Review
10.1517/14728210802568764©2008InformaUKLtdISSN1472-8214 1
Allrightsreserved:reproductioninwholeorinpartnotpermitted
Emergingtocolytics:challenges
indesigningandtestingdrugs
todelaypretermdeliveryand
prolongpregnancy
David M Olson
†
, Inge Christiaens, Sara Gracie, Yuka Yamamoto &
Bryan F Mitchell
†
AHFMR Interdisciplinary Team in Preterm Birth and Healthy Outcomes, Departments of Obstetrics
and Gynecology, Pediatrics and Physiology, University of Alberta, Edmonton, Canada
The global rate of preterm delivery (before 37 completed weeks of pregnancy)
is increasing and there are no effective means available to prevent this rise.
Prematurity is the principal cause of neonatal mortality and a major cause
of pediatric morbidity and long-term disability. Current strategies to prolong
pregnancy are based on inhibiting the mechanisms that effect uterine
smooth muscle (myometrium) contractions in women who are in preterm
labor. Most drugs in this group were developed for other purposes. Newer
strategies are designed to maintain a state of uterine quiescence and preg-
nancy, preventing the myometrium from initiating contractions and entering
preterm labor. Again, it may be possible to use existing drugs for pregnancy
maintenance. Several financial and practical barriers exist for developing
completely new drugs to delay labor. Designing clinical trials to test tocolytics
is complicated, as the health of two patients must be considered and the
nature of preterm birth and its outcomes are different at early preterm
labor (< 28 weeks) and late preterm labor (34 – 36 weeks).
Keywords: atosiban, morbidity, myometrium, neonatal, NSAIDs, pregnancy, prematurity,
preterm birth, preterm labor, progesterone, tocolytics, uterus
Expert Opin. Emerging Drugs (2008) 13(4):1-13
1. Background
Prematurity is the principal cause of neonatal mortality [1] and a major cause of
pediatric morbidity and long-term disability [2-4]; it is associated with at least
50% of all pediatric neurodevelopmental disorders [5]. Infants born preterm
(< 37 completed weeks of gestation) are at increased risk for a range of adverse
neonatal outcomes, including retinopathy of prematurity [6], respiratory distress
syndrome and bronchopulmonary dysplasia [7], severe brain injury [8], necrotizing
enterocolitis [9], and neonatal sepsis [10]. Long-term sequelae include risk for
motor and sensory impairment (including cerebral palsy, visual impairment, and
hearing impairment) [11,12], learning problems and neurocognitive impairment
(including lower IQ and lower academic achievement) [13-18], and behavioral
problems (e.g., attention deficit hyperactivity disorder, ADHD) [19-24]. Although
the risk for mortality and morbidity is higher among early preterm births
(< 32 weeks’ gestation), late preterm births (34 to 36 weeks’ gestation) [25] are
more common and rates are increasing [26], thus creating a serious public health
problem. Recent evidence is demonstrating that late preterm birth infants are also
at risk for subtle developmental delays [27].
In spite of approximately 40 years of study and pharmaceutical testing to
develop drugs that have the potential to arrest uterine myometrial contractility,
1. Background
2. Medical need
3. Scientific rationale
4. Competitive environment
5. Potential development issues
6. Existing treatment and
therapeutic class review
7. Current research goals
and emerging treatments
8. Expert opinion
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