Inclusion criteria

Of the 29 studies, 25 RCTs included women with a regular IVF/ICSI indication while four RCTs included women who had special indications for IVF: one trial included women who were low responders (i.e. women who respond poorly to controlled ovarian hyperstimulation (Kim 2011)); one included women with limited ovarian reserve (Daly 2002); one included women with PCOS (Hwang 2004); and another one included women with an ovarian cyst of over 5 mm in diameter or an endometrial thickness of over 5 mm and serum oestradiol concentration greater than 100 pmol/L after 14 days of GnRH agonist treatment (Shaker 1995).

Twenty‐one studies mentioned an age limit as an inclusion criteria. Eight studies only included women aged 38 years or less (Blockeel 2012; Cédrin‐Durnerin 2007; Cédrin‐Durnerin 2012; Franco Jr 2003; Hauzman 2013; Huirne 2006a; Salat‐Baroux 1988; Ye 2009). Nine studies only included women aged 39 years or less (Fanchin 2003; Garcia‐Velasco 2011; Huirne 2006c; Hwang 2004; Kolibianakis 2006; Nyboe Andersen 2011; Porrati 2010; Rombauts 2006; Vilela 2011). One study included women less than 40 years (Lukaszuk 2015). The other three studies used age limits above 40 years of age: one study used an upper limit of 41 years of age (Daly 2002), one study an upper limit of 42 years of age (Cédrin‐Durnerin 1996), and one study used an upper limit of 44 years of age (Engmann 1999). Six of these 21 studies defined lower limits of 18 years of age (Engmann 1999; Hauzman 2013; Huirne 2006a; Huirne 2006c; Nyboe Andersen 2011; Rombauts 2006).

Other common inclusion criteria were the presence of regular menstrual cycles (Blockeel 2012; Cédrin‐Durnerin 2007; Cédrin‐Durnerin 2012; Fanchin 2003; Garcia‐Velasco 2011; Hauzman 2013; Huirne 2006a; Nyboe Andersen 2011; Rombauts 2006; Ye 2009), and a body mass index (BMI) between 18 kg/m² and 25 kg/m² (Ye 2009), or less than 30 kg/m² (Blockeel 2012; Cédrin‐Durnerin 2007; Cédrin‐Durnerin 2012; Fanchin 2003; Hauzman 2013; Huirne 2006a; Kolibianakis 2006; Rombauts 2006).

Exclusion criteria

Nine studies excluded women with an evidence of poor response. Two studies defined poor response as any previous ART cycles with less than three oocytes (Huirne 2006a; Huirne 2006c), Huirne 2006a also excluded women if they had a history of three or more consecutive ART cycles without a clinical pregnancy. One study defined poor response as development of fewer than four follicles in previous IVF or ICSI cycles (Blockeel 2012). Three studies defined poor response as fewer than five oocytes in a previous IVF attempt or fewer than five follicles in a spontaneous cycle (Cédrin‐Durnerin 2007; Cédrin‐Durnerin 2012; Hauzman 2013), and one study defined poor response as more than three unsuccessful controlled ovarian stimulation cycles or a history of low or no ovarian response during FSH/hMG (Rombauts 2006). Two studies did not mention how they defined poor response to ovarian stimulation (Garcia‐Velasco 2011; Kolibianakis 2006).

Other common exclusion criteria were: a high baseline serum FSH level (Cédrin‐Durnerin 2007; Cédrin‐Durnerin 2012; Ditkoff 1996; Engmann 1999; Huirne 2006a; Hwang 2004; Kolibianakis 2006; Nyboe Andersen 2011), evidence of ovarian cysts or endometrioma (Aston 1995; Engmann 1999; Kolibianakis 2006), and PCOS (Blockeel 2012; Garcia‐Velasco 2011; Hauzman 2013; Huirne 2006a; Kim 2011; Porrati 2010; Rombauts 2006; Vilela 2011).

Combined oral contraceptive pill versus placebo or no pretreatment

In 17 trials (with 19 comparisons), the study group received pretreatment with a COCP, while the control group received no pretreatment. None of these studies used a placebo in the control group. Ten trials used ethinyl oestradiol as the oestrogen component in a daily dose of 30 μg (Cédrin‐Durnerin 2007; Garcia‐Velasco 2011; Huirne 2006a; Huirne 2006c; Kim 2011; Kolibianakis 2006; Nyboe Andersen 2011; Obruca 2002; Raoofi 2008; Rombauts 2006); seven trials used desogestrel 150 μg daily (Cédrin‐Durnerin 2007; Garcia‐Velasco 2011; Kolibianakis 2006; Nyboe Andersen 2011; Obruca 2002; Raoofi 2008; Rombauts 2006); three trials used levonorgestrel 150 μg daily as the progestogen component (Huirne 2006a; Huirne 2006c; Kim 2011); one trial used Diane‐35, which contained ethinyl oestradiol 35 μg and cyproterone acetate 2 mg (Hwang 2004); and two trials used a combination of ethinyl oestradiol 20 μg and levonorgestrel 100 μg (Porrati 2010; Vilela 2011). For other studies, there were not enough data available on the type of COCP used.

The starting days of pretreatment in 10 of the trials varied from cycle day one to five. Five studies started COCP pretreatment on cycle day one (Biljan 1998b; Kolibianakis 2006; Obruca 2002; Raoofi 2008; Rombauts 2006); two studies started the pretreatment on cycle day two or three (Cédrin‐Durnerin 2007; Huirne 2006a); one study started the pretreatment on a variable cycle day from one to five (Huirne 2006c); and one study started the pretreatment on cycle day five (Hwang 2004). There were not enough data available from five trials on the start day of pretreatment (Garcia‐Velasco 2011; Kim 2011; Nyboe Andersen 2011; Porrati 2010; Vilela 2011).

The duration of pretreatment in the 17 trials varied from 12 days to three consecutive cycles. Five studies used a fixed duration of 14 days of pretreatment (Biljan 1998b; Kolibianakis 2006; Raoofi 2008), or 21 days of pretreatment (Kim 2011; Porrati 2010); five studies used a variable duration of pretreatment of 12 to 16 days (Garcia‐Velasco 2011), 14 to 21 days (Nyboe Andersen 2011), 14 to 25 days (Vilela 2011), and 14 to 28 days (Huirne 2006a; Rombauts 2006). Three other studies used a variable duration of around two or three weeks minimum to around four weeks maximum (Cédrin‐Durnerin 2007, 15 to 21 days; Obruca 2002, 18 to 28 days; Huirne 2006c, 21 to 28 days). Hwang 2004 used the longest pretreatment duration of three consecutive cycles.

Two studies used agonists in both treatment groups. One study used buserelin acetate (long protocol) (Biljan 1998b) and one used a depot of triptorelin acetate (Raoofi 2008).

Ten studies used antagonists in both treatment groups. Four studies used ganirelix acetate (Blockeel 2012; Cédrin‐Durnerin 2007; Kolibianakis 2006; Rombauts 2006); three studies used cetrorelix acetate (Obruca 2002; Porrati 2010; Vilela 2011); one study used antide (Huirne 2006a); one study, a three‐arm parallel RCT, used cerotide in two of the treatment arms and a GnRH agonist in the second control arm (Kim 2011), and one study did not mention which GnRH antagonist was used (Nyboe Andersen 2011).

Four trials used an antagonist in the study group and an agonist in the control group. Two trials used cetrorelix acetate as antagonist and buserelin acetate as agonist (Huirne 2006c; Hwang 2004), and one used ganirelix acetate as antagonist and nafarelin acetate as agonist (Rombauts 2006). The other study did not mention which antagonists and agonists were used (Garcia‐Velasco 2011).

Progestogen versus placebo or no pretreatment

In seven trials, the study group was given a pretreatment with a progestogen, while the control group received placebo (Aston 1995), or no pretreatment (Cédrin‐Durnerin 2007; Ditkoff 1996; Engmann 1999; Hugues 1994; Salat‐Baroux 1988; Shaker 1995). Four studies used norethisterone 10 mg daily (Cédrin‐Durnerin 2007; Ditkoff 1996; Engmann 1999; Hugues 1994), one study used medroxyprogesterone acetate 10 mg daily (Aston 1995), and one study used ethynodiol acetate 4 mg daily (Salat‐Baroux 1988). Another study used a single injection of 100 mg, but did not mention what type of progestogen they used (Shaker 1995).

The starting days of pretreatment in all seven trials varied from cycle day one to 19. Two studies started the pretreatment with progestogen on cycle day one (Ditkoff 1996; Engmann 1999), two studies on cycle day 15 (Cédrin‐Durnerin 2007; Salat‐Baroux 1988), one study on cycle day 16 or 17 (Shaker 1995), and one study on cycle day 19 (Aston 1995). There were not enough data available from one study on the start day of pretreatment (Hugues 1994).

The duration of progestogen pretreatment varied from one to 21 days. In one study, the women received one single injection (Shaker 1995). One study used a duration of pretreatment of five days (Engmann 1999), one study used seven days (Aston 1995), and one study used eight days (Ditkoff 1996). Two trials used a variable duration of 10 to 15 days (Cédrin‐Durnerin 2007; Hugues 1994), and one trial used 11 to 17 days (Salat‐Baroux 1988).

Six trials used an agonist in both treatment groups. Three studies used buserelin acetate (Aston 1995; Engmann 1999; Shaker 1995), one study used triptorelin (Cédrin‐Durnerin 1996), one study used leuprolide acetate (Ditkoff 1996), and one study used dTRP6‐LHRH (Hugues 1994).

One trial used an antagonist (ganirelix acetate) in both treatment groups (Cédrin‐Durnerin 2007).

One trial did not use GnRH analogues for pituitary desensitisation. Women that participated in this study only received pure FSH and hMG (Salat‐Baroux 1988).

Oestrogen versus placebo or no pretreatment

In five trials, the study group was given a pretreatment with oestrogen, while the control group received no pretreatment. Three studies used 17β‐oestradiol (Cédrin‐Durnerin 2007; Cédrin‐Durnerin 2012; Fanchin 2003), and two studies used oestradiol valerate (Franco Jr 2003; Ye 2009). All these studies used 4 mg daily.

The starting days of pretreatment varied from cycle day 15 to 21. One study started the pretreatment on cycle day 20 (Fanchin 2003), and two on cycle day 21 (Franco Jr 2003; Ye 2009). One study started pretreatment seven days before the presumed onset of menses and administered up to the next Thursday after the occurrence of menstrual bleeding (Cédrin‐Durnerin 2012). One remaining study started the pretreatment 10 days before the presumed menses (Cédrin‐Durnerin 2007).

The duration of pretreatment varied from 10 to 17 days. In two studies the duration varied from 7 to 15 days (Cédrin‐Durnerin 2007; Cédrin‐Durnerin 2012). Three studies used a fixed duration of pretreatment of 10 days (Ye 2009), 11 days (Fanchin 2003), and 14 days (Franco Jr 2003).

Three trials used an antagonist in both treatment groups, one trial used ganirelix acetate (Cédrin‐Durnerin 2007), one trial used cetrorelix acetate (Fanchin 2003), and one trial did not report the name of the antagonist (Cédrin‐Durnerin 2012).

Two trials used an antagonist in the intervention group and an agonist in the control group, one trial used ganirelix acetate in the intervention group and nafarelin acetate in the control group (Franco Jr 2003), and one study used cetrotide in the intervention group and triptoreline in the control group (Ye 2009).

Combined oral contraceptive pill versus progestogen

There was only one study that compared COCP with progestogen (Cédrin‐Durnerin 2007). The women in the COCP group received ethinyl oestradiol 30 μg plus desogestrel 150 μg daily and the women in the progestogen group received norethisterone 10 mg daily. This study started the COCP pretreatment on cycle day two or three with a duration of 15 to 21 days. The progestogen pretreatment was started on cycle day 15 with a duration of 10 to 15 days. Both groups received the GnRH antagonist, ganirelix acetate.

Combined oral contraceptive pill versus oestrogen

Four trials compared a pretreatment of COCP with a pretreatment of oestrogen. One trial used ethinyl oestradiol 30 μg plus desogestrel 150 μg daily as a COCP and micronised 17β‐oestradiol 4 mg daily as oestrogen pretreatment (Cédrin‐Durnerin 2007). The COCP pretreatment started on cycle day two or three with a duration of 15 to 21 days. The oestrogen pretreatment started 10 days before the presumed menses with a duration of 10 to 15 days and both groups received the GnRH antagonist, ganirelix acetate. Another study used ethinyl oestradiol 30 μg plus levonorgestrel 150 μg daily as a COCP and oestradiol valerate 4 mg daily as oestrogen pretreatment (Hauzman 2013). The COCP pretreatment started on cycle day one or two and continued for 12 to 16 days. The oestrogen pretreatment started from day 20 of menstrual cycle for five to 12 days until the day before starting stimulation and both groups received the GnRH antagonist, ganirelix acetate. One study used ethinyl oestradiol plus desogestrel as COCP starting from day two to four of the cycle but their doses were not reported (Lukaszuk 2015). In the control group, women were pretreated with oral oestradiol 2 mg twice daily from the day 20 of the natural cycle to day one to four of the new cycle. Both groups received the GnRH agonist, triptorelin. One study did not mention which COCP was used, but used ethinyl oestradiol 2 mg as an oestrogen pretreatment (Daly 2002). This study only described that the oestrogen pretreatment was administered in the luteal phase of the preparation cycle, but did not report the exact starting days and durations of pretreatment. The COCP group received the GnRH agonist, leuprolide acetate, and the oestrogen group received the GnRH antagonist, ganirelix acetate.

Progestogen versus oestrogen

There was only one study that compared progestogen with oestrogen (Cédrin‐Durnerin 2007). The women in the progestogen group received norethisterone 10 mg daily and the women in the oestrogen group received micronised 17β‐oestradiol 4 mg daily. This study started the progestogen pretreatment on cycle day 15 with a duration of 10 to 15 days. The oestrogen pretreatment started 10 days before the presumed menses with also a duration of 10 to 15 days. Both groups received the GnRH antagonist, ganirelix acetate.

Primary outcome

Fifteen studies reported the number of live births or ongoing pregnancies (Cédrin‐Durnerin 2007; Cédrin‐Durnerin 2012; Daly 2002; Ditkoff 1996; Engmann 1999; Franco Jr 2003; Garcia‐Velasco 2011; Hauzman 2013; Huirne 2006a; Huirne 2006c; Kim 2011; Kolibianakis 2006; Nyboe Andersen 2011; Rombauts 2006; Ye 2009). Three studies defined ongoing pregnancy as a positive heart activity at a gestational age of 12 weeks (Huirne 2006a; Huirne 2006c; Kim 2011). One study used the same definition but did not mention when they performed the ultrasound scan (Ditkoff 1996). Two studies defined ongoing pregnancy as a pregnancy developing beyond 12 weeks (Cédrin‐Durnerin 2007; Kolibianakis 2006), and one study defined ongoing pregnancy as a pregnancy assessed by ultrasound at 12 to 16 weeks or later (Rombauts 2006). The remaining studies did not mention how they assessed ongoing pregnancy (Cédrin‐Durnerin 2012; Daly 2002; Engmann 1999; Franco Jr 2003; Garcia‐Velasco 2011; Hauzman 2013; Nyboe Andersen 2011; Ye 2009).

Ten studies reported the number of pregnancy losses. One study described this as the proportion of women with initially positive hCG in whom pregnancy failed to develop beyond 12 weeks of gestation (Kolibianakis 2006). The other nine studies did not describe a definition (Daly 2002; Engmann 1999; Franco Jr 2003; Garcia‐Velasco 2011; Hwang 2004; Kim 2011; Rombauts 2006; Salat‐Baroux 1988; Ye 2009).

Secondary outcomes

Twenty‐one studies reported the number of clinical pregnancies. Three studies defined clinical pregnancy as the presence of one or more foetal hearts confirmed with ultrasound, performed at least four weeks after embryo transfer (Fanchin 2003 or from six weeks after embryo transfer (Franco Jr 2003; Kim 2011). Two other studies used the same definition, but one of these also included the foetal sacs without heart activity (Huirne 2006c), and the other performed the ultrasound scan at seven weeks after embryo transfer (Hwang 2004). One study defined clinical pregnancy as the presence of one or more intrauterine sacs confirmed with ultrasound, at a gestational age of six weeks (Huirne 2006a). In one study, we used a positive pregnancy test with evidence of a gestational sac to define clinical pregnancy, because no clinical or ongoing pregnancy rate was available (Engmann 1999). One study defined clinical pregnancy as the evidence of a clinical gestational sac (Ditkoff 1996). In the other 12 studies, it was unclear how they defined this outcome (Aston 1995; Blockeel 2012; Cédrin‐Durnerin 2007; Cédrin‐Durnerin 2012; Daly 2002; Garcia‐Velasco 2011; Hauzman 2013; Nyboe Andersen 2011; Obruca 2002; Porrati 2010; Salat‐Baroux 1988; Ye 2009). If no clinical pregnancy rates were reported, we used the ongoing pregnancy rates (if available) for our analysis.

Ten studies reported the number of oocytes retrieved (Cédrin‐Durnerin 2007; Ditkoff 1996; Franco Jr 2003; Huirne 2006a; Huirne 2006c; Hwang 2004; Kim 2011; Obruca 2002; Rombauts 2006; Salat‐Baroux 1988). One study only mentioned the number of cumulus‐oocyte complexes (Kolibianakis 2006), and two studies mentioned the number of mature oocytes or follicles (Engmann 1999; Fanchin 2003), but we assumed that this meant the same as the number of oocytes retrieved and, therefore, we pooled the data of these studies.

Thirteen studies reported the number of days of gonadotrophin treatment (Blockeel 2012; Ditkoff 1996; Engmann 1999; Franco Jr 2003; Hauzman 2013; Huirne 2006a; Huirne 2006c; Hwang 2004; Kim 2011; Kolibianakis 2006; Porrati 2010; Rombauts 2006; Vilela 2011).

Thirteen studies reported the amount of gonadotrophins administered (Blockeel 2012; Cédrin‐Durnerin 2007; Cédrin‐Durnerin 2012; Fanchin 2003; Franco Jr 2003; Hauzman 2013; Huirne 2006a; Huirne 2006c; Kim 2011; Kolibianakis 2006; Porrati 2010; Rombauts 2006; Vilela 2011). Two studies reported the amount of gonadotrophins administered in the number of ampoules used, but we could not use these data in our analysis (Ditkoff 1996; Engmann 1999).

Other adverse outcomes

Six studies reported the number of women with ovarian cysts. In one study, we used the number of functional ovarian cysts with a diameter of 10 mm or more, measured after one week of GnRH agonist treatment (Engmann 1999). Three studies defined an ovarian cyst as an intraovarian sonolucent structure with a mean diameter of 14 mm or more, measured after seven days (Aston 1995) or eight days (Ditkoff 1996) of pituitary suppression, or on a day not specified (Franco Jr 2003). One study did not mention how they defined ovarian cyst formation and when they measured this (Huirne 2006a). One study only reported cyst formation as a reason for cycle cancellation, but it was unclear if there were more cysts formed that did not lead to cycle cancellation (Salat‐Baroux 1988). We did not use these data in our analysis.

Six studies reported the number of multiple pregnancies. One study defined multiple pregnancies as multiple clinical pregnancies (Huirne 2006c). One study described the number of ongoing or live born twin pregnancies (Hwang 2004). Four studies did not describe when the number of multiple pregnancies was measured (Cédrin‐Durnerin 2007; Franco Jr 2003; Garcia‐Velasco 2011; Kim 2011).

Five studies reported the number of women with OHSS. Two study used the WHO classification criteria to diagnose OHSS and divided the women in categories of mild (grade I), moderate (grade II) or severe (grade III) (Nyboe Andersen 2011; Rombauts 2006); the other three studies did not mention how they diagnosed OHSS (Franco Jr 2003; Hwang 2004; Ye 2009).

Six studies did not contribute data to the analyses: two of these studies reported 'per cycle' data and the numbers of cycles were not equivalent to the numbers of participants (Biljan 1998b; Shaker 1995); outcomes reported included clinical pregnancy rate, number of days of GnRH agonist and number of oocytes retrieved. One study reported outcome data in denominators other than 'per woman' such as 'per cycle', 'per embryo transfer' (Lukaszuk 2015), outcomes reported included clinical pregnancy, number of oocyte retrieved, multiple pregnancy, duration of stimulation days. Three studies had no available outcome data relevant to the review (Hugues 1994; Raoofi 2008; Tan 2001).

1.1.1. Combined oral contraceptive pill plus antagonist versus antagonist

There was a lower rate of live birth or ongoing pregnancy in women pretreated with COCP compared with no pretreatment (OR 0.74, 95% CI 0.58 to 0.95; 6 RCTs; 1335 women; I² = 0%; moderate quality evidence). The evidence suggested that if the chance of a live birth or ongoing pregnancy following no pretreatment was assumed to be 27%, the chance following pretreatment with COCP would be between 18% and 26%.

1.1.2. Combined oral contraceptive pill plus antagonist versus agonist

There was no clear evidence of a difference between the two treatment groups in live birth or ongoing pregnancy rates (OR 0.89, 95% CI 0.64 to 1.25; 4 RCTs; 724 women; I² = 0%; moderate quality evidence). The evidence suggested that if the chance of a live birth or ongoing pregnancy following no pretreatment was assumed to be 24%, the chance following pretreatment with COCP would be between 16% and 26%.

1.1.3. Combined oral contraceptive pill plus antagonist versus antagonist, low response

Among women with low response, there was insufficient evidence to determine whether there was a difference between the groups in live birth or ongoing pregnancy rates (OR 1.71, 95% CI 0.61 to 4.79; 1 RCT; 80 women).

1.1.4. Combined oral contraceptive pill plus antagonist versus agonist, low response

Among women with low response, there was insufficient evidence to determine whether there was a difference between the two treatment groups in live birth or ongoing pregnancy rates (OR 1.13, 95% CI 0.43 to 2.98; 1 RCT; 80 women).

1.2.1. Combined oral contraceptive pill plus antagonist versus antagonist

There was no clear evidence of a difference between the groups in rates of pregnancy loss (OR 1.36, 95% CI 0.82 to 2.26; 5 RCTs; 868 women; I² = 0%; moderate quality evidence). The evidence suggested that if the risk of a pregnancy loss following no pretreatment was assumed to be 6%, the risk following pretreatment with COCP would be between 5% and 13%.

1.2.2. Combined oral contraceptive pill plus antagonist versus agonist

There were fewer pregnancy losses recorded in women who had COCP pretreatment than in those who had no pretreatment (OR 0.40, 95% CI 0.22 to 0.72; 5 RCTs; 780 women; I² = 18%; moderate quality evidence). The evidence suggested that if the risk of a pregnancy loss following no pretreatment was assumed to be 10%, the risk following pretreatment with COCP would be between 3% and 8%.

1.2.3. Combined oral contraceptive pill plus antagonist versus antagonist, low response

Among women with low response, there was insufficient evidence to determine whether there was a difference between the groups in rates of pregnancy loss (OR 2.05, 95% CI 0.18 to 23.59; 1 RCT; 80 women).

1.2.4. Combined oral contraceptive pill plus antagonist versus agonist, low response

Among women with low response, there was insufficient evidence to determine whether there was a difference between the groups in rates of pregnancy loss (OR 1.00, 95% CI 0.13 to 7.47; 1 RCT; 80 women).

1.3.1. Combined oral contraceptive pill plus antagonist versus antagonist

There was no clear evidence of a difference between the two treatment groups in clinical pregnancy rates (OR 0.85, 95% CI 0.63 to 1.15; 5 RCTs; 740 women; I² = 76%). The presence of substantial heterogeneity was explored in sensitivity analysis and there was no change in the evidence using a random‐effects model (OR 0.86, 95% CI 0.39 to 1.91) or risk ratio (RR) (RR 0.90, 95% CI 0.73 to 1.11).

1.3.2. Combined oral contraceptive pill plus antagonist versus agonist

There was no clear evidence of a difference between the two treatment groups in clinical pregnancy rates (OR 0.84, 95% CI 0.59 to 1.20; 4 RCTs; 546 women; I² = 0%).

1.3.3. Combined oral contraceptive pill plus antagonist versus antagonist, low response

Among women with low response, there was insufficient evidence to determine whether there was a difference between the groups in rates of clinical pregnancy (OR 1.85, 95% CI 0.69 to 4.97; 1 RCT; 80 women).

1.3.4. Combined oral contraceptive pill plus antagonist versus agonist, low response

Among women with low response, there was insufficient evidence to determine whether there was a difference between the groups in rates of clinical pregnancy (OR 1.12, 95% CI 0.44 to 2.83); 1 RCT; 80 women).

1.3.5. Combined oral contraceptive pill plus agonist versus agonist

Two studies reported this comparison, but neither reported data suitable for analysis. One (Biljan 1998b) reported per‐cycle data and found no evidence of a difference between the groups. A second study reported a pregnancy rate of 9% in the study group and 11% in the control group, but did not report the number of women per group (Raoofi 2008).

1.4.1. Combined oral contraceptive pill plus antagonist versus antagonist

There was insufficient evidence to determine whether there was a difference between the groups in multiple pregnancy rates (OR 2.21, 95% CI 0.53 to 9.26; 2 RCTs; 125 women; I² = 0%; low quality evidence). The evidence suggested that if the risk of multiple pregnancy following no pretreatment was assumed to be 5%, the risk following pretreatment with COCP would be between 3% and 31%.

1.4.2. Combined oral contraceptive pill plus antagonist versus agonist

There was insufficient evidence to determine whether there was a difference between the groups in multiple pregnancy rates (OR 1.36, 95% CI 0.85 to 2.19; 4 RCTs; 546 women; I² = 0%; moderate quality evidence). The evidence suggested that if the risk of multiple pregnancy following no pretreatment was assumed to be 5%, the risk following pretreatment with COCP would be between 4% and 10%.

1.4.3. Combined oral contraceptive pill plus antagonist versus antagonist, low response

Among women with low response, there was insufficient evidence to determine whether there was a difference between the groups in multiple pregnancy rate (OR 2.11, 95% CI 0.36 to 12.24; 1 RCT; 80 women).

1.4.4. Combined oral contraceptive pill plus antagonist versus agonist, low response

Among women with low response, there was insufficient evidence to determine whether there was a difference between the groups in the multiple pregnancy rate (OR 1.37, 95% CI 0.29 to 6.56; 1 RCT; 80 women).

1.5.1. Combined oral contraceptive pill plus antagonist versus antagonist

There was insufficient evidence to determine whether there was a difference between the groups in OHSS rates (OR 0.98, 95% CI 0.28 to 3.40; 2 RCTs; 642 women; I² = 0%, low quality evidence).

1.5.2. Combined oral contraceptive pill plus antagonist versus agonist

There was insufficient evidence to determine whether there was a difference between the groups in OHSS rates (OR 0.63, 95% CI 0.20 to 1.96; 2 RCTs; 290 women; I² = 0%, low quality evidence).

1.6.1. Combined oral contraceptive pill plus antagonist versus antagonist

There was no clear evidence of a difference between the groups in the mean number of oocytes retrieved (MD 0.44, 95% CI ‐0.11 to 0.99; 6 RCTs; 1077 women; I² = 59%).

1.6.2. Combined oral contraceptive pill plus antagonist versus agonist

There was no clear evidence of a difference between the two treatment groups in the mean number of oocytes retrieved (MD 0.07, 95% CI ‐0.67 to 0.81; 4 RCTs; 552 women; I² = 0%).

1.6.3. Combined oral contraceptive pill plus antagonist versus antagonist, low response

Among women with low response, there was no clear evidence of a difference between the groups in the mean number of oocytes retrieved (MD 0.70, 95% CI ‐0.11 to 1.51; 1 RCT; 80 women).

1.6.4. Combined oral contraceptive pill plus antagonist versus agonist, low response

Among women with low response, there was no evidence of a difference between the groups in the number of oocytes retrieved (MD 0.10, 95% CI ‐0.75 to 0.95; 1 RCT; 80 women).

1.6.5. Combined oral contraceptive pill plus agonist versus agonist

Two studies looked at the number of oocytes retrieved, but the data were unsuitable for analysis. The first study reported a median of 11 oocytes retrieved (range seven to 19) in the study group (51 cycles) and a median of 10 oocytes retrieved (range seven to 15) in the control group (51 cycles) (Biljan 1998a). The second study reported a mean number of oocytes retrieved of approximately 5 (± 3) in the study group and 5 (± 6) in the control group, but did not report the number of women or cycles in each treatment group (Raoofi 2008).

1.7.1. Combined oral contraceptive pill plus antagonist versus antagonist

Six RCTs reported days of gonadotrophin treatment but data were unsuitable for pooling due to extreme statistical heterogeneity (I² = 95%) with differing directions of effect.

1.7.2. Combined oral contraceptive pill plus antagonist versus agonist

Four RCTs reported days of gonadotrophin treatment but data were unsuitable for pooling due to extreme statistical heterogeneity (I² = 95%) with differing directions of effect.

1.7.3. Combined oral contraceptive pill plus antagonist versus antagonist, low response

Among women with low response, there was no evidence of a difference between the groups in the mean days of gonadotrophin treatment (MD 0.10 days, 95% CI ‐0.47 to 0.67; 1 RCT; 80 women).

1.7.4. Combined oral contraceptive pill plus antagonist versus agonist, low response

Among women with low response, the mean number of days of gonadotrophin treatment was lower in women who had COCP treatment than in women who received no COCP pretreatment (MD ‐1.40 days, 95% CI ‐2.02 to ‐0.78; 1 RCT; n = 80).

1.7.5. Combined oral contraceptive pill plus agonist versus agonist

Only one study reported on the number of days of gonadotrophin treatment (Biljan 1998a). This study found a median of 10 days (range nine to 11) in the study group (51 cycles) and a median of 12 days (range 11 to 12) in the control group (51 cycles). The data were unsuitable for analysis.

1.8.1. Combined oral contraceptive pill plus antagonist versus antagonist

More gonadotrophins were administered to the group who received pretreatment with a COCP than in the group who did not (MD 190.10 IU/L, 95% CI 134.91 to 245.28; 7 RCTs; 1275 women; I² = 88%). Sensitivity analysis using a random‐effects model did not change the statistical significance of this finding (MD 306.84 IU/L, 95% CI 112.13 to 501.56).

1.8.2. Combined oral contraceptive pill plus antagonist versus agonist

Three RCTs reported the amount of gonadotrophins but data were unsuitable for pooling due to extreme statistical heterogeneity (I² = 94%) with differing directions of effect.

1.8.3. Combined oral contraceptive pill plus antagonist versus antagonist, low response

Among women with low response, there was no clear evidence of a difference between the two treatment groups in the mean amount of gonadotrophin administered (MD 20.00 IU/L, 95% CI ‐165.39 to 205.39; 1 RCT; 80 women).

1.8.4. Combined oral contraceptive pill plus antagonist versus agonist, low response

Among women with low response, the mean amount of gonadotrophin administered in the COCP group was lower than in the group who were not pretreated (MD ‐349.00, 95% CI ‐537.92 to ‐160.08; 1 RCT; 80 women).

1.9.1. Combined oral contraceptive pill plus antagonist versus antagonist

There was insufficient evidence to determine whether there was a difference between the groups in the number of women with ovarian cyst formation (OR 0.47, 95% CI 0.08 to 2.75; 1 RCT; 64 women).

1.9.2. Combined oral contraceptive pill plus agonist versus agonist

Two studies reported on cyst formation, but the data were unsuitable for analysis. The first study found that there was no cyst formation in the intervention group (51 cycles) and cysts in 27 women in the control group (51 cycles) (Biljan 1998a). This result was statistically significant according to the authors (OR 0.07, 95% CI 0.03 to 0.16; P < 0.0001). Raoofi 2008 reported no women with cyst formation in either group.

2.1.1. Progestogen plus agonist versus agonist

There was insufficient evidence to determine whether there was a difference between the groups in live birth or ongoing pregnancy rates (OR 1.35, 95% CI 0.69 to 2.65; 2 RCTs; 222 women; I² = 24%; low quality evidence). The evidence suggested that if the chance of a live birth or ongoing pregnancy following placebo or no pretreatment was assumed to be 17%, the chance following pretreatment with progestogen would be between 12% and 35%.

2.1.2. Progestogen plus antagonist versus antagonist

There was insufficient evidence to determine whether there was a difference between the groups in live birth or ongoing pregnancy rates (OR 0.67, 95% CI 0.18 to 2.54; 1 RCT; 47 women; low quality evidence). The evidence suggested that if the chance of a live birth or ongoing pregnancy following placebo or no pretreatment was assumed to be 25%, the chance following pretreatment with progestogen would be between 3% and 76%.

2.1.3. Progestogen plus gonadotrophins versus gonadotrophins

There was insufficient evidence to determine whether there was a difference between the groups in live birth or ongoing pregnancy rates (OR 0.63, 95% CI 0.09 to 4.23; 1 RCT; 42 women).

2.2.1. Progestogen plus agonist versus agonist

There was insufficient evidence to determine whether there was a difference between the groups in rates of pregnancy loss (OR 2.26, 95% CI 0.67 to 7.55; 2 RCTs; 222 women; I² = 0%; low quality evidence). The evidence suggested that if the risk of a pregnancy loss following placebo or no pretreatment was assumed to be 4%, the risk following pretreatment with progestogen would be between 2% and 22%.

2.2.2. Progestogen plus antagonist versus antagonist

The only study in this subgroup did not report on the number of pregnancy losses (Cédrin‐Durnerin 2007), but we calculated this number by subtracting the number of live births from the number of clinical pregnancies. There was no evidence of a difference in rates of pregnancy losses between the two treatment groups (OR 0.36, 95% CI 0.06 to 2.09; 1 RCT; 47 women; low quality evidence). The evidence suggested that if the risk of a pregnancy loss following placebo or no pretreatment was assumed to be 25%, the risk following pretreatment with progestogen would be between 1% and 67%.

2.2.3. Progestogen plus gonadotrophins versus gonadotrophins

The only trial in this subgroup found one pregnancy loss in each treatment group. Thus, there was insufficient evidence to determine whether there was a difference between the groups in rates of pregnancy loss (OR 1.00, 95% CI 0.06 to 17.12; 1 RCT; 42 women).

2.3.1. Progestogen plus agonist versus agonist

We pooled results of three studies. In one of these studies, we used the number of positive pregnancy tests, because there were no data on clinical pregnancy rate. There was evidence of a difference in clinical pregnancy rates between the two treatment groups, with more clinical pregnancies obtained in the group pretreated with a progestogen (OR 1.99, 95% CI 1.20 to 3.28; 3 RCTs; 374 women; I² = 0%).

2.3.2. Progestogen plus antagonist versus antagonist

There was insufficient evidence to determine whether there was a difference between the groups in clinical pregnancy rates (OR 0.52, 95% CI 0.16 to 1.71; 1 RCT; 47 women).

2.3.3. Progestogen plus gonadotrophins versus gonadotrophins

There was insufficient evidence to determine whether there was a difference between the groups in clinical pregnancy rates (OR 0.71, 95% CI 0.14 to 3.64; 1 RCT; 42 women).

2.4.1. Progestogen plus antagonist versus antagonist

There was insufficient evidence to determine whether there was a difference between the groups in multiple pregnancy rates (OR 1.05, 95% CI 0.06 to 17.76; 1 RCT; 47 women; low quality evidence).

2.6.1. Progestogen plus agonist versus agonist

There was insufficient evidence to determine whether there was a difference between the groups in the mean number of oocytes retrieved (MD ‐0.52, 95% CI ‐2.07 to 1.02; 2 RCTs; 222 women; I² = 15%). There was one other study that reported the mean number of oocytes retrieved, but because this was analyzed per cycle (instead of per woman randomized), we were unable to include the data (Shaker 1995).

2.6.2. Progestogen plus antagonist versus antagonist

There was insufficient evidence to determine whether there was a difference between the groups in the mean number of oocytes retrieved (MD 2.70, 95% CI ‐0.98 to 6.38; 1 RCT; 47 women).

2.6.3. Progestogen plus gonadotrophins versus gonadotrophins

There was insufficient evidence to determine whether there was a difference between the groups in the mean number of oocytes retrieved (MD 0.00, 95% CI ‐0.57 to 0.57; 1 RCT; 29 women).

2.7.1. Progestogen plus agonist versus agonist

There was insufficient evidence to determine whether there was a difference between the groups in the mean days of gonadotrophin treatment (MD 0.11 days, 95% CI ‐0.30 to 0.52; 2 RCTs; 222 women; I² = 88%). The presence of substantial heterogeneity was explored in sensitivity analysis using a random‐effects model and there was no substantial change in the evidence (MD 0.10, 95% CI ‐1.07 to 1.28).

2.8.1. Progestogen plus antagonist versus antagonist

There was insufficient evidence to determine whether there was a difference between the groups in the amount of gonadotrophin administered (MD 276.00 IU/L, 95% CI ‐75.53 to 627.53; 1 RCT; 47 women).

2.9.1. Progestogen plus agonist versus agonist

Fewer women had ovarian cyst formation in the group pretreated with a progestogen compared with those who had no progestogen pretreatment (OR 0.16, 95% CI 0.08 to 0.32; 3 RCTs; 374 women; I² = 1%).

3.1.1. Oestrogen plus antagonist versus antagonist

There was insufficient evidence to determine whether there was a difference between the groups in live birth or ongoing pregnancy rates (OR 0.79, 95% CI 0.53 to 1.17; 2 RCTs; 502 women; I² = 29%; low quality evidence). The evidence suggested that if the chance of a live birth or ongoing pregnancy following no pretreatment was assumed to be 30%, the chance following pretreatment with oestrogen would be between 19% and 35%.

3.1.2. Oestrogen plus antagonist versus agonist

There was insufficient evidence to determine whether there was a difference between the groups in live birth or ongoing pregnancy rates (OR 0.88, 95% CI 0.51 to 1.50; 2 RCTs; 242 women; I² = 0%; very low quality evidence). The evidence suggested that if the chance of a live birth or ongoing pregnancy following no pretreatment was assumed to be 35%, the chance following pretreatment with progestogen would be between 22% and 45%.

3.2.1. Oestrogen plus antagonist versus antagonist

There was insufficient evidence to determine whether there was a difference between the groups in rates of pregnancy loss (OR 0.16, 95% CI 0.02 to 1.47; 1 RCT; 49 women; very low quality evidence). The evidence suggested that if the risk of a pregnancy loss following no pretreatment was assumed to be 13%, the risk following pretreatment with oestrogen would be between 1% and 71%.

3.2.2. Oestrogen plus antagonist versus agonist

There was insufficient evidence to determine whether there was a difference between the groups in rates of pregnancy losses (OR 1.59, 95% CI 0.62 to 4.06; 1 RCT; 220 women; very low quality evidence). The evidence suggested that if the risk of a pregnancy loss following no pretreatment was assumed to be 7%, the risk following pretreatment with oestrogen would be between 5% and 24%.

3.3.1. Oestrogen plus antagonist versus antagonist

There was insufficient evidence to determine whether there was a difference between the groups in clinical pregnancy rates (OR 0.91, 95% CI 0.66 to 1.24; 4 RCTs; 688 women; I² = 50%).

3.3.2. Oestrogen plus antagonist versus agonist

There was insufficient evidence to determine whether there was a difference between the groups in clinical pregnancy rates (OR 0.76, 95% CI 0.45 to 1.27; 2 RCTs; 242 women; I² = 0%).

3.4.1. Oestrogen plus antagonist versus agonist

There was insufficient evidence to determine whether there was a difference between the groups in multiple pregnancy rates (OR 2.24, 95% CI 0.09 to 53.59; 1 RCT; 22 women; very low quality evidence).

3.5.1. Oestrogen plus antagonist versus agonist

There was insufficient evidence to determine whether there was a difference between the groups in OHSS rates (OR 1.54, 95% CI 0.25 to 9.42; 1 RCT; 220 women).

3.6.1. Oestrogen plus antagonist versus antagonist

More oocytes were retrieved in the group pretreated with oestrogen than in the no pretreatment group (MD 2.23, 95% CI 0.71 to 3.75; 2 RCTs; 139 women; I² = 0%).

3.6.2. Oestrogen plus antagonist versus agonist

There was insufficient evidence to determine whether there was a difference between the groups in the number of oocytes retrieved (MD 0.40, 95% CI ‐4.47 to 5.27; 1 RCT; 22 women).

3.7.1. Oestrogen plus antagonist versus antagonist

Women who were pretreated with oestrogen had more days of gonadotrophin treatment compared to those who did not receive pretreatment (MD 0.83 days, 95% CI 0.58 to 1.08; 2 RCTs; 529 women; I² = 0%).

3.7.2. Oestrogen plus antagonist versus agonist

Women pretreated with oestrogen had fewer days of gonadotrophin treatment than those who did not receive oestrogen pretreatment (MD ‐2.50 days, 95% CI ‐4.07 to ‐0.93; 1 RCT; 22 women).

3.8.1. Oestrogen plus antagonist versus antagonist

There was a higher total dose of gonadotrophin administered to women who were pretreated with oestrogen than to those who did not receive pretreatment (MD 168.38 IU/L, 95% CI ; 3 RCTs; 111.53 to 225.17, 668 women; I² = 0%).

3.8.2. Oestrogen plus antagonist versus agonist

There was insufficient evidence to determine whether there was a difference between the groups in the amount of gonadotrophin administered (MD ‐16.00 IU/L, 95% CI ‐470.12 to 438.12; 1 RCT; 22 women).

4.1.1. Combined oral contraceptive pill plus antagonist versus progestogen plus antagonist

There was insufficient evidence to determine whether there was a difference between the groups in live birth or ongoing pregnancy rates (OR 0.60, 95% CI 0.12 to 2.89; 1 RCT; 44 women; very low quality evidence).

4.2.1. Combined oral contraceptive pill plus antagonist versus progestogen plus antagonist

There was insufficient evidence to determine whether there was a difference between the groups in rates of pregnancy loss (OR 1.11, 95% CI 0.14 to 8.64; 1 RCT; 44 women)

4.3.1. Combined oral contraceptive pill plus antagonist versus progestogen plus antagonist

There was insufficient evidence to determine whether there was a difference between the groups in clinical pregnancy rates (OR 0.71, 95% CI 0.19 to 2.73; 1 RCT; 44 women).

4.4.1. Combined oral contraceptive pill plus antagonist versus progestogen plus antagonist

There was insufficient evidence to determine whether there was a difference between the groups in multiple pregnancy rates (OR 2.32, 95% CI 0.19 to 27.59; 1 RCT; 44 women).

4.6.1. Combined oral contraceptive pill plus antagonist versus progestogen plus antagonist

There was insufficient evidence to determine whether there was a difference between the groups in the mean number of oocytes retrieved (MD 1.40, 95% CI ‐3.24 to 6.04; 1 RCT; 44 women).

4.8.1. Combined oral contraceptive pill plus antagonist versus progestogen plus antagonist

There was insufficient evidence to determine whether there was a difference between the groups in the mean quantity of gonadotrophin administered (MD 164.00 IU/L, 95% CI ‐249.03 to 577.03; 1 RCT; 44 women).

5.1.1. Combined oral contraceptive pill plus antagonist versus oestrogen plus antagonist

There was insufficient evidence to determine whether there was a difference between the groups in live birth or ongoing pregnancy rates (OR 1.11, 95% CI 0.54 to 2.29; 2 RCTs; 146 women; I² = 0%; very low quality evidence). This finding was sensitive to the choice of statistical model, and was no longer statistically significant when a sensitivity analysis was conducted to examine the effect of calculating the RR rather than OR (RR 0.15, 95% CI 0.02 to 1.08).

5.1.2. Combined oral contraceptive pill plus agonist versus oestrogen plus antagonist

There was a lower rate of live birth or ongoing pregnancy in women pretreated with COCP than in those who received oestrogen pretreatment (OR 0.08, 95% CI 0.01 to 0.79; 1 RCT; 25 women; very low quality evidence).

5.2.1. Combined oral contraceptive pill plus agonist versus oestrogen plus antagonist

There was insufficient evidence to determine whether there was a difference between the groups in rates of pregnancy loss (OR 1.09, 95% CI 0.06 to 19.63; 1 RCT; 25 women; very low quality evidence).

5.3.1. Combined oral contraceptive pill plus antagonist versus oestrogen plus antagonist

There was insufficient evidence to determine whether there was a difference between the groups in rates of clinical pregnancy (OR 1.19, 95% CI 0.60 to 2.37; 2 RCTs; 146 women; I² = 0%).

5.3.2. Combined oral contraceptive pill plus agonist versus oestrogen plus antagonist

There was a higher rate of clinical pregnancy in women pretreated with oestrogen than in those who received COCP pretreatment (OR 0.13, 95% CI 0.02 to 0.82; 1 RCT; 25 women).

5.4.1. Combined oral contraceptive pill plus antagonist versus oestrogen plus antagonist

There were no data on multiple pregnancies.

5.6.1. Combined oral contraceptive pill plus antagonist versus oestrogen plus antagonist

There was insufficient evidence to determine whether there was a difference between the groups in the mean number of oocytes retrieved (MD 0.90, 95% CI ‐3.59 to 5.39; 1 RCT; 46 women).

5.7.1. Combined oral contraceptive pill plus antagonist versus oestrogen plus antagonist

There was no clear evidence of a difference in the number of days of gonadotrophin treatment between the two treatment groups (MD ‐0.60 days, 95% CI ‐1.23 to 0.03; 1 RCT; 100 women).

5.8.1. Combined oral contraceptive pill plus antagonist versus oestrogen plus antagonist

There was insufficient evidence to determine whether there was a difference between the groups in the amount of gonadotrophin administered (MD 181.56 IU/L, 95% CI ‐344.73 to 707.86; 2 RCTs; 146 women; I² = 59%). There was no change in the evidence on sensitivity analysis using a random‐effects model (MD 113.73 IU/L, 95% CI ‐383.62 to 611.08).

6.1.1. Progestogen plus antagonist versus oestrogen plus antagonist

There was insufficient evidence to determine whether there was a difference between the groups in rates of live birth or ongoing pregnancy (OR 2.04, 95% CI 0.43 to 9.70; 1 RCT; 48 women).

6.2.1. Progestogen plus antagonist versus oestrogen plus antagonist

There were no pregnancy losses (1 RCT; 48 women).

6.3.1. Progestogen plus antagonist versus oestrogen plus antagonist

There was no evidence of a difference in clinical pregnancy rates between the two treatment groups (OR 2.30, 95% CI 0.57 to 9.22; 1 RCT; 48 women).

6.6.1. Progestogen plus antagonist versus oestrogen plus antagonist

There was insufficient evidence to determine whether there was a difference between the groups in the mean number of oocytes retrieved (MD ‐0.50, 95% CI ‐4.55 to 3.55; 1 RCT; 48 women).

6.8.1. Progestogen plus antagonist versus oestrogen plus antagonist

There was insufficient evidence to determine whether there was a difference between the groups in the mean quantity of gonadotrophin administered (MD 310.00 IU/L, 95% CI ‐32.30 to 652.30; 1 RCT; 48 women).