Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1999-07-07
2002-04-23
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S078080, C428S500000, C524S916000, C604S048000
Reexamination Certificate
active
06375970
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to the intrauterine use of compliant polymeric substances in pregnant women to reduce the incidence of preterm birth comprising polymeric compositions selected for ability to prevent amniotic fluid leakage in cases of ruptured amniotic membranes and to provide a physical cervical barrier to migration of microbes, and optionally for ability to release therapeutic agents to prevent labor and/or infection.
BACKGROUND OF THE INVENTION
In the United States, approximately 300,000 newborns are born prematurely every year, a figure that represents about 6% to 10% of all newborns. Preterm premature rupture of fetal membranes (PROM) is a factor in a majority of these births. About 20% of these premature infants die in the first month. Survivors may suffer short or long term morbidity involving every organ system. The hospitalization costs of the acute antepartum maternal care, the neonatal intensive care and the immediate care of the prematurely born infant, are enormous and often exceed $500,000 per case. Additional costs for care of the premature newborn continue to accrue after discharge from the hospital and potentially throughout the child's life, including further care due to life long handicaps and the cost of lost productivity due to these handicaps.
The cause of premature labor or rupture of the fetal membranes is almost certainly multifactorial. One factor leading to PROM is breach of the cervical barrier that separates the vagina, which is colonized by a multitude of microbial families, from the sterile intrauterine environment. Such a breach of the cervical barrier can be due to the virulence of a given bacterial population or to deficits in immune or biochemical mechanisms that control the advance of microbes through the cervical canal. Alternatively, or concurrently, mechanical defects due to structural uterine or cervical abnormalities or prematurely occurring biochemical changes in the cervical tissue which lead to the premature opening of the cervical canal can cause or contribute to the process which ultimately culminates in PROM.
Two fundamental physiological processes in the uterine corpus and cervix are required for premature expulsion of the fetus to occur. In the uterine corpus (the body of the uterus), the muscular myometrium must change from a relaxed state, which is crucial to the continuation of pregnancy, to a state characterized by a rhythmic contractile activity that culminates in the expulsion of the products of conception. Meanwhile, the cervix must gradually yield, soften, efface and dilate. The softened and dilated cervix can no longer support the fetal chorioamniotic membranes, and eventually the membranes stretch and balloon through the cervical opening into the vagina. Occasionally, this ballooning action overcomes the tensile strength of the chorioamniotic membranes and leads to their rupture. Additionally, cervical softening and dilatation may allow the access of microbes into the lower uterine segment.
There are three main structural components of the cervix: smooth muscle, collagen, and the connective tissue “ground substance”. The last is composed of the cervical glycosaminoglycans such as dermatan sulfate, chondroitin sulfate, and hyaluronic acid. Changes that take place in the collagen and in the connective tissue matrix of the cervix appear to be the primary factors allowing the cervix to soften and open in both normal and preterm labor. During pregnancy, dermatan and chondroitin sulfates bind tightly to collagen fibers and secure them in a dense collagen framework that ensures that the cervix remains firm and closed during normal pregnancy. The hyaluronic acid content is believed to play a role in the water retention capacity of the cervical tissue. At the end of pregnancy (or in events leading to premature labor), the cervical structure is completely remodeled so that it becomes soft and easily distensible. Collagen degradation becomes predominant as collagenase and other associated enzymes are activated and cervical dermatan sulfate concentrations diminish, causing disruption of the collagen framework and cervical matrix. The breakdown and loss of collagen and dermatan/chondroitin sulfates increase the flexibility and distensibility of the cervix, while the cervix also becomes swollen, soft and fragile due to increased hyaluronic acid and water content.(8)
With progressive softening, flexibility and distensibility of the cervical tissue, the mechanical support for the overlying chorioamniotic membranes gradually fails, leading to stretching of the fetal membranes in response to uterine activity and an increased risk of PROM. Mechanical stretching of the fetal membranes up-regulates the production of several amniotic factors, including prostaglandin E2 and interleukin-8. Stretch also increases the interstitial collagenases and matrix metalloproteinase- 1 (MMP- 1) within the membranes. (8) Prostaglandin E2 increases uterine irritability, decreases fetal membrane collagen, and increases production of MMP- 1 by human fibroblasts. (9,10) Interleukin-8, which is produced by amniotic and chorionic cells, is chemotactic for neutrophils and stimulates collagenase activity. The production of interleukin-8, which is present in low concentration in the amniotic fluid during the normal second trimester but in much higher concentrations late in gestation, is inhibited by progesterone. These processes leading to the PROM represent an acceleration or exaggeration of normal physiologic process, which in the normal pregnancy lead to a spontaneous rupture of membranes during labor.
There is indirect evidence that genital tract infection precipitates rupture of the membranes in animals and humans. In pregnant rabbits, cervical inoculation with
Escherichia coil
resulted in positive cultures for
E. coli
in the amniotic fluid and decidual tissue of ninety-seven percent of the treated animals and preterm delivery in half of the treated animals, while cervical inoculation of saline in control animals resulted in no infections or preterm births. (11) The identification of pathologic microorganisms in human vaginal flora soon after membrane rupture also support the idea that bacterial infection plays a role in the pathogenesis of premature membrane rupture. (12) Epidemiologic data demonstrate an association between colonization of the genital tract with group B streptococci,
Chlamydia trachomatis, Neisseria gonorrhoeae
, and the microorganisms that cause bacterial vaginosis and an increased risk of preterm premature rupture of the membranes. (13, 14).
Intrauterine infection may predispose women to rupture of the fetal membranes through any of several potential mechanisms, each of which induces degradation of the extracellular matrix. Proteases secreted by vaginal microbes can degrade collagen and weaken the fetal membranes. The host inflammatory response to bacterial infection, which is mediated by polymorphonuclear neutrophils and macrophages that are recruited to the site of infection, causes production of cytokines, matrix metalloproteinases, and prostaglandins. These substances further decrease the tissue support and the tensile strength of fetal membranes and also increase uterine activity, all of which contribute to the eventual rupture of the membranes.
Approximately 70% of premature births occur after PROM or pre-term labor (17). In spite of major advances in the fields of neonatal and perinatal medicine the outcome of PROM in the second or early third trimester is still associated with high mortality and morbidity. A major contributor to these sub-optimal outcomes following PROM is oligohydramnios (an inadequate amount of amniotic fluid surrounding the fetus). Oligohydramnios is a factor in perinatal asphyxia, chorioamnionitis, abruptio placenta, hypoplastic fetal lung, fetal compression abnormalities and amniotic band formation. The gestational age at which the rupture of membranes occurs and the persistence of oligohydramnios after PROM have a profound influence on perinatal outcome
Di Nola-Baron Liliana
Marshall Gerstein & Borun
Page Thurman K.
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