Uterine electromyography and light-induced fluorescence in the management of term and preterm labor.

OBJECTIVE: Understanding the physiology of the uterus and cervix during term and preterm parturition is crucial for developing methods to control their function and is essential to solving clinical problems related to labor. To date, only crude, inaccurate, and subjective methods are used to assess changes in uterine and cervical function in pregnancy. METHODS: In the past several years, we have developed noninvasive methods to quantitatively evaluate the uterus and cervix based on recording of uterine electrical signals from the abdominal surface (uterine electromyography) and measurement of light-induced fluorescence (LIF) of cervical collagen (Collascope), respectively. Both methods are rapid and allow immediate assessment of uterine contractility and cervical ripening. RESULTS: Studies in animals and humans indicated that uterine and cervical performance can be monitored successfully during pregnancy using those approaches and that these techniques can be used during labor to better define management in a variety of conditions associated with labor. CONCLUSION: The potential benefits of the proposed instrumentation and methods include reducing the rate of preterm delivery, improving maternal and perinatal outcome, monitoring treatment, decreasing cesarean rate and providing research methods to understand uterine and cervical function.

Methods and devices for the management of term and preterm labor.

In this review, we outline studies showing that the uterus (myometrium) and cervix pass through a conditioning step in preparation for labor. This step is not easily identifiable with present methods designed to assess the uterus or cervix. In the uterus, this seemingly irreversible step consists of changes in the electrical properties that make muscle more excitable and responsive and produce forceful contractions. In the cervix, the step consists of softening of the connective tissue components. Progesterone and nitric oxide appear to have important roles in these processes. The progress of labor can be assessed noninvasively using electromyographic (EMG) signals from the uterus (the driving force for contractility) recorded from the abdominal surface. Uterine EMG bursts detected in this manner characterize uterine contractile events during human and animal pregnancy. A low uterine EMG activity, measured transabdominally throughout most of pregnancy, rises dramatically during labor. EMG activity also increases substantially during preterm labor in humans and rats and may be predictive of preterm labor. A quantitative method for assessing the cervix is also described. A collascope estimates cervical collagen content from a fluorescent signal generated when collagen crosslinks are illuminated with an excitation light of about 340 nm. The system has proved useful in rats and humans at various stages of pregnancy and indicates that cervical softening occurs progressively in the last one-third of pregnancy. In rats, collascope readings correlate with resistance measurements made in the isolated cervix, which may help to assess cervical function during pregnancy and indicate controls and treatments.

Inhibition of cervical ripening by local application of cyclooxygenase 2 inhibitor.

OBJECTIVE: Our goal was to test the hypothesis that the previously demonstrated progesterone-independent prolongation of pregnancy in rats treated with cervical application of the cyclooxygenase 2 inhibitor nimesulide is the result of inhibition of cervical ripening. STUDY DESIGN: Timed-pregnant Sprague-Dawley rats were randomly allocated to treatment with 50 mg nimesulide or vehicle, applied daily on the cervix for 5 days (days 14-18). On day 19 the animals were humanely killed and the cervices were removed. In the first series of experiments the cervices of animals treated with nimesulide (n = 10) or vehicle (n = 10) were examined with a cervimeter, which stretches the cervical tissues in incremental steps of 0.2 mm at 1-minute intervals. A steeper slope through the linear portion of the resulting force-versus-displacement curve indicates more resistance to stretch. In the second series of experiments the cervices of animals treated with nimesulide (n = 11) or vehicle (n = 11) were examined with the Collascope optical device. The cervical content of cross-linked collagen was measured with light-induced fluorescence. The fluorescence spectrum at 390 nm (peak wavelength of the collagen spectrum) was determined. For standardization, the ratio of counts of collagen peak over reference counts was used in the final analyses as an indicator of cross-linked collagen content. RESULTS: Animals treated with cervical application of nimesulide had significantly higher resistance to stretch than controls (slope: 0.2564 +/- 0.1213 vs 0.1387 +/- 0.0652; P =.019). The cervical content of cross-linked collagen was not significantly different between nimesulide-treated animals and controls (light-induced fluorescence ratios: 3.2134 +/- 0.7390 vs 2.7892 +/- 0.8518; P =.227). CONCLUSIONS: Treatment with cervical application of the cyclooxygenase 2 inhibitor nimesulide prevents the physiologic process of cervical ripening in late pregnancy. The inhibition is not the result of changes in cross-linked collagen content. Inhibition of cervical ripening with locally administered cyclooxygenase 2 inhibitor may be a potentially valuable treatment for patients at risk for preterm delivery.

Changes in light-induced fluorescence of cervical collagen in guinea pigs during gestation and after sodium nitroprusside treatment.

Light-induced fluorescence (LIF) of collagen was used to investigate in vivo changes in cervical collagen in guinea pigs during gestation and following sodium nitroprusside treatment. Natural fluorescence of collagen is due to collagen cross-linking molecules that connect single collagen fibers and therefore provide rigidity of the cervical stroma. LIF of cervical collagen was measured from the surface of the exocervix in anesthetized nonpregnant and timed pregnant guinea pigs at different times of gestation with an instrument designed in our lab (Collascope). Measurements were also performed in guinea pigs at midgestation before and 8 hours after intracervical treatment with sodium nitroprusside. Collagen fluorescence decreased significantly as pregnancy progressed, reached lowest values at delivery, and increased gradually postpartum. Treatment with sodium nitroprusside, but not with the vehicle, caused a significant decrease in LIF (p = 0.007). We conclude, that LIF changes in the cervix reflect the gradual cervical softening (ripening) during pregnancy and the return to the rigid state of the cervix postpartum. Cervical softening during pregnancy, and after sodium nitroprusside treatment, is associated with a decrease in collagen cross-links. Measurements of LIF can be used to investigate cervical softening in vivo.

Origin of cervical collagenase during parturition.

Cervical biopsy specimens were obtained under standard conditions from the posterior lip of the uterine cervix in 105 patients. A significant increase of collagenase activity was observed during parturition as determined with an assay with iodine 125-labeled native triple-helical collagen type I as the substrate. The collagenase was not likely to originate from cervical fibroblasts because in situ hybridization failed to detect synthesis of the specific procollagenase messenger ribonucleic acid. However, migration of polymorphonuclear leukocytes into the cervical stroma occurred on onset of labor, and an antibody specific for human leukocyte collagenase that did not cross react with fibroblast collagenase revealed the presence of the enzyme in the granules of polymorphonuclear leukocytes and subsequently in the extracellular matrix of the cervix. Therefore it is likely that the cells critically involved in collagen degradation during cervical dilatation are not resident fibroblasts but rather polymorphonuclear leukocytes emigrating from blood vessels.

Collagenase activity in the human cervix uteri after prostaglandin E2 application during the first trimester.

Cervix biopsies were obtained during the first trimester from plurigravidae and primigravidae at various times after intracervical application of prostaglandin E2. The tissues were extracted with Ca(2+)-containing buffer, and collagenase activity was determined in these extracts using a solid phase assay in which triple helical 125I-labelled collagen was cleaved. Collagenase was detected in all samples but elevated activity was present only during a short temporal window after prostaglandin application. Maximal activity was observed 1 and 2 h after application of prostaglandin in multigravidae and 4 h in primigravidae. These data can explain why collagenase activity in cervical tissues after prostaglandin application had previously not been found. They indicate somewhat different mechanisms of cervical ripening in primigravide compared to multigravidae.

Collagenase activity in the cervix of non-pregnant and pregnant women.

Cervical biopsies were obtained from non pregnant patients and from pregnant at various stages of gestation and during labour. The tissues were extract with a Ca(++)-containing buffer, and collagenase activity was determined in these extracts using a solid phase assay in which triple helical 125I-labelled collagen was cleaved. Collagenase was detected in all samples but significantly elevated activity was only present in labour at 6-8 cm cervical dilatation. This provides direct evidence for the crucial role of specific collagen degradation during cervical ripening and dilatation.