women
Setting: assisted reproduction
Comparisons of progesterone and oestrogen regimens

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Comparison

Progesterone regimens

Live birth/ongoing pregnancy ‐ short vs long protocol

293 per 1000

309 per 1000
(251 to 372)

OR 1.08

(0.81 to 1.43)

910

(1 RCT)

⊕⊕⊝⊝
Lowa,b,c

Live birth/ongoing pregnancy ‐ low vs high dose protocol

342 per 1000

253 per 1000
(161 to 370)

OR 0.65

(0.37 to 1.13)

285

(1 RCT)

⊕⊝⊝⊝
Very lowa,c,d

OHSS ‐ short vs long protocol

Not reported in any studies

OHSS ‐ low vs high dose protocol

Not reported in any studies

*The basis for the assumed risk is the risk in the control group. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: odds ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

aSerious risk of bias due to inadequate reporting of study methods. Risk of bias unclear in most study domains.

bSerious imprecision; findings compatible with meaningful benefit in either arm or with no effect.

cNumber of studies was not sufficient for assessment of publication bias.

dVery serious imprecision with low event rate; findings compatible with meaningful benefit in either arm or with no effect.

Figures and Tables -
Summary of findings 7. Progesterone + oestrogen regimens for assisted reproduction cycles
Navigate to table in Review
Comparison 1. Human chorionic gonadotropin (hCG) vs placebo or no treatment

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Live birth/ongoing pregnancy rate Show forest plot

3

527

Odds Ratio (M‐H, Fixed, 95% CI)

1.76 [1.08, 2.86]

1.1 Live birth

1

38

Odds Ratio (M‐H, Fixed, 95% CI)

2.2 [0.38, 12.87]

1.2 Ongoing pregnancy

2

489

Odds Ratio (M‐H, Fixed, 95% CI)

1.73 [1.05, 2.87]

2 Clinical pregnancy rate Show forest plot

5

746

Odds Ratio (M‐H, Fixed, 95% CI)

1.30 [0.90, 1.88]

3 Clinical pregnancy rate: subgroup analysis by COH method Show forest plot

5

746

Odds Ratio (M‐H, Fixed, 95% CI)

1.30 [0.90, 1.88]

3.1 Human gonadotropins with clomiphene citrate without GnRH agonists

1

131

Odds Ratio (M‐H, Fixed, 95% CI)

1.24 [0.54, 2.86]

3.2 Human gonadotropins with or without GnRH agonists

3

513

Odds Ratio (M‐H, Fixed, 95% CI)

1.50 [0.94, 2.40]

3.3 Human gonadotropins with or without GnRH antagonists

1

102

Odds Ratio (M‐H, Fixed, 95% CI)

0.81 [0.33, 1.99]

4 Miscarriage rate Show forest plot

2

140

Odds Ratio (M‐H, Fixed, 95% CI)

1.51 [0.37, 6.21]

5 OHSS Show forest plot

1

387

Odds Ratio (M‐H, Fixed, 95% CI)

4.28 [1.91, 9.60]
Figures and Tables -
Comparison 1. Human chorionic gonadotropin (hCG) vs placebo or no treatment
Navigate to table in Review
Comparison 2. Progesterone vs placebo or no treatment

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Live birth/ongoing pregnancy rate Show forest plot

5

642

Odds Ratio (M‐H, Fixed, 95% CI)

1.77 [1.09, 2.86]

1.1 Live birth

1

156

Odds Ratio (M‐H, Fixed, 95% CI)

4.21 [0.93, 19.18]

1.2 Ongoing pregnancy

4

486

Odds Ratio (M‐H, Fixed, 95% CI)

1.53 [0.91, 2.57]

2 Clinical pregnancy rate Show forest plot

7

841

Odds Ratio (M‐H, Fixed, 95% CI)

1.89 [1.30, 2.75]

3 Clinical pregnancy: subgroup analysis by COH method Show forest plot

7

841

Odds Ratio (M‐H, Fixed, 95% CI)

1.89 [1.30, 2.75]

3.1 Clomiphene citrate alone without GnRH agonists

1

56

Odds Ratio (M‐H, Fixed, 95% CI)

5.0 [0.54, 45.92]

3.2 Human gonadotropins with clomiphene citrate without GnRH agonists

2

306

Odds Ratio (M‐H, Fixed, 95% CI)

1.58 [0.86, 2.90]

3.3 Human gonadotropins with or without GnRH agonists

4

479

Odds Ratio (M‐H, Fixed, 95% CI)

1.99 [1.22, 3.26]

4 Clinical pregnancy: subgroup analysis by treatment duration Show forest plot

7

841

Odds Ratio (M‐H, Fixed, 95% CI)

1.89 [1.30, 2.75]

4.1 Stop at pregnancy test

3

257

Odds Ratio (M‐H, Fixed, 95% CI)

1.42 [0.74, 2.74]

4.2 Up to 12 weeks

4

584

Odds Ratio (M‐H, Fixed, 95% CI)

2.17 [1.37, 3.43]

5 Miscarriage rate Show forest plot

3

425

Odds Ratio (M‐H, Fixed, 95% CI)

1.22 [0.49, 3.03]

6 Multiple pregnancy Show forest plot

1

34

Odds Ratio (M‐H, Fixed, 95% CI)

5.87 [0.22, 155.76]
Figures and Tables -
Comparison 2. Progesterone vs placebo or no treatment
Navigate to table in Review
Comparison 3. Progesterone vs hCG regimens

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Live birth or ongoing pregnancy rate Show forest plot

5

833

Odds Ratio (M‐H, Fixed, 95% CI)

0.95 [0.65, 1.38]

1.1 Progesterone vs hCG

4

434

Odds Ratio (M‐H, Fixed, 95% CI)

0.92 [0.54, 1.57]

1.2 Progesterone vs progesterone + hCG

2

399

Odds Ratio (M‐H, Fixed, 95% CI)

0.97 [0.58, 1.64]

2 Clinical pregnancy rate Show forest plot

16

2355

Odds Ratio (M‐H, Fixed, 95% CI)

1.08 [0.90, 1.30]

2.1 Progesterone vs hCG

11

1378

Odds Ratio (M‐H, Fixed, 95% CI)

1.20 [0.94, 1.53]

2.2 Progesterone vs progesterone + hCG

7

977

Odds Ratio (M‐H, Fixed, 95% CI)

0.95 [0.72, 1.25]

3 Clinical pregnancy: progesterone vs progesterone + hCG: subgroup analysis by COH method Show forest plot

4

722

Odds Ratio (M‐H, Fixed, 95% CI)

0.91 [0.65, 1.29]

3.1 Human gonadotropins with clomiphene citrate without GnRH agonists

1

20

Odds Ratio (M‐H, Fixed, 95% CI)

1.71 [0.22, 13.41]

3.2 Human gonadotropins with or without GnRH agonists

3

702

Odds Ratio (M‐H, Fixed, 95% CI)

0.90 [0.63, 1.27]

4 Clinical pregnancy: progesterone vs hCG: subgroup analysis by treatment duration Show forest plot

7

872

Odds Ratio (M‐H, Fixed, 95% CI)

1.16 [0.85, 1.58]

4.1 Stop at pregnancy test

6

783

Odds Ratio (M‐H, Fixed, 95% CI)

1.16 [0.84, 1.61]

4.2 Up to 12 weeks when pregnant

1

89

Odds Ratio (M‐H, Fixed, 95% CI)

1.15 [0.46, 2.84]

5 OHSS Show forest plot

5

1293

Odds Ratio (M‐H, Fixed, 95% CI)

0.46 [0.30, 0.71]

5.1 Progesterone vs hCG

4

615

Odds Ratio (M‐H, Fixed, 95% CI)

0.57 [0.32, 1.00]

5.2 Progesterone vs progesterone + hCG

3

678

Odds Ratio (M‐H, Fixed, 95% CI)

0.36 [0.18, 0.69]

6 Miscarriage rate Show forest plot

5

832

Odds Ratio (M‐H, Fixed, 95% CI)

1.24 [0.66, 2.31]

6.1 Progesterone vs hCG

5

735

Odds Ratio (M‐H, Fixed, 95% CI)

1.30 [0.66, 2.55]

6.2 Progesterone vs progesterone + hCG

1

97

Odds Ratio (M‐H, Fixed, 95% CI)

0.88 [0.15, 5.06]

7 Multiple pregnancy Show forest plot

1

209

Odds Ratio (M‐H, Fixed, 95% CI)

0.44 [0.07, 2.65]

7.1 Progesterone vs hCG

1

112

Odds Ratio (M‐H, Fixed, 95% CI)

0.73 [0.07, 7.23]

7.2 Progesterone vs progesterone + hCG

1

97

Odds Ratio (M‐H, Fixed, 95% CI)

0.24 [0.01, 4.77]
Figures and Tables -
Comparison 3. Progesterone vs hCG regimens
Navigate to table in Review
Comparison 4. Progesterone vs progesterone + oestrogen

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Live birth/ongoing pregnancy rate Show forest plot

9

1651

Odds Ratio (M‐H, Fixed, 95% CI)

1.12 [0.91, 1.38]

1.1 Oral oestrogen

6

1266

Odds Ratio (M‐H, Fixed, 95% CI)

1.11 [0.87, 1.42]

1.2 Transdermal oestrogen

2

219

Odds Ratio (M‐H, Fixed, 95% CI)

0.97 [0.56, 1.67]

1.3 Vaginal oestrogen

1

166

Odds Ratio (M‐H, Fixed, 95% CI)

1.41 [0.76, 2.59]

2 Clinical pregnancy rate Show forest plot

14

2169

Odds Ratio (M‐H, Fixed, 95% CI)

0.86 [0.72, 1.04]

2.1 Oral oestrogen

9

1427

Odds Ratio (M‐H, Fixed, 95% CI)

1.01 [0.80, 1.27]

2.2 Transdermal oestrogen

3

364

Odds Ratio (M‐H, Fixed, 95% CI)

0.43 [0.26, 0.70]

2.3 Vaginal oestrogen

2

301

Odds Ratio (M‐H, Fixed, 95% CI)

1.07 [0.67, 1.71]

2.4 Oral and transdermal oestrogen

1

77

Odds Ratio (M‐H, Fixed, 95% CI)

0.30 [0.10, 0.96]

3 Clinical pregnancy: subgroup analysis by COH method Show forest plot

8

1183

Odds Ratio (M‐H, Fixed, 95% CI)

0.94 [0.73, 1.22]

3.1 Human gonadotropins with or without GnRH agonists

7

1080

Odds Ratio (M‐H, Fixed, 95% CI)

0.92 [0.70, 1.21]

3.2 Human gonadotropins with or without GnRH antagonists

2

103

Odds Ratio (M‐H, Fixed, 95% CI)

1.12 [0.51, 2.44]

4 Clinical pregnancy: subgroup analysis by treatment duration Show forest plot

10

1851

Odds Ratio (M‐H, Fixed, 95% CI)

0.89 [0.73, 1.08]

4.1 Stop at pregnancy test

2

177

Odds Ratio (M‐H, Fixed, 95% CI)

0.67 [0.34, 1.32]

4.2 Up to 12 weeks when pregnant

8

1674

Odds Ratio (M‐H, Fixed, 95% CI)

0.91 [0.74, 1.12]

5 Miscarriage rate Show forest plot

10

1908

Risk Difference (M‐H, Fixed, 95% CI)

‐0.00 [‐0.03, 0.03]

5.1 Oral oestrogen

7

1370

Risk Difference (M‐H, Fixed, 95% CI)

0.01 [‐0.02, 0.04]

5.2 Transdermal oestrogen

1

160

Risk Difference (M‐H, Fixed, 95% CI)

‐0.01 [‐0.09, 0.07]

5.3 Vaginal oestrogen

2

301

Risk Difference (M‐H, Fixed, 95% CI)

‐0.01 [‐0.08, 0.07]

5.4 Oral and transdermal oestrogen

1

77

Risk Difference (M‐H, Fixed, 95% CI)

‐0.10 [‐0.22, 0.01]

6 OHSS Show forest plot

2

461

Odds Ratio (M‐H, Fixed, 95% CI)

0.58 [0.20, 1.68]

6.1 Oral oestrogen

1

402

Odds Ratio (M‐H, Fixed, 95% CI)

0.71 [0.22, 2.29]

6.2 Transdermal oestrogen

1

59

Odds Ratio (M‐H, Fixed, 95% CI)

0.19 [0.01, 4.20]
Figures and Tables -
Comparison 4. Progesterone vs progesterone + oestrogen
Navigate to table in Review
Comparison 5. Progesterone vs progesterone + GnRH agonist

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Live birth or ongoing pregnancy rate Show forest plot

9

2861

Odds Ratio (M‐H, Random, 95% CI)

0.62 [0.48, 0.81]

1.1 Single dose

5

1536

Odds Ratio (M‐H, Random, 95% CI)

0.59 [0.39, 0.87]

1.2 Multiple dose

5

1325

Odds Ratio (M‐H, Random, 95% CI)

0.64 [0.42, 0.98]

2 Clinical pregnancy rate Show forest plot

8

2435

Odds Ratio (M‐H, Random, 95% CI)

0.66 [0.51, 0.85]

2.1 Single dose

5

1536

Odds Ratio (M‐H, Random, 95% CI)

0.63 [0.44, 0.91]

2.2 Multiple dose

4

899

Odds Ratio (M‐H, Random, 95% CI)

0.67 [0.44, 1.04]

3 Clinical pregnancy: subgroup analysis by COH method Show forest plot

7

2373

Odds Ratio (M‐H, Random, 95% CI)

0.71 [0.56, 0.90]

3.1 Gonadotropins with or without GnRH agonists

6

1919

Odds Ratio (M‐H, Random, 95% CI)

0.77 [0.61, 0.99]

3.2 Gonadotropins with or without GnRH antagonists

2

454

Odds Ratio (M‐H, Random, 95% CI)

0.53 [0.30, 0.92]

4 Clinical pregnancy: subgroup analysis by treatment duration Show forest plot

6

2253

Odds Ratio (M‐H, Random, 95% CI)

0.76 [0.62, 0.95]

4.1 Stop at pregnancy test

5

1683

Odds Ratio (M‐H, Random, 95% CI)

0.71 [0.57, 0.89]

4.2 Up to 12 weeks when pregnant

1

570

Odds Ratio (M‐H, Random, 95% CI)

0.97 [0.70, 1.35]

5 Miscarriage rate Show forest plot

2

420

Odds Ratio (M‐H, Fixed, 95% CI)

1.37 [0.53, 3.52]

5.1 Single dose

1

150

Odds Ratio (M‐H, Fixed, 95% CI)

1.0 [0.18, 5.65]

5.2 Multiple dose

2

270

Odds Ratio (M‐H, Fixed, 95% CI)

1.57 [0.50, 4.92]

6 Multiple pregnancy Show forest plot

4

1450

Odds Ratio (M‐H, Fixed, 95% CI)

0.76 [0.54, 1.05]

6.1 Single dose

3

874

Odds Ratio (M‐H, Fixed, 95% CI)

0.76 [0.52, 1.13]

6.2 Multiple dose

2

576

Odds Ratio (M‐H, Fixed, 95% CI)

0.74 [0.40, 1.36]

7 OHSS Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected
Figures and Tables -
Comparison 5. Progesterone vs progesterone + GnRH agonist
Navigate to table in Review
Comparison 6. Progesterone regimens

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Live birth or ongoing pregnancy rate Show forest plot

25

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

1.1 IM vs oral

1

40

Odds Ratio (M‐H, Fixed, 95% CI)

0.71 [0.14, 3.66]

1.2 IM vs vaginal/rectal

7

2039

Odds Ratio (M‐H, Fixed, 95% CI)

1.24 [1.03, 1.50]

1.3 Vaginal/rectal vs oral

4

857

Odds Ratio (M‐H, Fixed, 95% CI)

1.19 [0.83, 1.69]

1.4 Low dose vaginal vs high dose vaginal

5

3720

Odds Ratio (M‐H, Fixed, 95% CI)

0.97 [0.84, 1.11]

1.5 Short protocol vs long protocol

5

1205

Odds Ratio (M‐H, Fixed, 95% CI)

1.04 [0.79, 1.36]

1.6 Micronised vs synthetic

2

470

Odds Ratio (M‐H, Fixed, 95% CI)

0.90 [0.53, 1.55]

1.7 Vaginal ring vs vaginal gel

1

1271

Odds Ratio (M‐H, Fixed, 95% CI)

1.09 [0.88, 1.36]

1.8 Subcutaneous vs vaginal gel

2

1465

Odds Ratio (M‐H, Fixed, 95% CI)

0.92 [0.74, 1.14]

1.9 Vaginal vs rectal

1

147

Odds Ratio (M‐H, Fixed, 95% CI)

1.28 [0.64, 2.54]

2 Clinical pregnancy rate Show forest plot

41

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2.1 IM vs oral

3

123

Odds Ratio (M‐H, Fixed, 95% CI)

1.96 [0.89, 4.32]

2.2 IM vs vaginal/rectal

13

2932

Odds Ratio (M‐H, Fixed, 95% CI)

1.14 [0.97, 1.33]

2.3 Vaginal/rectal vs oral

7

2815

Odds Ratio (M‐H, Fixed, 95% CI)

0.89 [0.75, 1.05]

2.4 Low dose vaginal vs high dose vaginal

12

5659

Odds Ratio (M‐H, Fixed, 95% CI)

0.98 [0.87, 1.09]

2.5 Short protocol vs long protocol

6

1128

Odds Ratio (M‐H, Fixed, 95% CI)

1.14 [0.87, 1.50]

2.6 Micronised vs synthetic

4

2388

Odds Ratio (M‐H, Fixed, 95% CI)

0.79 [0.66, 0.96]

2.7 Vaginal ring vs vaginal gel

1

1271

Odds Ratio (M‐H, Fixed, 95% CI)

1.05 [0.84, 1.31]

2.8 Subcutaneous vs vaginal gel

2

1465

Odds Ratio (M‐H, Fixed, 95% CI)

0.88 [0.71, 1.08]

2.9 Vaginal vs rectal

1

147

Odds Ratio (M‐H, Fixed, 95% CI)

1.32 [0.68, 2.56]

3 Miscarriage rate Show forest plot

26

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

3.1 IM vs oral

3

123

Odds Ratio (M‐H, Fixed, 95% CI)

1.43 [0.34, 6.11]

3.2 IM vs vaginal/rectal

6

1468

Odds Ratio (M‐H, Fixed, 95% CI)

0.79 [0.56, 1.13]

3.3 Vaginal/rectal vs oral

5

2220

Odds Ratio (M‐H, Fixed, 95% CI)

1.18 [0.76, 1.82]

3.4 Low dose vaginal vs high dose vaginal

9

4333

Odds Ratio (M‐H, Fixed, 95% CI)

0.73 [0.55, 0.98]

3.5 Short protocol vs long protocol

3

662

Odds Ratio (M‐H, Fixed, 95% CI)

0.96 [0.61, 1.50]

3.6 Micronised vs synthetic

2

1793

Odds Ratio (M‐H, Fixed, 95% CI)

1.16 [0.69, 1.95]

3.7 Subcutaneous vs vaginal gel

2

1465

Odds Ratio (M‐H, Fixed, 95% CI)

0.82 [0.44, 1.54]

3.8 Vaginal vs rectal

1

147

Odds Ratio (M‐H, Fixed, 95% CI)

1.21 [0.31, 4.71]

4 OHSS Show forest plot

2

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

4.1 IM vs oral

1

40

Odds Ratio (M‐H, Fixed, 95% CI)

1.0 [0.06, 17.18]

4.2 Low dose vaginal vs high dose vaginal

2

1251

Odds Ratio (M‐H, Fixed, 95% CI)

0.91 [0.57, 1.46]

5 Multiple pregnancy Show forest plot

14

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

5.1 IM vs oral

2

83

Odds Ratio (M‐H, Fixed, 95% CI)

4.23 [1.16, 15.40]

5.2 IM vs vaginal/rectal

1

505

Odds Ratio (M‐H, Fixed, 95% CI)

0.97 [0.60, 1.59]

5.3 Vaginal/rectal vs oral

1

283

Odds Ratio (M‐H, Fixed, 95% CI)

1.13 [0.50, 2.58]

5.4 Low dose vaginal vs high dose vaginal

5

2888

Odds Ratio (M‐H, Fixed, 95% CI)

1.24 [0.85, 1.80]

5.5 Short protocol vs long protocol

4

820

Odds Ratio (M‐H, Fixed, 95% CI)

1.13 [0.80, 1.60]

5.6 Vaginal vs rectal

1

147

Odds Ratio (M‐H, Fixed, 95% CI)

0.96 [0.19, 4.91]

6 Clinical pregnancy: IM vs vaginal/rectal: subgroup analysis by COH method Show forest plot

11

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

6.1 Human gonadotropins with or without GnRH agonists

10

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.2 Human gonadotropins with or without GnRH antagonists

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7 Clinical pregnancy: IM vs vaginal/rectal: subgroup analysis by treatment duration Show forest plot

7

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

7.1 Stop at pregnancy test

2

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.2 Up to 12 weeks when pregnant

5

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

8 Clinical pregnancy: vaginal/rectal vs oral: subgroup analysis by treatment duration Show forest plot

6

2775

Odds Ratio (M‐H, Fixed, 95% CI)

0.87 [0.73, 1.04]

8.1 Stop at pregnancy test

2

619

Odds Ratio (M‐H, Fixed, 95% CI)

0.70 [0.50, 0.98]

8.2 Up to 12 weeks when pregnant

4

2156

Odds Ratio (M‐H, Fixed, 95% CI)

0.95 [0.77, 1.17]

9 Clinical pregnancy: low vs high dose vaginal: subgroup analysis by COH method Show forest plot

9

3512

Odds Ratio (M‐H, Fixed, 95% CI)

1.05 [0.91, 1.22]

9.1 Human gonadotropins with or without GnRH agonists

8

3388

Odds Ratio (M‐H, Fixed, 95% CI)

1.05 [0.91, 1.22]

9.2 Human gonadotropins with or without GnRH antagonists

1

124

Odds Ratio (M‐H, Fixed, 95% CI)

1.04 [0.49, 2.22]

10 Clinical pregnancy: low vs high dose vaginal: subgroup analysis by duration of treatment Show forest plot

9

3514

Odds Ratio (M‐H, Fixed, 95% CI)

1.07 [0.92, 1.24]

10.1 Stop at pregnancy test

3

318

Odds Ratio (M‐H, Fixed, 95% CI)

1.11 [0.67, 1.83]

10.2 Up to 12 weeks when pregnant

6

3196

Odds Ratio (M‐H, Fixed, 95% CI)

1.06 [0.91, 1.24]

11 Clinical pregnancy: short vs long protocol: subgroup analysis by COH method Show forest plot

4

902

Odds Ratio (M‐H, Fixed, 95% CI)

1.02 [0.75, 1.40]

11.1 Human gonadotropins with or without GnRH agonists

2

482

Odds Ratio (M‐H, Fixed, 95% CI)

0.87 [0.58, 1.32]

11.2 Human gonadotropins with or without GnRH antagonists

2

420

Odds Ratio (M‐H, Fixed, 95% CI)

1.27 [0.79, 2.05]
Figures and Tables -
Comparison 6. Progesterone regimens
Navigate to table in Review
Comparison 7. Progesterone + oestrogen regimens

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Live birth/ongoing pregnancy rate Show forest plot

2

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

1.1 Short protocol vs long protocol

1

910

Odds Ratio (M‐H, Fixed, 95% CI)

1.08 [0.81, 1.43]

1.2 Low dosage vs high dosage

1

285

Odds Ratio (M‐H, Fixed, 95% CI)

0.65 [0.37, 1.13]

2 Clinical pregnancy rate Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2.1 Low dosage vs high dosage

1

285

Odds Ratio (M‐H, Fixed, 95% CI)

0.81 [0.48, 1.37]

3 Miscarriage rate Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

3.1 Low dosage vs high dosage

1

285

Odds Ratio (M‐H, Fixed, 95% CI)

3.13 [0.86, 11.39]

4 Multiple pregnancy Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

4.1 Low dosage vs high dosage

1

285

Odds Ratio (M‐H, Fixed, 95% CI)

0.25 [0.06, 1.12]
Figures and Tables -
Comparison 7. Progesterone + oestrogen regimens
Navigate to table in Review