Abstract:
An apparatus for assessing the risk of preterm delivery and the success of induction of labor at term uses a steered ultrasound beam to assess microstructure of the cervix revealed by backscatter power attenuation at a range of angles. It is believed that objective and precise description of cervical microstructure will reveal stage of cervical remodeling an as such may reveal risk of preterm delivery and/or success of labor induction. The backscatter power loss can be combined with elasticity measurements to provide a more precise indication of tissue structure.

Description:
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH 
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     CROSS-REFERENCE TO RELATED APPLICATIONS 
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     BACKGROUND OF THE INVENTION 
     The present invention relates generally to ultrasonic equipment and in particular to an ultrasound machine and method of operating the ultrasound machine to assess cervical structure for the purpose of monitoring a pregnancy. 
     Abnormal cervical behavior contributes to both post-term and preterm pregnancy. With respect to the former, failed inductions of labor cause an increase in cesarean delivery, with longer hospitalizations and greater maternal/neonatal morbidity. Ultrasound prediction (measuring cervical length) and biochemical testing of cervical secretions do not effectively predict which patients at term will have successful inductions. 
     Preterm delivery is an even greater problem, resulting in significant infant mortality and morbidity (including long-term neurodisability) costing more than $26 billion annually in the US alone. Despite intense research, preterm birth rates have increased over the past century in part due to a lack of effective therapies in the face of a greater number of high-risk pregnancies. Drugs that reduce inflammation and/or inhibit uterine contractions do not prevent preterm birth, nor does cerclage (a suture around the cervix to tie it closed). Currently, ultrasound is used to measure cervical length in an effort to predict preterm delivery (associated with shortening). However, the American College of Obstetricians and Gynecologists cautions that the predictive value of this assessment is of uncertain significance because there are no therapies proven to prevent preterm birth. 
     The underlying cause of both post-term delivery and preterm delivery appears to be abnormal cervical remodeling (delayed in the first case, premature or accelerated in the second). Cervical remodeling occurs normally during pregnancy and results in a softening of cervical tissue before cervical shortening. The ability to accurately assess and study cervical remodeling (in an effort to understand normal versus abnormal changes) could provide improved prediction of preterm delivery, guide development of innovative therapeutic strategies, and permit treatment monitoring of those pregnancies, as well as predict which patients will have successful inductions of labor. 
     SUMMARY OF THE INVENTION 
     The present invention provides a method of directly and objectively measuring changes (collagen organization and softening) in cervical microstructure using backscattered ultrasound. The relationship between backscatter and angle can reveal the shape of microstructural scatterers, for example collagen within the cervix, whose reorganization is believed to be fundamental to cervical remodeling. This ultrasonic measurement of microstructure may be combined with an ultrasonic elasticity measurement (of softening) to produce a diagnostic tool for preterm delivery as well as for prediction of successful induction of labor. 
     Specifically then, the present invention provides a method of assessing cervical remodeling in pregnancy by applying an ultrasonic beam to the tissue of the cervical canal at a plurality of angles with respect to an axis of the cervix. Received echo signals are used to determine backscatter of the ultrasonic beam at the angles and processed to determine a relationship between angle and backscatter indicative of cervical remodeling. A measurement based on this relationship is output to an operator. 
     It is thus a feature of one embodiment of the present invention to assess cervical remodeling by measurement of small structures within cervical tissue. 
     The process of deducing the relationship between angle and backscatter may compensate for system-based, angle-related sensitivity of the ultrasound machine. 
     It is thus a feature of at least one embodiment of the invention to boost the sensitivity of the measurement by compensating for instrument-based backscatter variations. 
     The determination of the relationship between backscatter and angle may compare backscatter power over a range of frequencies at different angles. 
     It is thus a feature of at least one embodiment of the invention to provide a more robust measurement by evaluating multiple ultrasonic frequencies. 
     The determination of the relationship between backscatter and angle may combine backscattered data taken at symmetrical positive and negative angles about a normal to the cervical wall. 
     It is thus a feature of at least one embodiment of the invention to accentuate backscatter caused by microstructure such as should be symmetrical. 
     The plurality of angles may be within a plane containing the axis of the cervix and centered on a perpendicular to that axis and/or may be within a plane normal to the axis of the cervix and centered on a perpendicular to that axis. 
     It is thus a feature of at least one embodiment of the invention to permit multiple measurements of tissue of different microstructure orientations hypothesized to exist in the cervical wall. 
     An embodiment of the invention may include the step of measuring elasticity of the cervical tissue so that the output measurement may be a combination of elasticity and the relationship between backscatter and angle. 
     It is thus a feature of at least one embodiment of the invention to better differentiate between backscatter caused by tissue scatterer size and backscatter caused by cross-linking. 
     The elasticity may be obtained through acoustic radiation force impulse (ARFI) measurement. 
     It is thus a feature of at least one embodiment of the invention to provide a simple method of elasticity measurement that does not require compressive movement of the transducer or an independent compression probe, permitting use of an ultrasonic transducer within the cervical canal. 
     The ultrasonic transducer may have a diameter substantially less than 5 mm. 
     It is thus a feature of at least one embodiment of the invention to provide a probe that may be easily inserted into the cervix without substantially dilating the tissue to be measured. 
     The measurement may provide an indication of a likelihood of preterm delivery or an indication of likely due date. 
     It is thus a feature of at least one embodiment of the invention to provide simple metrics to a physician related to important information about a pregnancy. 
     These particular objects and advantages may apply to only some embodiments falling within the claims, and thus do not define the scope of the invention. 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         FIG. 1  is a simplified cross-sectional view of the uterus showing the cervical canal and an ultrasonic probe suitable for use with the present invention positioned within the cervical canal; 
         FIG. 2  is a perspective and side elevational view of the probe of  FIG. 1  showing axial transducers for steering an ultrasonic beam at a range of axial angles within the cervix; 
         FIG. 3  is a figure similar to that of  FIG. 2  providing a perspective and end elevational view of the probe of  FIG. 1  showing circumferential transducers for steering an ultrasonic beam at a range of circumferential angles; 
         FIG. 4  is an exaggerated fragmentary cross-sectional view of the cervical tissue showing a hypothesized organization of collagen in the cervical tissue early in pregnancy; 
         FIG. 5  is a block diagram of an ultrasound machine suitable for use with the probe of  FIGS. 1-3  including a processor executing a stored program to process data used in the present invention; 
         FIG. 6  is a flowchart of the program used in the processor of  FIG. 5 ; 
         FIG. 7  is a plot of backscatter power spectra at different beam angles showing a decrease in backscatter power at increased angles as a function of frequency; 
         FIG. 8  is a plot of backscatter as a function of angle for center frequencies of 9 MHz for cervical tissue and for a phantom with spherical scatterers; 
         FIG. 9  is a side elevational view of the probe of  FIG. 1  in the cervix showing the excitation of shear waves from a “pushing pulse” emitted by the probe in quantitative acoustic radiation force impulse measurements; 
         FIG. 10  is a simplified model relating backscatter loss and elasticity to empirically derived preterm risk boundaries; 
         FIG. 11  is an example output displayed for the ultrasound machine of  FIG. 5  depicting a risk of preterm delivery in simplified fashion; 
         FIG. 12  is a graphical display of a backscatter power image for investigational study; 
         FIG. 13  is a graphical display representing a model of backscatter measurements during a normal pregnancy superimposed on measurements from a particular patient used for predicting due date or making decisions about delivery; 
         FIG. 14  is a figure similar to that of  FIG. 11  showing a simplified display indicating concurrence between a given pregnancy and a statistically normal pregnancy; and 
         FIG. 15  is a perspective representation of a handheld device for implementing the present invention. 
     
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT 
     Referring now to  FIG. 1 , the present invention provides an ultrasound probe  10  having a generally cylindrical body  12  that may fit within the cervical canal  14  of the uterus  16  to extend along the uterine and cervical axis  17  and to be surrounded by cervical tissue  18 . In a preferred embodiment, the cylindrical body  12  has an outside diameter substantially less than 5 mm so as to fit within the cervical canal without substantial dilation of the cervical tissue  18 . 
     Referring now to  FIG. 2 , the outer surface of the cylindrical body  12  provides an axial transducer array  20  extending along the cylindrical body  12  and generally aligned with the axis  17  when the ultrasound probe  10  is within the cervical canal  14 . The axial transducer array  20  has a plurality of independently operating transducer elements  22  that may provide for beam steering of a type known in the art. In particular, an ultrasonic beam  24  may be generated and steered over a range of axial angles  26  lying generally within a plane containing the axis  17  and symmetric about a center axis  28  perpendicular to axis  17 . In the preferred embodiment, a range of ±20° is obtained. A beam  24   a  at one angular extreme and  24   b  at the other angle extreme can alternatively illuminate a voxel  30  of the cervical tissue  18  so that backscatter  32   a  or  32   b  at these two angular extremes and a range of angles in between may be collected by the same axial transducer array  20 . 
     Referring to  FIG. 3 , a circumferential transducer array  34  may optionally be provided crossing the axial transducer array  20  at right angles and arranged around the circumference of the cylindrical body  12  to allow for beam steering of ultrasonic beam  38  within a range of angles  36  in a plane normal to the axis  17  and symmetric about the center axis  28 . In this way, the voxel  30  may also be illuminated by beams  38   a  and  38   b  over the range of angles  36  and backscatter detected at the cylindrical body  12 . 
     In one embodiment, the transducer array may provide for 7.5 MHz operation with  64  array elements at 100 μm pitch. It will be understood that a two dimensional transducer array having multiple perpendicular rows and columns can be used instead of the cruciform array described above to provide measurements of the ranges of both angles  26  and  36 . 
     Referring now to  FIG. 4 , while the inventors do not wish to be bound by a particular theory, it is believed that the cervical tissue  18  is comprised of at least two layers of collagen-based tissue including an inner layer  40   a  and an outer layer  40   b . The inner layer  40   a  may contain collagen fibers  42  arranged parallel to the axis  17  that may be measured by the beams  24  produced by the axial transducer array  20 , whereas the outer layer  40   b  may contain collagen fibers  44  arranged circumferentially about axis  17  to be measured by the beams  38  produced by the circumferential transducer array  34 . 
     Referring now to  FIG. 5 , the ultrasound probe  10  may communicate via a flexible cable  46  with an ultrasound machine  48  of the type generally known in the art including, for example, a digital signal processor  60  receiving ultrasonic data and generating ultrasonic output signals, in turn communicating with a standard computer processor  50  executing a program  52  contained in memory  51  to implement the present invention. Generally, the ultrasound machine  48  may also communicate with the display terminal  56  for the outputting of data and a user data entry device  58  such as a keyboard or the like to control operation of the ultrasound machine and to input data according to techniques well known in the art. 
     Generally phased ultrasonic signals will be created by a digital signal processor  60  under instructions from the processor  50  and transmitted along cable  46  to the transducer arrays of the ultrasound probe  10  to create ultrasonic beams at desired angles and to measure backscatter therefrom. The backscatter signals will be received by ultrasound probe  10  and transmitted through cable  46  to the digital signal processor  60  for analysis by the program  52 , the results of which may be displayed on the terminal  56  as will be described. 
     Referring now to  FIG. 6 , at a first step of the program  52  indicated by process block  62 , ultrasonic beams are generated either axially or circumferentially or both, at a range of frequencies, and backscatter acoustic power from those beams is measured by the ultrasound probe  10  for analysis. 
     Referring now to  FIG. 7 , backscatter information obtained over a range of frequencies at a range of angles provides multiple power spectra  64   a  and  64   b . In this figure, power spectrum  64   a  is taken normal to the cervical wall along the center axis  28  exhibiting the highest degree of backscatter and power spectrum  64   b  is a combination (averaging) of the power spectra obtained at the extreme angles of the beam angulation (i.e. ±20°). Because the tissue structure effects intended to be measured will be symmetric about center axis  28 , this averaging process provides for improved signal-to-noise ratio in the measurement while rejecting asymmetrical effects. Multiple additional power spectra may optionally be obtained at different angles. 
     In a preferred embodiment, the axial transducer array  20  is used to obtain measurements of backscatter at shallow voxel depths corresponding to layer  40   a  of  FIG. 4 , and circumferential transducer array  34  is used to obtain power spectra at deeper voxel depths corresponding to layer  40   b  of the tissue  18 . 
     In a simple embodiment, backscatter at each depth may be characterized by these two power spectra  64   a  and  64   b  by establishing a noise floor  66 , representing the lowest signal strength of the power spectrum for either of the spectra  64   a  or  64   b  and determining a 10 db limit  68  above this noise floor  66  used to define upper and lower frequency limits  70   a  and  70   b  of the power spectra  64   a  and  64   b . Between these limits  70   a  and  70   b , the area under each of the spectra  64   a  and  64   b  is integrated (for example, from frequencies from 3 to 9 MHz). The resultant backscatter power measurement at the extreme angles ( 64   b ) is compared to the backscattered power  64   a  at zero-degree steering angle (perpendicular to the cervical axis  17 ). 
     This measured-backscattered power value is then compared to a machine-backscattered power value (not shown) resulting from machine specific features, for example, the effective reduction in ultrasound aperture with angle caused by geometrical considerations and a decrease in the sensitivity of the axial transducer array  20  and circumferential transducer array  34  with angle, both of which cause an machine-dependent apparent loss in backscatter power. The machine specific backscattered power value may be determined by the use of a phantom containing spherical isotropic scatterers. This machine-backscattered power value may be computed for each measurement from a stored power spectrum (not shown) using the same integration limits  70   a  and  70   b  described above. The measured-backscattered power value is corrected by the machine-backscattered power value to reveal the excess backscattered power loss caused by structure of the cervical tissue  18 . This latter excess-backscattered power loss value from each of the axial transducer array  20  and circumferential transducer array  34  may be weighted and combined or displayed individually to the user through the graphic terminal  56  or may be further processed as will be described further below. 
     Referring now to  FIG. 8 , an alternative measurement of backscatter computes received backscatter power curves  71  as a function of one or more frequencies at multiple angular measurements  72  for both the phantom described above and the cervical tissue  18 . A difference in slope of these curves  71  provides the excess-backscattered power loss value that may be displayed to the user as above. 
     Referring again to  FIG. 7 , an alternative measurement parameterizing backscatter, such as the backscatter coefficient, effective scatterer size, integrated backscatter, mean scatterer spacing or number of scatterers per unit volume could be derived from these angle-dependent power spectra and used to describe the cervical tissue in greater detail. 
     Alternatively, in any of these cases, the angle related excess-backscattered power loss, or related parameter, as quantified (in one or more dimensions) may be applied to an empirically-derived model that may include additional input parameters entered by the user, for example, conception date, cervical length, age of the patient and other data. The model then provides a statistically founded output related to fundamental information desired by the physician, for example risk of preterm delivery, or state of the cervix with respect to a state for successful delivery as will be described below. 
     In a preferred embodiment the excess-backscattered power loss is combined with elasticity data for the same tissue. The elasticity data augments the backscatter data to better distinguish among microstructure with similar backscattering but different elasticities. While the applicant does not wish to be bound to a particular theory, it is believed that backscatter power loss is increased when the beam encounters anisotropic tissue such as exists in the unripened cervix in comparison to when the beam encounters isotropic tissue in the ripened cervix. This unripened tissue appears to be made up of organized, cylindrical microstructures. At normal incidences (that is, when the cylinder axes of the microstructures are perpendicular to the propagation axis of the ultrasonic wave) a cylinder that is small compared to the acoustic wavelength (as is expected to be the case with collagen structures in the cervix) creates a backscattering that can be explained primarily in terms of resonances related to elastic circumferential waves. However, a wave that encounters a cylinder at a non-normal angle to its axis (either positive or negative angle) excites both longitudinal and circumferential modes of vibration increasing power loss. The extent of the power loss, therefore, can reveal the degree of organization of the tissue. 
     Backscatter, however, will be similar for long cylindrical fibers that are cross-linked and short cylindrical fibers with no cross-linking. Accordingly, elasticity can be used to resolve these two cases with the longer fibers that produce generally a stiffer and less elastic tissue distinguished by their elasticity from the shorter fibers. 
     Referring now to  FIG. 9  and as shown by process block  61  of  FIG. 6 , the ultrasound probe  10  may be used to measure not only the backscatter as described above, but also the elasticity of the tissue  18  by using the technique of quantitative acoustic radiation force impulse (qARFI). In this technique, a focused compression “push wave”  80  is generated generally along center axis  28  which produces incidental shear waves  82  passing through the tissue  18  generally parallel to the axis  17 . B-mode imaging pulses  84  may be used to detect the tissue displacement caused by the shear waves  82  and track a crest of those waves to determine shear wave velocity such as is proportional to Young&#39;s modulus, a measure of elasticity. Tools for qARFI and are available from Siemens under the trade name ACUSON S2000 (Virtual Touch Tissue Quantification). 
     Referring to  FIG. 10 , a model  90  may be generated (in this case depicted as a 3-dimensional surface) that takes backscatter power loss and shear wave sound speed as inputs to provide an output point  92  on a model surface empirically linked to risk of preterm delivery. As indicated by the  FIG. 11 , this output point  92  may be mapped to a simple scale  94  depicting risk of preterm delivery relative to broad categories, for example high-risk, medium risk, and low risk, and/or a numeric output  96  may be provided providing the same information, for example, as a percentage. The model may incorporate additional input dimensions as described above, such as gender, conception date, and the like, such multidimensional models providing a multidimensional surface not readily depicted. 
     Referring to  FIG. 12 , elasticity data and backscatter data may also be displayed as an image  97  in the manner of a conventional B-mode image or superimposed on a B-mode image to characterize different portions of the cervical tissue in the image. In this way, the phenomenon of graduated ripening of the cervix from the proximal to distal portions may be studied. 
     Referring now to  FIG. 13  and as shown by process block  107  of  FIG. 6 , it will be understood that the measured data of backscatter and/or shear wave sound speed may also be used to evaluate the course of pregnancy, for example, by the generation of boundaries  100  indicating the state  102  of remodeling of the cervix, for example, at the time of a standard vaginal delivery in a sampled population together with data from an individual patient, assisting the physician in assessing a due date and or appropriate time for induced labor for delivery. Again, as shown in  FIG. 14  and process block  109  of  FIG. 6 , the data of the model of  FIG. 13  may be extracted to a simple display  104  having zones  106  showing degrees of remodeling of the cervix for delivery and providing a quantitative output  108  for the physician. 
     Referring to  FIG. 15 , although the present invention may be incorporated into a standard imaging ultrasound machine providing B-mode imaging capabilities, the present invention may also be provided in a portable stand-alone instrument  110  in which the ultrasound probe  10  may connect to a handheld unit  112  providing a simple graphic display  114  and as little as a single activation button  116 , and preprogrammed to make the measurements of the present invention. 
     It is specifically intended that the present invention not be limited to the embodiments and illustrations contained herein, but include modified forms of those embodiments including portions of the embodiments and combinations of elements of different embodiments as come within the scope of the following claims. For example, the invention does not require a cervical probe but conceivably could be done transabdominally.