Table 1.

Evidence regarding risk of ovulation after deliberate extension of the standard 7-day pill-free interval

Reference, sources of support	Study population	Study design/intervention	Definition of ovulation	Results	Strengths	Weaknesses	Quality
8-day PFI
Hamilton and Hoogland, 1989 [14] No source of support stated	30 women aged 20–30 Netherlands, new users	RCT, triphasic 30 mcg EE and 0.5, 0.75, 1.00 mg norethindrone; randomized to a complete pill pack (n=12), a pill pack with a placebo for day 1 (n=9) or a pill pack with a placebo pill for day 2 (n=9); 1 cycle of missed pills	No definition	1 ovulation in 9 cycles (11%) (serum progesterone level 33.4 nmol/L); 1 women with luteinized unruptured follicle. Cervical mucus unfavorable	- Women had history of regular cycles	- Small sample - No definition of ovulation - Randomization procedures not described - Single center	I, fair, indirect
Hedon et al., 1992 [15] No source of support stated	47 women, age 18–40 years, France, mix of new and previous users	RCT; 35 mcg EE/250 mg norgestimate; control group (n=5) which did not miss any pills and 16 treatment groups with 5 groups extending the PFI to 8 (n=4), 9 (n=4), 10 (n=4) or 11 (n=6); 1 cycle of missed pills	Normal follicular maturation and normal luteal secretion	No ovulations in 4 cycles	- Women had history of regular cycles - Definition of ovulation	- Small sample - Randomization procedures not described - Some women participated in more than one study group - Single center	I, poor, indirect
9-day PFI
Landgren and Diczfalusy, 1984 [19] WHO (HRP)	10 women, mean age 25.9, Sweden, users for ≥3 months	Descriptive study; 30 mcg EE/150 mcg LNG; 3 consecutive cycles of missed pills	Normal follicular maturation and normal luteal secretion	No ovulations in 30 cycles; one woman had normal follicular activity but an inadequate rise in luteal activity	- Women had history of regular cycles - Definition of ovulation	- Small sample	II-3, fair, indirect
Killick et al., 1990 [17] Schering Laboratories	28 women, mean age 26.2, United Kingdom, new users	RCT; randomized to 3 COC formulations: (a) monophasic 30 mcg EE/150 mcg LNG, (b) monophasic 30 mcg EE/75 mcg gestodene or (c) triphasic 30 mcg EE/50 mcg LNG, 40 mcg EE/75m mcg LNG, 30 mcg EE/125 mcg LNG. PFI increased from 7 to 9 then 11 days, or 11 then 9 days, in 2nd and 3rd of 4 cycles	No definition but measured serum hormone levels, follicle diameter, cervical mucus scores	No ovulations in 28 cycles; 2 women with LH surges but no follicle wall rupture (unclear if women were in the 9 or 11 PFI group) Mean cervical mucus Insler scores did not increase. No significant differences in follicular activity, hormone levels or cervical mucus quality between COC formulations	- Women had history of regular cycles	- Small sample - No definition of ovulation - Randomization procedures not described - Single center	I, fair, indirect
Hedon et al., 1992 [15] No source of support stated	Same as Hedon et al., 1992 [15], 8-day PFI	Same as Hedon et al., 1992 [15], 8-day PFI	Same as Hedon et al., 1992 [15], 8-day PFI	No ovulations in 4 cycles	Same as Hedon et al., 1992 [15], 8-day PFI	Same as Hedon et al., 1992 [15], 8-day PFI	I, poor, indirect
Creinin et al., 2002 [10] Ortho-McNeil Pharmaceutical Corporation	69 healthy women, 18–38 years, USA, 1-month users	RCT; 20 mcg EE/100 mcg LNG (n=34) and triphasic 35 mcg EE/180 mcg norgestimate; 35 mcg EE/215 35 mcg norgestimate; EE/250 mcg norgestimate (n=35); 1 cycle of missed pills	Serum progesterone ≥3 ng/mL	3 women in the 20 mcg pill group (3/34 cycles; 8.8%) and 2 women in the 35 mcg pill group (2/35 cycles; 5.7%) had presumptive ovulation, but follicle diameter <13 mm.	- Women had history of regular cycles - Moderate sample - Definition of ovulation - Randomization procedures described - Multiple centers		I, good, indirect
10-day PFI
Landgren and Csemiczky, 1991 [18] Organon AB	20 women, mean ages 27.4 and 28.1, Sweden, users for ≥3 months	RCT; 2 COC groups: (a) monophasic 30 mcg EE/150 mcg desogestrel; (b) triphasic 30 mcg EE/50 mcg LNG, 40 mcg EE/75 mcg LNG, 30 mcg EE/125 mcg LNG; 1 cycle of missed pills	Same as Landgren and Diczfalusy, 1984, 9-day PFI	2 women ovulated (2/20 cycles, 10%), one in each COC group No significant differences in follicular growth or serum hormone levels between COC groups.	- Women had history of regular cycles - Definition of ovulation	- Small sample - Randomization procedures not described - Single center	I, fair, indirect
Hedon et al., 1992 [15] No source of support stated	Same as Hedon et al., 1992 [15], 8-day PFI	Same as Hedon et al., 1992 [15], 8-day PFI	Same as Hedon et al., 1992 [15], 8-day PFI	No ovulations 4 cycles	Same as Hedon et al., 1992 [15], 8-day PFI	Same as Hedon et al., 1992 [15], 8-day PFI	I, poor, indirect
Elomaa et al., 1998 [12] Wyeth-Ayerst International Inc.	99 women, mean age 26, Finland, Netherlands and Belgium, 1-month users	RCT; randomized to 3 groups: monophasic 20 mcg EE/150 mcg desogestrel; monophasic 30 mcg EE/75 mcg gestodene; triphasic 30 mcg EE/50 mcg gestodene, 40 mcg EE/70 mcg gestodene, 30 mcg EE/100 mcg gestodene; 1 cycle of missed pills	No definition	No ovulations in 98 cycles; 1 woman taking monophasic 30 mcg pill with LUF (9.6 nmol/L progesterone level)	- Women had history of regular cycles - Moderate sample - Randomization procedures described - Multiple centers	- No definition of ovulation	I, good, indirect
Klipping et al., 2008 [33] Bayer Schering Pharma	105 women (50 in group of interest), ages 18–35, Netherlands	RCT, 2 groups followed for 3 cycles: 20 mcg EE/3 mg drospirenone either with 7- or 4-day PFI increased to 10 or 7 days in 3rd cycle; ovarian ultrasound, estradiol, LH, FSH and progesterone were measured	Collapse of ovarian follicle or presence of follicle-like structure ≥15 mm	4 women ovulated in 21/7 group (4/50 cycles, 8%)	- Moderate sample of those in 21/7 group - Definition of ovulation - Randomization procedures described	- Unclear if women had history of regular cycles - Single center	I, fair, indirect
11-day PFI
Killick et al., 1990 [17] Schering Laboratories	Same as Killick et al., 1990 [17], 9-day PFI	Same as Killick et al., 1990 [17], 9-day PFI	Same as Killick et al., 1990 [17], 9-day PFI	No ovulations in 28 cycles; 2 women with LH surges but no follicle wall rupture (unclear if women were in the 9 or 11 PFI group). Mean cervical mucus Insler scores did not increase. No significant differences in follicular activity, hormone levels or cervical mucus quality between COC formulations	Same as Killick et al., 1990 [17], 9-day PFI	Same as Killick et al., 1990 [17], 9-day PFI	I, fair, indirect
Hedon et al., 1992 [15] No source of support stated	Same as Hedon et al., 1992 [15], 8-day PFI	Same as Hedon et al., 1992 [15], 8-day PFI	Same as Hedon et al., 1992 [15], 8-day PFI	No ovulations in 6 cycles	Same as Hedon et al., 1992 [15], 8-day PFI	Same as Hedon et al., 1992 [15], 8-day PFI	I, poor, indirect
Letterie and Chow, 1992 [21] No source of support stated	15 women, aged less than 35, USA, new users	RCT; triphasic 35 mcg EE/500 mcg norethindrone, 35 mcg EE/750 mcg norethindrone, 35 mcg EE/1000 mcg norethindrone; 3 groups (1 described here): missing 4 consecutive COCs on days 1–4 (n=5); 1 cycle of missed pills	Serum progesterone ≥3 ng/mL	No ovulations in 5 cycles	- Women had history of regular cycles. - Definition of ovulation - Randomization procedures described	- Small sample - Single center	I, fair, indirect
14-day PFI
Letterie, 1998 [20] No source of support stated	10 women, age 25 to 28 years, USA, new users	RCT; 2 pill regimens: (a) inactive pills days 1–5, 50 mcg EE/1 mg norethindrone days 6–10, 0.70 mg norethindrone days 11–19; inactive pills days 20–28 for a total PFI of 14 days; (b) inactive pills days 1–7, 50 mcg EE/0.70 mg norethindrone days 8–12, 0.70 mg norethindrone days 13–21, inactive pills days 22–28 for a total PFI of 14 days; pill-taking regimen restricted to the periovulatory period; 2 consecutive cycles of missed pills	Serum progesterone ≥6 ng/mL	6 women ovulated in 20 cycles; all occurred during the 2nd cycle	- Women had history of regular cycles - Definition of ovulation	- Small sample - Randomization procedures not described - Single center	I, fair, indirect
PFI extended until a specific follicular size is achieved
Killick, 1989 [16] No source of support stated	10 women, ages not given, UK, current users for at least 3 months	Descriptive study; triphasic 30 mcg EE/50 mcg LNG for 6 days, 40 mcg EE/75 mcg LNG for 5 days, 30 mcg EE/125 mcg LNG for 10 days; daily pelvic ultrasonography starting with PFI and continuing until dominant follicle of 12 mm seen; on that day, women resumed COCs; when dominant follicle of 18 mm was seen, 5000 U of hCG was administered; daily monitoring continued until dominant follicle disappeared	No definition	12-mm follicles developed between 7 and 16 days (median of 11 days); 2 women never had follicle of 16 mm and were not given hCG; other 8 women received hCG and experienced follicle wall rupture within 48 h; serum EE and progesterone values were within the range of normal ovulatory cycles		- Small sample - No definition of ovulation	II-3, poor, indirect
Elomaa and Lahteenmaki, 1999 [11] Wyeth Medica Ireland	5 women, 18–30 years, Finland	Descriptive study; 20 mcg EE/75 mcg gestodene; after 21 days of pill taking, the PFI continued until 16-mm follicle was achieved, at which time the woman resumed taking COCs; 100 mcg of GnRH analog (buserelin) was administered on the third day of pill taking; daily monitoring continued until dominant follicle disappeared	Significant LH increase defined as 30% increase in mean concentration of 3 consecutive LH samples in midfollicular phase	4 of 5 women ovulated; 1 had unruptured follicle; 16-mm follicle developed between 14 and 26 days after stopping COCs, median 18 days	- Women had history of regular cycles - Definition of ovulation	- Small sample	II-3, fair, indirect

Abbreviations: EE=ethinyl estradiol; GnRH=gonadotropin-releasing hormone; FSH=follicle-stimulating hormone; LH=luteinizing hormone; LNG=levonorgestrel; PFI=pill-free interval; WHO=World Health Organization.