Return to fertility after cessation of a continuous oral
contraceptive
Kurt Barnhart, M.D., M.S.C.E.,a Sebastian Mirkin, M.D.,b Gary Grubb, M.D., M.P.H.,b
and Ginger Constantine, M.D.b
a
b
Department of Obstetrics and Gynecology, PENN Fertility Care, University of Pennsylvania, Philadelphia, Pennsylvania; and
Women’s Health, Clinical Research and Development, Wyeth Research, Collegeville, Pennsylvania
Objective: To evaluate the return to fertility among women planning to become pregnant after the use of a continuous regimen of levonorgestrel 90 mg and ethinyl E2 20 mg.
Design: Descriptive analysis of pregnancy outcomes after participation in a contraceptive trial.
Setting: Multicenter trial.
Subject(s): Participants in a phase 3 contraceptive trial who discontinued to become pregnant.
Intervention(s): Eligible subjects were contacted at 3 and 12 months after treatment discontinuation to determine
if and when they had conceived.
Main Outcome Measure(s): Kaplan-Meier analysis displaying the time until conception after oral contraceptive
discontinuation.
Result(s): In the phase 3 trial, 34 of 2,134 subjects cited a desire for pregnancy as a reason for discontinuation. Of
these, 4 were already pregnant before stopping treatment, 4 initiated other contraception, and 5 were lost to followup. Of the remaining 21 subjects at risk of pregnancy, the pregnancy rate was 57% at 3 months, 81% at 12 months,
and 86% (18 of 21) (95% confidence interval 64% to 97%) at 13 months after discontinuation of treatment.
Conclusion(s): These findings suggest that a continuous oral contraceptive with levonorgestrel 90 mg and ethinyl
E2 20 mg does not delay the return to fertility. (Fertil Steril 2009;91:1654–6. 2009 by American Society for Reproductive Medicine.)
Key Words: Return to fertility, oral contraceptive, low-dose, continuous, noncyclic
The traditional oral contraceptive (OC) 28-day cycle regimen
of 21 active pills and 7 placebo pills was created to promote
monthly withdrawal bleeding and mimic the natural menstrual cycle (1). However, many common adverse effects associated with OCs, including pelvic pain, breast tenderness,
bloating or swelling, and use of pain medications, become
significantly worse during the 7-day hormone-free interval
than during the 21 days that women are taking estrogen and
progestin, especially in long-term OC users (2). Continuous
OC use (a pill is taken every day without a pill-free or placebo
interval) eliminates the hormone-free interval and subsequent
withdrawal bleeding associated with cyclic OCs, although
breakthrough bleeding is common (3).
Some hormonal contraceptive options such as depot medroxyprogesterone lead to amenorrhea, which may in turn
lead to a delay in return to fertility because of hypothalamic
Received October 15, 2007; revised February 8, 2008; accepted February
13, 2008; published online May 7, 2008.
Supported by a grant from Wyeth Research, Collegeville, Pa.
K.B. was an investigator for this poststudy follow-up and received research funding from Wyeth Research, Collegeville, Pa. Other sources
of research funding and/or financial relationships include Novo Nordisk
(consultant), Organon (speaker and investigator), Johnson & Johnson,
Duramed, Xanodyne, Boehringer Ingelheim, Third Wave, Pfizer, and
MGI Pharma (investigator). S.M., G.G., and G.C. are employees of
Wyeth Research. Other financial affiliation for G.G. is Johnson & Johnson. S.M. and G.C. have no other financial affiliation to disclose.
Reprint requests: Kurt Barnhart, M.D., M.S.C.E., 3701 Market St., Ste.
801, Philadelphia, PA 19104 (FAX: 215-615-4200; E-mail: kbarnhart@
obgyn.upenn.edu).
1654
suppression and anovulation (4, 5). Theoretically continuous
OC use could also result in hypothalamic suppression. Even
with cyclic OCs, the question of return to fertility or time to
pregnancy has been controversial for some time (6, 7). Some
data suggest that although there may be a slight delay in time
to pregnancy compared with after discontinuation of cyclic
combination OCs, no permanent impairment results (8).
This report describes the return to fertility of women after using a continuous combined low-dose formulation containing
levonorgestrel 90 mg and ethinyl E2 20 mg (LNG/EE).
MATERIALS AND METHODS
This was a prospective follow-up of subjects that took place
after their participation in a large phase 3, multisite, openlabel contraceptive trial of a low-dose continuous LNG/EE
(3). Criteria for inclusion in the phase 3 study included healthy
women aged 18 to 49 years who were sexually active and at
risk for becoming pregnant and had regular (21- to 35-day)
menstrual cycles for 3 months preceding their first clinic visit.
Exclusion criteria included standard contraindications for
OCs and use of drugs or conditions that could interfere with
contraceptive efficacy.
The phase 3 study and poststudy follow-up process were
reviewed by the Institutional Review Board at each site and
an independent ethics committee and conducted in accordance with the ethical principles that have their origin in
the Declaration of Helsinki and are consistent with good clinical practice and the applicable regulatory requirements. All
participants provided written informed consent.
Fertility and Sterility Vol. 91, No. 5, May 2009
Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/09/$36.00
doi:10.1016/j.fertnstert.2008.02.122
The primary endpoint of this follow-up study was return to
fertility within 12 months after the last dose of continuous
LNG/EE. Subjects were included in this follow-up study
regardless of the length of time that they took continuous
LNG/EE (see Table 1). Women who stopped treatment because
they said they planned to become pregnant were contacted
twice by phone at 3 and 12 months after discontinuation of continuous LNG/EE to determine whether they were pregnant. At
each contact, subjects reported if and when they had conceived.
If subjects were not pregnant, they were asked if they still were
trying to conceive or if they had resumed contraception. A Kaplan-Meier analysis of the time from treatment discontinuation
to estimated day of conception was performed.
RESULTS
Of the 2,134 women included in the phase 3 trial, 34 stopped
taking continuous LNG/EE because they planned to become
pregnant. Of these 34 subjects, 4 were found to be pregnant
before the start of the follow-up process and were contraceptive failures in the phase 3 trial, 4 initiated other contraception
in the first month after discontinuation of the continuous OC
(despite previously stated interest in planning a pregnancy),
and 5 were lost to follow-up. For the remaining 21 subjects,
the mean SD duration of treatment with continuous LNG/
EE was 197 120.2 days (range, 27 to 364 days). The demo-
graphic characteristics of the 21 subjects are listed in Table 1.
Compared with the phase 3 population (3), these subjects
were younger (mean age, 26.9 and 29.5 years, respectively)
and of lower mean body weight (mean weight, 67.0 and
72.4 kg, respectively). Six (28.6%) subjects were nulligravid
compared with 38.5% in the phase 3 study.
The pregnancy rate was 57% (12 of 21; 95% confidence interval [CI] 34% to 78%) at 3 months and 81% (17 of 21; 95%
CI 58% to 95%) at 12 months after discontinuation of continuous LNG/EE (Fig. 1). The median time from treatment discontinuation to estimated date of conception was 4 months.
After the 12-month poststudy follow-up, information was
sought on the remaining 4 of 21 subjects who had not become
pregnant. One subject had an estimated date of conception of
376 days after the last treatment, for a total 13-month pregnancy rate of 86% (18 of 21; 95% CI 64% to 97%). For the
3 remaining subjects who did not conceive (including 1 nulligravid subject), 1 had stopped trying to become pregnant by
12 months, and 2 were lost to follow-up after 12 months.
The 18 pregnancies resulted in 17 live births and 1 spontaneous abortion. Twelve reported delivery outcomes of healthy
babies. The reported Apgar scores (n ¼ 9) were R9 at 5 minutes, and the reported weights (n ¼ 10) averaged 3.54 kg
(range, 3.26 kg to 4.08 kg).
TABLE 1
Demographic characteristics and time to pregnancy in women who discontinued a continuous
combined OC containing LNG 90 mg and EE 20 mg to become pregnant.
Subject
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Age (y)
Race
Weight (kg)
Gravidity/parity
Days in study
Time (d) to pregnancy
after last continuous
LNG/EE OC
22
25
31
25
23
28
30
30
21
25
30
32
26
27
24
25
24
31
26
35
27
Hispanic
White
White
White
White
White
White
White
White
White
White
White
White
Black
White
White
White
White
White
White
White
52.7
66.4
62.3
69.2
66.5
59.2
69.1
48.4
55.0
82.7
71.4
56.4
55.4
110.0
59.6
53.6
70.7
82.7
74.6
71.9
68.2
1/1
3/3
2/1
3/3
1/1
1/0
2/1
1/1
0/0
0/0
2/2
2/1
0/0
2/0
1/0
0/0
0/0
2/2
1/0
1/1
0/0
334
126
168
241
274
80
364
33
133
130
48
364
120
110
160
364
152
189
364
364
27
14
17
19
20
32
41
47
49
68
75
77
107
111
127
131
212
261
376
Lost to follow-up
Not pregnant
Not pregnant
Barnhart. Continuous OC and return to fertility. Fertil Steril 2009.
Fertility and Sterility
1655
FIGURE 1
tility (6) and differences in study methodology, notably data
collection after the delivery.
Time to return to fertility. Kaplan-Meier survival
function estimates.
The primary limitation of this poststudy follow-up was the
small number of patients with no comparison group. However, these data are consistent with other findings regarding
the impact of fertility of current cyclic hormonal contraception, and they are supported by a separate study after the
phase 3 trial of the continuous LNG/EE OC. Among 187
women who stopped OC use after 6 to 12 months and completed 3 months of follow-up, the median time to return to
menses was 32 days, and the incidence of spontaneous menses or pregnancy within 90 days was 98.9% (13).
Based on a pregnancy rate of 86% at 13 months, the return
to fertility after up to 13 months of use of a continuous LNG/
EE is comparable to that of cyclic OCs. These findings suggest that a continuous OC of 90 mg LNG and 20 mg EE
does not delay return to fertility.
Barnhart. Continuous OC and return to fertility. Fertil Steril 2009.
DISCUSSION
This is the first report to address the concern that the prolonged amenorrhea that occurs with continuous OC use may
affect return to fertility and suggests that there is no delay in
return to fertility after use of continuous LNG/EE. Among
the 21 women who planned to become pregnant and remained
at risk of pregnancy after stopping continuous LNG/EE OC,
86% became pregnant within 13 months after the discontinuation of the OC. These findings are supported by a recent case
study that showed the rapid resumption of ovulation and menstruation after stopping use of a continuous combined OC
containing LNG/EE (9).
The pregnancy rate shown in this poststudy follow-up of
continuous OCs is comparable with that shown in several
studies of cyclic OCs. The larger studies have shown a 1year return-to-fertility rate of 84% to 88% following cyclic
OC use (6, 7, 10, 11). Two of these studies (6, 7) had a nonhormonal contraceptive comparison group and the time to
pregnancy was longer for cyclic OC users than for nonhormonal contraceptive users. In one study (6), the time to
pregnancy was 5.88 cycles for OC users versus 3.18 cycles
(P<.001) for users of various nonhormonal methods (i.e.,
intrauterine device, barrier, rhythm, and withdrawal). This
study also found that 88% of former OC users were pregnant after 12 months. In another study (7), the time to pregnancy was 7.7 months for former OC users versus 3.9
months (adjusted P<.001) for condom users, with a total
of 83.8% of OC users having conceived by 12 months.
One exception to the larger study findings of a 12-month return-to-fertility rate in the 84% to 88% range is a 1982 study
(12) of married women, which found a 1-year return-tofertility rate of 72% following OC discontinuation. Possible
explanations for this outlying result could be the higher
doses of OCs used in the early 1980s delaying return to fer1656
Barnhart et al.
Continuous OC and return to fertility
Acknowledgments: The authors acknowledge the contribution of the principal investigators and staff at the clinical sites that conducted the study protocol and thank Vincent Haudiquet, Ph.D., of Wyeth Research for the statistical
analysis and Mr. John Patton of Wyeth Research for assistance in the preparation of this manuscript.
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