Source: McIntosh N, A Blouse and L Schaefer. 1995. Norplant®
Implants for Family Planning Service Programs, 2nd ed. JHPIEGO Corporation: Baltimore,
Maryland.
Background
The Norplant contraceptive implants system is an
effective, reversible contraceptive method that provides protection from pregnancy for up
to 5 years. It was developed by the Population Council, an international organization
established in 1952 to improve contraceptive technology.
The history of contraceptive implants may be thought of in
four stages:
- research on the concept of an implantable
contraceptive which began in 1966;
- development of the Norplant implants system by 1974;
- initiation of long-term clinical trials in six
countries (Brazil, Chile, Denmark, the Dominican Republic, Finland and Jamaica) starting
in 1975; and
- introduction of the method into family planning
programs worldwide beginning in 1983.
Description
The Norplant implants system consists of six small
flexible capsules made of Silastic® tubing and filled with a synthetic
progestin, levonorgestrel (LNG) (Figure 1).
Figure 1. Norplant Capsule, Actual Size
Source: Population Council 1990.
The capsules are inserted just under the skin
(subdermally) on the inner side of a woman's upper arm(Figure 2) using a minor
surgical procedure. They provide highly effective contraception for up to 5 years.
Moreover, after the Norplant implants are removed, normal fertility promptly returns.
Figure 2. Norplant Implants Insertion Site
The active contraceptive hormone in Norplant implants is
the progestin, levonorgestrel (LNG). It is a steroid hormone with potent progesterone-like
activity and weak androgenic properties. It is a synthetic derivative of testosterone. Its
chemical structure is depicted in Figure 3.
Figure 3. Structure of Levonorgestrel
The implants are made from medical grade Silastic tubing
which is a co-polymer of dimethylsiloxane and methylvinylsiloxane. Each capsule is 34
millimeters (mm) long, with a diameter of 2.4 mm and contains 36 milligrams (mg) of
levonorgestrel in a dry crystalline (powder) form. The capsules are sealed at each end
with Silastic (polydimethylsiloxane) Medical Grade Adhesive A.
The materials used in the production of Norplant implants
are not new to medicine. Levonorgestrel has been used for more than 30 years in combined
(estrogen and progestin) oral contraceptives (COCs) and in progestin-only minipills
(POPs). The Silastic tubing used to make the capsules has been used in humans (prosthetic
valves and other surgical devices) since the 1950s, and the Silastic Medical Adhesive
(Silicone Type A) has been used extensively in surgical implants such as cardiac
pacemakers for many years (Croxatto 1993).
What is new about Norplant implants is the way they
deliver the contraceptive drug into the body: the levonorgestrel continuously passes
through the capsule walls into the bloodstream at a relatively constant rate for up to 5
years. Thus, this method makes it possible for a single act of contraceptive acceptance to
replace more than 1,800 days of pill taking.
Packaging
The contraceptive is prescribed as a set. One sealed,
sterile plastic pouch contains six subdermal capsules, each filled with 36 mg of
levonorgestrel, for use in one woman.
Storage and Shelf Life
The sterile packs of Norplant implants should be stored
away from excessive heat (temperature range: 20-50oC) and moisture. An
unopened, undamaged sterile pack of Norplant capsules, if properly stored, has a shelf
life of 5 years (currently 3 years in the United Kingdom and the United States). The
last date for insertion (expiration date) is stamped on each box.
Effective Life
If inserted anytime before the expiration date
(shelf life), Norplant implants are effective for up to 5 years. The implants should be
removed by the end of the fifth year (effective life). If desired, a new set of
implants may be inserted immediately after removal.
Pharmacokinetics
A blood level of levonorgestrel sufficient to prevent
pregnancy is reached within 8 to 24 hours after insertion of Norplant implants and is
maintained at an effective level for at least 5 years (Croxatto 1993; Sivin 1993).
Initially, the six-capsule system has a relatively high release rate, about 85 micrograms
per day (µg/day) during the first few weeks of use. This decreases to about 50 µg/day by
9 months, to 35 µg/day by 18 months, and finally to a steady level of 30 µg/day for the
rest of the 5-year period (Population Council 1990).
Within 24 hours after inserting a set of Norplant implants
under the skin in the upper arm, a mean LNG serum level of between 1.0 and 2.0 nanograms
per milliliter (ng/ml) is reached and maintained for several days. This compares to
initial blood levels of 3 to 5 ng/ml of progesterone for low-dose oral contraceptives
(Nash 1990). The concentration of LNG declines relatively rapidly during the first weeks
of use to a mean level between 0.25 and 0.4 ng/ml by 6 months (Figure 4). This
level is sufficient to prevent pregnancy and decreases only slightly during the remaining
4.5 years (Population Council 1990).
Circulating levels of LNG among individual users differ by
a factor of several fold and many values fall outside the mean ranges stated above.
Several factors account for this variation among subjects. One factor is the
subject-to-subject variation in the rate of LNG metabolism. Another is variation in
the weight of individuals and fat-to-muscle ratios. A third factor is variability
in the levels of the sex hormone binding globulin
Figure 4. Mean Levels of Levonorgestrel
Source: Nash 1990.
(SHBG), a large molecule that
circulates in the blood stream. Unlike other progestins, levonorgestrel binds tightly to
SHBG which tends to maintain higher LNG levels in the blood (Weiner and Johansson 1976). In
addition, there is evidence that two local factors may affect LNG release from
the implants:
- the thickness of the fibrous sheath that forms around each
capsule, and
- the vascular (blood vessel) pattern and amount of fat
tissue surrounding the capsules (Population Council 1990).
Finally, the time required for one half the LNG to be
cleared from the body after removal of all six capsules is about 40 hours. Therefore,
following removal of the implants, plasma LNG becomes unmeasurable within a few days
(Croxatto et al 1988).
Mechanism of Action
Pregnancy is prevented through a combination of
mechanisms. The two primary means are:
- production of thick, scanty cervical mucus which prevents
sperm penetration, and
- inhibition of ovulation in about 50% of menstrual cycles.
Other, secondary actions which may add to these
contraceptive effects include:
- suppression of endometrial growth (hypoplasia), and
- decreased natural progesterone production by the ovary
during the postovulatory (luteal) phase in those cycles in which ovulation occurs.
Effect on Cervical Mucus
Perhaps the most important contraceptive effect of the LNG
in the implants is the change in the composition of the cervical mucus it causes-even in
those women menstruating regularly. Research has shown that within 24 to 48 hours after
insertion, the cervical mucus becomes thick, is decreased in amount and does not permit
sperm to pass through it. For example, in postcoital tests with women using Norplant
implants, few sperm were able to reach the endocervical canal and those that did had
decreased motion (Brache et al 1985; Croxatto et al 1987). This effect is similar to that
seen with other progestin-only contraceptives (POCs) and combined oral contraceptive
pills. In addition, this action has been confirmed in laboratory tests which showed
markedly reduced movement of sperm through cervical mucus obtained from implants users
compared with women not using a hormonal contraceptive during the pre-ovulatory
phase of their cycles.
Effect on Ovulation
In studies conducted to determine how often ovulation
occurred in implants users, serial blood samples were drawn twice weekly and natural
progesterone measured. As shown in Table 1, during the first year only about 11% of
cycles were considered ovulatory while by year 5, more than 50% were ovulatory (Population
Council 1990).1 Research using ultrasonography and measurements of
circulating natural progesterone have demonstrated that blocking ovulation is an important
contraceptive action in preventing pregnancy (Brache et al 1990).
Table 1. Frequency of Ovulation in Women Using Norplant
Implants
| Years of
Norplant Implants Use |
Number of
Women |
Ovulatory
(%) |
Anovulatory
(%) |
Uncertain
(%) |
| 1 |
27 |
11 |
82 |
7 |
| 2 |
21 |
62 |
29 |
10 |
| 3 |
36 |
28 |
64 |
8 |
| 4 |
23 |
44 |
52 |
4 |
| 5 |
48 |
52 |
46 |
2 |
| 6 |
19 |
74 |
26 |
0 |
| 7 |
15 |
60 |
33 |
7 |
| Average (1-7 years) |
189 |
44 |
50 |
5 |
Source: Population Council 1990.
How Ovulation is Prevented
The small amount of LNG which is continuously released
from the capsules acts on special areas of the brain (hypothalamus and anterior pituitary
gland) to:
- decrease the secretion of follicle-stimulating hormone
(FSH) and luteinizing hormone (LH), and
- block (or significantly reduce) the LH surge at mid-cycle (Figure
5).
Figure 5. Mean LH Levels of Norplant Implants Users
Source: Alvarez et al
1986.
Thus, in implants users
ovulation is either prevented (no LH surge) or, if ovulation does occur, progesterone
levels are reduced (Davies and Newton 1992). As depicted in Figure 6, mean natural
progesterone levels even in "ovulatory" cycles are significantly less
than those in women not using a hormonal contraceptive (Population Council 1990).
Figure 6. Mean Progesterone Levels in Norplant Implants
Users
Source: Alvarez et al 1986.
This is due to the action of LNG and similar other
19-nortestosterone steroids in limiting secretion of progesterone, but not
estrogen, from the corpus luteum which forms in the ovary following ovulation (Figure 7).
As a consequence, even in ovulatory cycles, natural progesterone levels may be too low for
the fertilized egg (zygote) to successfully implant in the cells lining the uterine cavity
(endometrium).
Figure 7. Mean Estrogen Levels in Norplant Implants
Users
Source: Alvarez et al 1986.
Whether ovulation is prevented (or just impaired due to
decreased function of the corpus luteum) varies from cycle to cycle. It depends on several
factors, such as the duration of implants use as shown in Table 1.
Effect on Endometrium
Levonorgestrel and other synthetic progestins block
progesterone receptors (specific proteins located inside the uterine endometrial cells
that bind progesterone). This action causes the endometrial cells which line the uterine
cavity to have fewer, smaller glands which function poorly (i.e., they do not have much
secretory activity). This added effect of LNG is thought to further reduce the likelihood
of successfulimplantation and is an important secondary effect in implants users.
Clinical Experience
The effectiveness of a contraceptive method usually
is the most important factor, both for the individual (or couple) trying to choose a
method and for the health worker. For valid comparisons of effectiveness to be made among
the most commonly used methods, failure rates must be presented not only for individuals
using the method consistently and correctly, but also for typical users.
Data presented in this way, showing the range of failures rates for the first year of use
for most contraceptive methods, are illustrated in Figure 8.
Effectiveness of Norplant Implants
The Norplant system is one of the most effective
contraceptive methods ever developed. The first year pregnancy rate is only 0.2 per 100
woman-years, and the 5-year cumulative rate is just 1.6 (Sivin 1988). With the exception
of voluntary sterilization, the Copper T 380A IUD and progestin-only injectables, no other
contraceptive method is so effective.
Clinical experience with Norplant implants has been gained
from many years of research and clinical evaluation worldwide. By 1990, more than 55,000
women from 46 countries, including the USA, had participated in these clinical trials.
Based on results from all countries, the Pearl index (i.e., number of pregnancies times
1200 divided by total months of use) is 0.2 for the first 2 years and 0.9, 0.5 and 1.1 per
100 woman-years for the third through fifth years (Darney et al 1990b.) The first and
second year failure rates compare favorably with the lowest expected failure rates for
male and female voluntary sterilization (Trussell et al 1990).
Figure 8. Estimated Range of Failure Rates for
Contraceptives Used Worldwide
Adapted from: Population Action International 1991.
Effectiveness and Body Weight
Early studies demonstrated an increased gross
cumulative pregnancy rate in women weighing more than 70 kg (9.3 versus 4.5 in users
weighing 60 to 69 kg). These studies, however, were carried out using capsules made from a
harder, more dense type of tubing.
Subsequent studies using a softer, less dense tubing have
shown much lower pregnancy rates (Table 2). With the less dense tubing, the 5-year
cumulative pregnancy rate in women weighing more that 70 kg is only slightly higher (2.4
versus 1.5) than for lighter women (Sivin 1988). Because the softer, less dense tubing is
the product now used worldwide, service providers no longer need to be concerned about
recommending Norplant implants to heavier women (> 70 kg).
Table 2. Comparison of Cumulative Pregnancy Rates: Less
Versus More Dense Tubing
| Weight
of Women
|
Cumulative
Pregnancy Rates
Tubing Density |
Less
Densea |
More
Dense |
| < 50 kg |
0 |
0.3 |
| 50-59 kg |
2.0 |
4.3 |
| 60-69 kg |
1.5 |
4.5 |
| > 70 kg |
2.4 |
9.3 |
a This is the product now marketed
worldwide.
Source: Sivin 1988.
Pregnancy may be more likely in Norplant implants users
who take medications which increase the production of the liver enzymes that metabolize
(break down) the levonorgestrel released from the implants. (These drugs decrease the
effectiveness of combination and progestin-only contraceptive pills as well.) Drugs which
fall into this category include:
- anti-epilepsy (seizure disorder) drugs such as
barbiturates (phenobarbital), phenytoin (Dilantin®) and carbamazepine
(Tegretol®) but not valproic acid, and
- antibiotics (only rifampin and griseofulvin2).
Contrary to earlier reports, antibiotics other than
rifampin (for tuberculosis) and griseofulvin (antifungal) now are not thought to
reduce the effectiveness of Norplant implants and combined (estrogen and progestin) oral
contraceptives (COCs) or progestin-only pills (POPs) (Angle, Huff and Lea 1991).
1 To be
classified as "compatible with ovulation," a progesterone level above 9.5
nanamoles per liter (nM/l) in at least one sample was required as well as values above 6.4
nM/l in the sample immediately following or preceding it.
2 Because griseofulvin usually is used only for
a short period of time (2 to 4 weeks), women taking it for fungal infections can continue
to use Norplant implants. They should use a backup method while taking griseofulvin and
until the start of the next menstrual period after stopping the antibiotic.
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