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Researchers have been altering formulations and
delivery systems for hormonal contraceptives — used by more than 100
million women worldwide1 — to develop new versions that are
safer, more acceptable, and easier to use. New products are now entering
the market, some only in the developed world but some also in developing
countries.
"New methods are coming to the market, and
that translates into more choices," says Dr. Miriam Zieman, a family
planning expert at Emory University School of Medicine in Atlanta,
Georgia, USA, who has extensively studied one of the new delivery systems.
"We hope more choices will result in greater method acceptability,
client satisfaction, consistent use, continuation, and ultimately fewer
unplanned pregnancies."
A major change in hormonal contraception since
combined oral contraceptives (COCs) were introduced in the early 1960s has
been the development of low-dose hormonal formulations to decrease side
effects, says Dr. Malcolm Potts, president emeritus of FHI and professor
of population and family planning at the University of California at
Berkeley, USA.
High-dose COCs in the 1960s and 1970s contained as
much as 50 µg to 150 µg estrogen and 10 mg progestin, and were reported
to be associated with risks of serious cardiovascular side effects,
including venous thrombosis (a blood clot in a vein), heart attack, and
stroke. But, notes Dr. Potts, "these risks were still less than those
associated with unplanned pregnancies and much less than other daily risks
we all take."
Most countries now distribute mostly low-dose pills
containing 35 µg or less estrogen and 400 µg or less progestin (of which
there are several types). According to a report by a World Health
Organization committee of experts on cardiovascular disease and steroidal
hormone contraception, women who use low-dose COCs and do not smoke, do
not have high blood pressure, and do not have diabetes are not at
increased risk of heart attack or stroke when compared with non-users.2
Healthy users of low-dose COCs do have a three- to sixfold higher risk of
venous thrombosis than healthy women who do not use COCs, but the absolute
risk remains minimal.3 Additional research has shown that
certain types of progestins may slightly increase the risk of venous
thrombosis and other cardiovascular complications among COC users.4
Further reducing estrogen
Today, pills with 20 µg or less estrogen are
available in several countries, including Chile, India, Malaysia, New
Zealand, and the United States and Puerto Rico. Research suggests that
these pills are associated with a decrease in most side effects when
compared with pills with higher estrogen content. For example, in a U.S.
study conducted between 1998 and 1999 among 463 women using pills with 20
µg versus 35 µg estrogen, the common side effects of bloating, breast
tenderness, and nausea were approximately half as frequent among users of
the 20 µg pills.5
One potential disadvantage of lowering estrogen
doses is loss of menstrual cycle control. Reports of menstrual
disturbances vary greatly;6 but, overall, COCs containing low
doses of estrogen appear to cause more menstrual disturbances.7
However, for all COCs, spotting and bleeding disturbances are most
frequent during the first few cycles of use, after which they often
decrease or disappear.8 If a woman using COCs containing 20 µg
estrogen does have persistent spotting or bleeding problems, providers can
consider switching to pills that contain 30 µg to 35 µg estrogen.9
Research also shows that changing the type of progestin and the dosing
regimen may improve cycle control.10
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What Are Cochrane Reviews?
Cochrane Reviews are evidence-based systematic
reviews published in the Cochrane Library to provide the
highest-quality information on specific medical topics to health
care providers, clients, administrators, and funders. FHI is a
contributor to the international collaborative group producing
reviews dealing with fertility regulation. More information on the
Cochrane Library and Cochrane Reviews can be found at http://www.update-software.com/Cochrane/default.htm.
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More data are needed to fully understand the impact of COCs containing 20
µg estrogen, says Dr. David Grimes, vice president of biomedical affairs
at FHI. Toward this aim, María Gallo, an FHI research associate, Dr.
Kavita Nanda, an FHI associate medical director, and colleagues are
writing a Cochrane Review comparing the contraceptive efficacy,
discontinuation rates, bleeding patterns, and side effects associated with
pills containing 20 µg estrogen with those containing more than 20 µg
estrogen. Results of the review are expected in 2003.
Improving ease of use
While COC pills are a traditional way to deliver
contraceptive hormones, two novel systems for providing the same hormones
(estrogen and progestin) were approved by the U.S. Food and Drug
Administration in 2001 and are now available in the United States. Both
systems — a weekly transdermal contraceptive patch and a three-week
vaginal ring — have characteristics that may make them easier for women
to use correctly and consistently. This may improve compliance, a problem
among many COC users.
| Cathryn Jirlds/FHI |
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The contraceptive patch is worn for one week,
discarded, and replaced with a new one. A patch-free week follows
three weeks of consecutive use.
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The transdermal contraceptive, called Ortho Evra
and developed by U.S.-based Ortho-McNeil Pharmaceutical, Inc., is a
20-square-cm patch that can be applied to the abdomen, upper torso, upper
outer arm, or buttocks, where it continuously releases low doses of
estrogen and progestin through the skin and into the bloodstream. A single
patch is worn for one week, discarded, and replaced with a new one. Three
weeks of use are followed by a patch-free week to allow for menses (much
like the pill-free interval for most COCs).
The vaginal ring, called NuvaRing and developed by
U.S.-based Organon, Inc., is a flexible and transparent ring that is
slightly smaller than a diaphragm and is inserted into the vagina, where
it continuously releases low doses of estrogen and progestin. Each ring is
worn for three weeks in a row and then discarded. After a ring-free week
for menses, the client inserts a new ring.
"The nice thing about these new methods is
they do not require daily attention," says Dr. Zieman, an author of
several recent studies of the Ortho Evra patch. "And, unlike implants
or intrauterine devices, the transdermal contraceptive patch and the
vaginal ring are user-controlled."
| NuvaRing/Organon |
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NuvaRing is inserted into the vagina, worn for
three weeks in a row, and then discarded. After a ring-free week,
the client inserts a new ring.
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Researchers at FHI are completing a Cochrane Review comparing the Ortho
Evra patch and NuvaRing with COCs. Randomized controlled trials from the
United States, Canada, Europe, and South Africa have shown that the
contraceptive efficacy, cycle control, contraindications, and side effect
profiles are generally comparable between the contraceptive patch and
low-dose COC pills. However, patch users are more likely to report breast
discomfort and have reported the additional adverse events of application
site reactions and, rarely, patch detachment.11
Of note, Ortho Evra patch users may have higher
compliance rates than COC users. Pooled data from the United States and
Canada showed that some 800 women using the patch used it perfectly during
89 percent of their cycles, while some 600 COC users used the pill
perfectly only 79 percent of the time.12 The higher compliance
rate among contraceptive patch users may result from the convenience of
the patch, researchers have noted. Results also suggested that the patch's
ease of use was particularly important for young women, who often have the
most difficulty remembering to take contraceptive pills consistently.13
No randomized controlled trials have been conducted
to compare NuvaRing with COCs. Large nonrandomized trials suggest that the
efficacy and side effects of NuvaRing are comparable to those of COCs,
although NuvaRing users more frequently report vaginitis, vaginal
discharge, and vaginal irritation.14 Like Ortho Evra patch
users, NuvaRing users may have higher compliance rates than COC users (92
percent versus 75 percent in one group of comparative studies).15
A possible advantage of NuvaRing over other
low-dose hormonal methods, including the Ortho Evra patch, is its effect
on cycle control. The ring contains only 15 µg estrogen, but studies
suggest that this low dose of estrogen is not associated with increased
intermenstrual bleeding. About two-thirds of some 100 vaginal ring users,
compared with fewer than half of some 100 COC users, reported expected
bleeding patterns during all their cycles.16 Such good cycle
control may have been attributable to correct use of the method or,
according to the authors, the fact that the ring continuously releases
hormones, which prevents the daily fluctuations in hormone levels that
occur during COC use.
Novel products such as the Ortho Evra patch and
NuvaRing are advances that will appeal to some women. But, Dr. Potts
notes, cost may prohibit such products from making a worldwide impact in
the near future. (Currently, in the United States, the monthly cost of the
patch or NuvaRing may be almost twice that of COCs.17) "At
a world level," he says, "what we need in vast quantities are
low-dose, low-cost contraceptive pills that women know how to use
consistently and correctly."
— Kerry L. Wright
References
- World Contraceptive Use 2001, wall chart. New
York, NY: United Nations Population Division, 2002.
- World Health Organization. Cardiovascular Disease and
Steroid Hormone Contraception: Report of a WHO Scientific Group. WHO
Technical Report Series 877. Geneva, Switzerland: World Health
Organization, 1998.
- World Health Organization; Hannaford PC, Owen-Smith V.
Using epidemiological data to guide clinical practice: review of studies
on cardiovascular disease and use of combined oral contraceptives. BMJ
1998;316(7136):984-87; Vandenbroucke JP, Rosing J, Bloemenkamp KW, et
al. Oral contraceptives and the risk of venous thrombosis. N Engl J
Med 2001;344(20):1527-35.
- Vandenbroucke; Kovacs P. The risk of cardiovascular
disease with second- and third-generation oral contraceptives. Medscape
Women's Health eJournal 2002;7(4). Available: http://www.medscape.com/viewarticle/439354
(One must first register for Medscape.com.)
- Rosenberg MJ, Meyers A, Roy V. Efficacy, cycle control,
and side effects of low- and lower-dose oral contraceptives: a
randomized trial of 20 µg and 35 µg estrogen preparations. Contraception
1999;60(6):321-29.
- Rosenberg MJ, Long SC. Oral contraceptives and cycle
control: a critical review of the literature. Adv Contracept
1992;8(Suppl 1): 35-45.
- Saleh WA, Burkman RT, Zacur HA, et al. A randomized
trial of three oral contraceptives; comparison of bleeding patterns by
contraceptive types and steroid levels. Am J Obstet Gynecol
1993;168(6 Pt 1):1740-45; Endrikat J, Muller U, Dusterberg B. A
twelve-month comparative clinical investigation of two low-dose oral
contraceptives containing 20 µg ethinylestradiol/75 µg gestodene and
30 µg ethinylestradiol/ 75 µg gestodene, with respect to efficacy,
cycle control, and tolerance. Contraception 1997;55(3):131-37;
Akerlund M, Rode A, Westergard J. Comparative profiles of reliability,
cycle control, and side effects of two oral contraceptive formulations
containing 150 micrograms desogestrel and either 30 micrograms or 20
micrograms ethinyl estradiol. Br J Obstet Gynaecol
1993;100(9):832-38.
- Endrikat; Rosenberg, Long.
- Endrikat.
- Rosenberg, Long; van Vliet HA, Grimes DA, Helmerhorst
FM, et al. Biphasic versus triphasic oral contraceptives for
contraception. Contraception 2002;65(5):321-24.
- Audet MC, Moreau M, Koltun WD, et al. Evaluation of
contraceptive efficacy and cycle control of a transdermal contraceptive
patch vs an oral contraceptive: a randomized controlled trial. JAMA
2001;285(18):2347-54; Dittrich R, Parker L, Rosen JB, et al. Trans—
dermal contraception: evaluation of three transdermal norelgestromin/ethinyl
estradiol doses in a randomized, multicenter, dose-response study. Am
J Obstet Gynecol 2002;186(1):15-20; Hedon B, Helmerhorst FM, Cronje
HS, et al. Com— parison of efficacy, cycle control, compliance and
safety in users of a contraceptive patch vs an oral contraceptive. Int
J Gynaecol Obstet 2000;70 (Suppl 1):78.
- Archer DF, Bigriff A, Smallwood GH. Assessment of
compliance with a weekly contraceptive patch (Ortho Evra/Evra) among
North American women. Fertil Steril 2002;77(2 Suppl 2): 27-31.
- Rosenberg MJ, Waugh MS, Long S. Unintended pregnancies
and use, misuse, and discontinuation of oral contraceptives. J Reprod
Med 1995;40(5):355-60; Potter LS. Oral contraceptive compliance and
its role in the effectiveness of the method. In Cramer JA, Spilker B,
eds. Patient Compliance in Medical Practice and Clinical Trials.
New York, NY: Raven Press, 1991.
- Dieben TO, Roumen JME, Apter D. Efficacy, cycle control,
and user acceptability of a novel combined contraceptive vaginal ring. Obstet
Gynecol 2002;100(3):585-93; Roumen FJ, Apter D, Mulders TM, et al.
Efficacy, tolera— bility, and acceptability of a novel contraceptive
vaginal ring releasing etonogestrel and ethinyl estradiol. Hum Reprod
2001;16(3):469-75.
- Dieben.
- Bjarnadotfir RI, Tuppurainen M, Killick SR. Comparison
of cycle control with a combined contraceptive vaginal ring and oral
levonorgestrel/ethinyl estradiol. Am J Obstet Gynecol
2002;186(3):389-95.
- Planned Parenthood Federation of America, Inc. Birth
Control: Your Contraceptive Choices. Available: http://www.plannedparenthood.org/bc/cchoices4.html.
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| Since Norplant was
introduced in the 1980s, researchers have worked to simplify this
very safe and effective contraceptive implant comprised of six
3-cm levonorgestrel-releasing capsules.1 They succeeded
by developing in the 1990s what is now trademarked as Jadelle: an
implant containing only two 4-cm levonorgestrel-releasing rods.
Now, Jadelle is beginning to be introduced into the developing
world as an alternative to — and potential replacement for —
Norplant.
The biggest practical difference between the two implants is
that Jadelle is easier to insert and remove, an advantage for both
clients and providers.
"We recognized that six capsules were rather complicated
to remove and insert, so we had hoped that we could develop more
efficient implants," says Irving Sivin, senior scientist with
the New York-based Population Council's implant development
program. The Population Council developed Jadelle and also
Norplant, which is now approved in more than 60 countries,
including the United States.
Among clinicians using standard techniques to remove Norplant
or Jadelle, Jadelle took only half the time to remove (a mean of
approximately 5 minutes for Jadelle versus 10 minutes for
Norplant).2 Saving time in this way, Sivin says, may
give providers more opportunity to counsel or otherwise help
clients. Jadelle is also associated with fewer insertion and
removal complications. In a study conducted among some 1,000 women
using Norplant or Jadelle, 15 percent of Norplant users had some
type of removal complication (such as bruising, pain, broken
implants, or multiple incisions), compared with only 7 percent of
Jadelle users.3
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Click to see a larger version
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Of note, duration of effectiveness is up to seven years for
Norplant and only up to five years for Jadelle, which may be
another important practical consideration for potential users.
Otherwise, the two delivery systems are comparable. "The
pregnancy rates have been identical for the two, at 1.1 per 100
women over a five-year period, roughly two pregnancies per 1,000
women per year," says Sivin. In the study of some 1,000 women
using Norplant or Jadelle, mean annual discontinuation rates due
to menstrual disturbances (such as prolonged or heavy bleeding,
intermenstrual spotting, and absence of bleeding) were
approximately 4 per 100 women for both delivery systems.4
Jadelle has been approved in several European countries,
Thailand, and Indonesia. In 2002 the International Planned
Parenthood Federation added the method to its commodities list.
USAID has not yet added it to its commodities list but will be
working with the manufacturer to establish a public-sector price.
Meanwhile, the Population Council is planning activities with
PROFAMILIA in the Dominican Republic to determine the client
preferences, educational materials, and provider training
necessary for family planning programs to make a transition from
Norplant to Jadelle.
— Kerry L. Wright
References
- Croxatto HB. Progestin implants for female
contraception. Contraception 2002;65(1):15-19; Sivin I,
Moo-Young A. Recent developments in contraceptive implants at
the Population Council. Contraception
2002;65(1):113-19.
- Sivin I, Campodonico I, Kiriwat O, et al. The
performance of levonorgestrel rod and Norplant contraceptive
implants: a five-year randomized study. Hum Reprod
1998;13(12):3371-78.
- Sivin, Campodonico, Kiriwat.
- Sivin, Campodonico, Kiriwat.
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