A New View of an Old Therapy

Gestiva for
Preventing
Prematurity Major Rebecca Cypher, MSN, PNNP

There are
significant
consequences
iIn August 2006, the Food and Drug Administra-
tion’s (FDA) Advisory Committee for Repro-
ductive Health Drugs held a public meeting to
discuss the safety and efficacy of a new drug
application submitted by Adeza Biomedical in
May 2006. Gestiva, the proposed trade name
after FDA approval (FDA, 2006b). Approval
would make Gestiva the only FDA-approved
drug to prevent preterm birth in women with a
history of preterm delivery. At the time of this
writing, Gestiva has been given priority review
and a final decision is expected from the FDA
to the survivors for a progestin known as 17-P, was presented soon. Once approved, Gestiva will be supplied
as a medication indicated for the prevention of as a 5-mL multiple-dose vial with each milliliter
and their
preterm birth in pregnant women with a his- containing 250 mg of 17-P (FDA, 2006a).
families in terms
tory of at least one spontaneous preterm birth
of associated (FDA, 2006a). Preterm Birth:
disabilities and The agency’s committee recommended, by The Scope of the Problem
the related a vote of 13-8, that the clinical data regarding Defined as delivery before 37 completed weeks
Gestiva were adequate to recommend FDA from the first day of the last menstrual period
societal and
approval. The committee also recommended (Iams & Creasy, 2004), the U.S. preterm birth
economic costs. that further studies on Gestiva be conducted rate is now 12.7 percent, which is an increase

322 © 2007, AWHONN http://nwh.awhonn.org

of more than 20 percent since 1990 (Centers
for Disease Control and Prevention, 2006).
Improvements in the care and treatment of pre-
mature infants have increased survival rates, but
data continue to show that preterm birth has
had a significant impact on infant mortality.
A recent study found that in 2002, pre-
term birth contributed to more than one-third
of infant deaths within the first year of life
(Callaghan, MacDorman, Rasmussen, Qin, &
Lackritz, 2006). The National Center for Health
Statistics (2006) noted that 17 percent of infant
deaths in 2002 were attributed to preterm birth;
however, two-thirds of the infants who died were
born prematurely. This has led to speculation
that prematurity plays a greater role in infant
death than what the current reporting systems
have led public health officials to believe.
In addition, there are significant conse-
quences to the survivors and their families in
terms of associated disabilities and the related
societal and economic costs. The latest statistics
by the March of Dimes (2006a) estimate that
more than $26.2 billion in costs including medi-
cal care, educational needs and lost productivity
were associated with prematurity. As a result,
these rising statistics have led research investiga-
tors to focus on preterm birth prevention.
Physiology of
Progesterone in Pregnancy
The woman, the fetus and the placenta act as
one functional unit to sustain pregnancy until
delivery. Contributing to this unit are several
hormones, which include estrogen, androgens,
and progestogens (Blackburn, 2003; Liu, 2004).
Progesterone and 17 alpha-hydroxyprogester-
one (17-OHP) are the major progestogens in
pregnancy. These naturally occurring hormones
have many actions and play an important role
in maintaining pregnancy. Changes in proges-
terone levels may also play a role in the initia-
tion of labor (Buster & Carson, 2002; Meis,
2005; Meis & Connors, 2004).
During pregnancy, naturally occurring Preterm birth
progesterone is produced and secreted by the
is a complex
ovaries, adrenal gland, corpus luteum and
placenta. Specifically, the corpus luteum is the problem with
main producer of progesterone until six weeks many overlapping
gestation, when the placenta takes over (Buster contributing
& Carson, 2002; Liu, 2004). Progesterone ap-
risk factors and
pears to act as a smooth muscle relaxant on
possible causes.
the gravid uterus, helping to maintain uterine
quiescence. Progesterone has immunosuppres-
sive properties that block the effects of oxytocin
on the myometrium. Most importantly,

The Mystery of Preterm Birth

Preterm birth is a complex problem with many Get the Facts
overlapping contributing risk factors and pos-
sible causes. The current methods for the diag- Centers for Disease
nosis and treatment of preterm labor are mostly Control and Prevention
based on literature in which there are significant http://www.cdc.gov/reproductive
gaps in evidence; ultimately very little is known health/MaternalInfantHealth/PBP.htm
about how preterm birth can be prevented.
March of Dimes
Interventions are primarily based on the
medical model of identifying each suspected
http://www.marchofdimes.com
cause or risk factor for preterm birth with the Prematurity.org
expectation that the preterm birth rate would Major Rebecca Cypher,
http://www.prematurity.org MSN, PNNP, is a clini-
decrease. Research studies have typically focused
cal specialist at Wilford
on interventions including early identification
Hall Medical Center in
of preterm labor through patient education,
San Antonio, TX. The
pharmacological suppression of contractions, views expressed in this
antimicrobial therapy of vaginal microorgan- article are those of the
isms, the use of cerclage to reinforce the cervix, author and do not reflect
maternal stress reduction, adequate nutrition, the official policy of the
better access to prenatal care, and reduced physi- Department of Defense or
cal activity (Behrman & Butler, 2006). Despite other departments of the
the many attempts at intervening, the overall U.S. government.
rate of preterm birth continues to steadily rise. DOI: 10.1111/j.1751-486X.2007.00169.x

June | July 2007 Nursing for Women’s Health 323


progesterone is a potent
inhibitor of the formation
of gap junctions between the myome-
trial cells of the uterus. These intercel-
lular communications are essential in
coordinating uterine activity leading to
labor (Liu; Meis, 2005; Meis & Con-
nors, 2004).
17-OHP is known to be an inter-
mediary in the production of andro-
gens, estrogens and corticosteroids
(Meis & Connors, 2004). This type of
progestogen predominantly originates
in the corpus luteum during the first
trimester and then the ovaries for the
remainder of the pregnancy (Buster
& Carson, 2002). Naturally occurring
17-OHP has also been found to have a
weak action in prolonging pregnancy.
However, when 17-OHP is exposed to
caproic acid, 17 alpha-hydroxyproges-
terone caproate (17-P) is created. In
this form, 17-P has been shown to have
twice the progestational activity and
acts twice as long when compared with
free progesterone (Meis & Connors).
Past and Future of
Progesterone Therapy
Of all the treatments researched for pre-
term birth prevention, progestational
supplementation has demonstrated the
greatest promise. Historically, proges-
terone was used as a therapy for women
with threatened abortion, history of
recurrent miscarriages and postpartum
uterine cramping. The medication used
was Delalutin®, which was approved by
the FDA in 1956 but taken off the mar-
ket in 2000 as it was no longer being
produced (FDA, 2006a). Subsequently,
324 Nursing for Women’s Health
A number of studies have
examined whether
progesterone treatment
may be effective in
preventing preterm
birth.
a number of studies have examined
whether progesterone treatment may
be effective in preventing preterm birth.
These studies have yielded conflicting
results, which have either supported or
questioned the effectiveness of 17-P for
preterm birth prevention. This dispar-
ity prompted the National Institute for
Child Health and Human Development
(NICHD) to conduct a multicenter trial
(Meis et al., 2003).
Randomized Trials
In 2003, the publication of two large
randomized placebo-controlled trials
of 17-P and progesterone suppositories
rekindled interest in the obstetric arena
(da Fonseca, Bittar, Carvalho, & Zugaib,
2003; Meis et al., 2003). Unlike studies
that targeted multiple risk factors such
as positive fetal fibronectin and prior
preterm birth, these two studies looked
at supplemental progesterone as an
effective method of reducing the rates
of preterm birth in women who had a
history of a prior preterm birth.
The primary clinical trial was
sponsored by the NICHD and con-
ducted by the Maternal-Fetal Medicine
Units Network (Meis et al., 2003). This
was the largest trial, with an enroll-
ment of 463 women who had at least
one documented prior preterm birth.
Participants were randomized to either
weekly injections of 250 mg 17-P or an
oil placebo. Of these 463 women, 418
women (90.3 percent) completed dos-
ing through 36 + 6 weeks or delivery
(279 women in the 17-P group and
139 women in the placebo group).
The trial was terminated early
because efficacy was attained at the
time of the interim analysis. Final
results showed a 34 percent reduc-
tion in preterm births prior to 37 + 0
weeks. Infants born to women treated
with 17-P had significantly lower rates
of necrotizing enterocolitis, intraven-
tricular hemorrhage and supplemental
oxygen use. A small increase in second
trimester miscarriages and stillbirths in
the 17-P group was noted as com-
pared with the placebo group, but this
was not statistically significant (FDA,
2006b; Meis et al., 2003).
The second study was conducted
at a university in Brazil. The research-
ers recruited 142 women with single-
ton pregnancies that were at risk for
preterm delivery. Of this group, 72
women were started on 100 mg pro-
gesterone vaginal suppositories daily
and 70 women were given a placebo.
All women had contraction monitoring
once a week for 60 minutes between 24
and 36 weeks gestation. The incidence
of preterm delivery in the progesterone
group was 13.8 percent (10/72) com-
pared with 28.5 percent (20/70) in the
placebo group, a statistically significant
finding (da Fonseca et al., 2003).
Several years later, two meta-analy-
ses were published using data from
these two studies as well as data from
earlier studies that used supplemental
progesterone. The combined risk of
recurrent preterm birth was reduced by
approximately 40 percent to 55 percent
in those who used progesterone supple-
mentation (Dodd, Flenady, Cincotta,
& Crowther, 2006; Sanchez-Ramos,
Kaunitz, & Delke, 2005). This suggests
that supplemental progesterone may
be effective in several ways including
inhibiting one pathway that is shared
by the multiple causes of preterm birth,
inhibiting several pathways or
Volume 11 Issue 3
inhibiting one highly prevalent pathway
or cause (Behrman & Butler, 2006).
Safety and Dosing
The evidence for the safety of 17-P use
in pregnancy is based on theoretical
consideration, animal studies and clini-
cal trials. During pregnancy, progester-
one and 17-P are produced in amounts
that exceed the current pharmacologi-
cal dosing used for recurrent preterm
births. The safety of 17-P administra-
tion in pregnancy is well-documented
in a variety of studies. There appear to
be no teratogenic effect on the fetus or
neonate. The researchers concluded that
there is no significant risk to the mother,
fetus or newborn when 17-P is adminis-
tered in pregnancy (Meis, 2005).
The NICHD is also completing a
study exploring impact of the medica-
tion on the developmental milestones
and physical health in children born to
women who received 17-P. There ap-
pears to be no teratogenic effects on the
fetus or neonate. Finally, initial results
from the NICHD study have failed to
show any association with developmen-
tal delays in children between 30 and 64
months of age (FDA, 2006a; Meis et al.,
2003).
At the time of this writing, 17-P
is not commercially available in the
United States. In some facilities, 17-P
is now compounded by pharmacists. If
approved, the proposed dosing regimen
of Gestiva is a weekly intramuscular
injection of 250 mg 17-P in 1 mL castor
oil with 46 percent benzyl benzoate
and 2 percent benzyl alcohol (FDA,
2006a). Injections should ideally be
started between 16 + 0 weeks and 20 +
weeks gestation. Injections should be
concluded at 36+ weeks or at the time
of birth. The most common side effects
reported by women were injection site
pain and swelling (FDA, 2006a).
Future of
Preterm Birth Prevention
Preterm birth and the consequences of
prematurity are national health care
June | July 2007
priorities. The Prematurity Research
Expansion and Education for Moth-
ers Who Deliver Infants Early Act was
signed into law by President Bush in
December 2006, authorizing increased
federal support for education and
research on prematurity (March of
Dimes, 2006b). Focusing on preven-
tion may lead to significant progress
toward the reduction of preterm birth.
Progesterone therapy in the form of
Gestiva or similar medications might
be an intervention that makes this hope
a reality. NWH
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