In vivo Raman spectroscopy monitors cervical change during labor

Abstract

Background: Biochemical cervical change during labor is not well understood, in part, because of a dearth of technologies capable of safely probing the pregnant cervix in vivo. The need for such a technology is 2-fold: (1) to gain a mechanistic understanding of the cervical ripening and dilation process and (2) to provide an objective method for evaluating the cervical state to guide clinical decision-making. Raman spectroscopy demonstrates the potential to meet this need, as it is a noninvasive optical technique that can sensitively detect alterations in tissue components, such as extracellular matrix proteins, lipids, nucleic acids, and blood, which have been previously established to change during the cervical remodeling process.

Objective: We sought to demonstrate that Raman spectroscopy can longitudinally monitor biochemical changes in the laboring cervix to identify spectral markers of impending parturition.

Study design: Overall, 30 pregnant participants undergoing either spontaneous or induced labor were recruited. The Raman spectra were acquired in vivo at 4-hour intervals throughout labor until rupture of membranes using a Raman system with a fiber-optic probe. Linear mixed-effects models were used to determine significant (P<.05) changes in peak intensities or peak ratios as a function of time to delivery in the study population. A nonnegative least-squares biochemical model was used to extract the changing contributions of specific molecule classes over time.

Results: We detected multiple biochemical changes during labor, including (1) significant decreases in Raman spectral features associated with collagen and other extracellular matrix proteins (P=.0054) attributed to collagen dispersion, (2) an increase in spectral features associated with blood (P=.0372), and (3) an increase in features indicative of lipid-based molecules (P=.0273). The nonnegative least-squares model revealed a decrease in collagen contribution with time to delivery, an increase in blood contribution, and a change in lipid contribution.

Conclusion: Our findings have demonstrated that in vivo Raman spectroscopy is sensitive to multiple biochemical remodeling changes in the cervix during labor. Furthermore, in vivo Raman spectroscopy may be a valuable noninvasive tool for objectively evaluating the cervix to potentially guide clinical management of labor.

Keywords: biochemical; induction; labor management; optical; preterm labor; spectroscopy; technology.

Figure 1.. In vivo Raman spectroscopy fiber optic probes for cervical monitoring during labor.

a) Speculum-based optical probe used at the start of the study. b) Speculum-free optical probe developed during the course of the study and used for subsequent measurements.

Figure 2.. Spectral model of cervical change as a function of time to delivery.

a) Model fit to the study population using a restricted cubic spline with 65 degrees of freedom. Shaded boxes indicate spectral features that contribute significant variability with time to delivery based on LASSO analysis and correspond to important biochemical components known to be present in the cervix. Blue arrows indicate decreases, while purple indicates increases and red indicates a shift in peak center location. b-d) Insets show features of interest which are included in the analysis in Figure 4.

Figure 3.. Representative patient spectra acquired at various time points during labor.

a-c) Patients who underwent induction of labor. d) Patient who presented in spontaneous labor as determined by the admitting provider.

Figure 4.. Linear mixed effect models of the change in peak ratios as a function of time to delivery and effacement in the study population.

a-c) Linear mixed effects model of the spectral ratio as a function of time to delivery. d-f) Linear mixed effects model of the spectral ratio as a function of cervical effacement as determined by the provider on bimanual exam. g-i) d-f) Linear mixed effects model of the spectral ratio as a function of cervical dilation as determined by the provider on bimanual exam. Based on spectra from 21 patients

Figure 5.. Non-negative least squares biochemical model of change in pure components over time.

a-c) Linear mixed effect model of the coefficient value assigned to each component as a function of time to delivery. d) Representative patient spectrum with model fit and residual. Based on spectra from 21 patients.

Figure 6.. Spectra of pure components included in non-negative least squares biochemical model.