Table 3.

Evidence regarding risk of pregnancy or ovulation after vaginal ring dosing errors

Reference, sources of support	Study population	Study design/intervention	Definition of adherence/ dosing error	Outcome	Results	Strengths	Weaknesses	Quality
Nondeliberate extension of the RFI
Bjarnadottir et al., 2002 [28]	121 women using NuvaRing for 635 cycles, ages 18–40, multiple centers in 5 European countries	Prospective comparative analysis (adherent versus nonadherent cycles) of data from 1 RCT and 2 nonrandomized trials; NuvaRing users followed for 6 cycles of standard use^a ; FU after cycles 3 and 6 or at premature discontinuation	- Period of ring use did not deviate >48 h from scheduled 21 days × 24 h, and RFI did not deviate >24 h from the scheduled 7 days × 24 h	Pregnancy: tested via urine if pregnancy suspected during study and via serum test for β-hCG at end of study	No pregnancies in 635 cycles reported despite RFI extended >24 h from scheduled period in 3.5% of cycles (~22)	- Large sample - Pregnancy measurement described - Adherence tracked on diary cards - Multiple centers	- Unclear if women had regular cycles - Details on length of extended RFI not reported nor # of cycles with other types of dosing errors	II-2, poor, direct
Dieben et al., 2002 [30] (Some data also reported in Roumen et al., 2001 [36] and Roumen et al., 2002 [37]) NV Organon	2322 women using NuvaRing for 23, 298 cycles, mean age 28.2, multiple centers in Europe, Canada, USA	Prospective comparative analysis (adherent versus nonadherent cycles) of data collected from 2 noncomparative studies; NuvaRing users followed for 13 cycles; FU occurred during 1st week after cycles 3, 6, 9 and 13 months postinitiation of standard use^a	- Same as above - Shortened RFIs imply duration <6 days; extended RFIs imply duration >8 days	Same as Bjarnadottir et al., 2002 [28]	14.4% of users (~3355 cycles) were nonadherent; 4.8% of users (~1118 cycles) had extended RFI; 11 pregnancies among nonadherent women (11/3355 cycles, 0.33%): 1 had 11-day RFI, 1 had 14-day RFI, 9 had 2+ consecutive days without ring use during ring-use period or misunderstood proper use. 10 pregnancies among adherent women (10/19,943 cycles, 0.05%)	- Large sample - Adherence tracked on diary cards and interactive voice recording systems - Multiple centers	- Unclear if women had regular cycles - Pregnancy rates not reported separately for different types of dosing errors (unable to calculate since # of cycles with different dosing errors not known)	II-2, poor, direct
Ahrendt et al., 2006 [27] Oragon	499 women, mean age 26.6, multiple centers in 10 European countries	Prospective comparative analysis (adherent versus nonadherent cycles) of data collected from 1 RCT; NuvaRing users followed for 13 cycles of standard use^a	Same as Bjarnadottir et al., 2002 [28]	Same as Bjarnadottir et al., 2002 [28]	No pregnancies reported among nonadherent women despite RFI extended >24 h from scheduled period in 4.9% of cycles (3.6% of cycles for >24–48 h and 1.3% for >48 h); 1 pregnancy reported among adherent women.	- Large sample - Pregnancy measurement described - Adherence tracked on diary cards - Multiple centers	- Unclear if women had regular cycles - Details on # of adherent and nonadherent cycles not provided	II-2, poor direct
Brucker et al., 2008 [29] Organon	5823 women using NuvaRing, median age 29.4, Germany	Prospective noncomparative study; FU visits at 3, 6 months postinitiation of standard use^a	- Definition of adherence not stated	Pregnancy — method of measurement not stated	7 pregnancies (0.12% of users); 3 due to nonadherence [extended RFI in 2 and interruption of ring use (timing and duration not known) in 1]; 1 due to repeated ring expulsion or loss; 3 unknown	- Large sample	- Unclear if women had regular cycles - No definition of adherence - Adherence not systematically tracked - Pregnancy measurement not described - Limited information on nonadherence - Single center	II-3, poor, direct
Deliberate dosing errors
Mulders and Dieben, 2001 [32] NV Organon	16 women, ages 18–35 years, 1 center, Netherlands	Prospective noncomparative analysis of data collected from randomized crossover study; NuvaRing use for 3 weeks extended by additional 2 weeks, 2 groups, NuvaRing use was either pre- or proceeded by 1 cycle of 30 mcg EE/150 mcg desogestrel (n=8 for each group). Ovarian ultrasound, LH, FSH, estradiol and progesterone measured	- Standard use^a - Extended ring use for additional 2 weeks simulates forgotten ring removal	Ovulation — definition not stated	- No ovulations in 16 cycles with dosing errors - Follicular size remained small during the extended period of ring use - Largest follicular diameters and highest concentrations of estradiol were during 1st week of ring use	- Adherence tracked on diary cards	- Unclear if women had regular cycles - Small sample - No definition of ovulation	II-3, poor, indirect
Mulders et al., 2002 [31] NV Organon	51 women, ages 18–35 years, 1 center, Netherlands	PD study with 3-group randomization: (a) NuvaRing standard use^a for cycle 1, use for 21-days with extended RFI until ovulation for cycle 2 (n=15); (b) NuvaRing standard use^a for cycle 1, use for 3 days with extended RFI until ovulation for cycle 2 (n=15); (c) NuvaRing use for 21 days with extended RFI until 13-mm follicle detected by ultrasound, followed by standard use^a for cycle 2 (n=15),	- Criteria not provided, but adherence was determined by number of hours of ring use per day	Ovulation — definition not stated	Median time to ovulation was 19 (Group 1) and 17 (Group 2) days after ring removal (cycle 2), with 1st ovulation after 13 (Group 1) and 12 (Group 2) days; median time to develop 13-mm follicle (cycle 1) for Group 3 was 11 days (range 8–21 days); 50% of women needed extension of RFI ≥4 days. Ring insertion after extended RFI for Group 3 interfered with ovarian function	- Moderate sample - Adherence tracked on diary cards - Randomization procedures described	- Unclear if women had regular cycles - Criteria for adherence not provided - No definition of ovulation - Single center	^b

Abbreviations: FU=follow-up; PD=pharmacodynamic.

Standard use for vaginal ring defined as 21 days of ring use followed by 7-day ring-free interval.

Quality of pharmacodynamic studies not assessed.