THE TECHNOLOGY PIPELINE

What's in the technology pipeline?

By Yona Tadir, MD

Out of Israel come several potentially useful ob/gyn devices, the development of which is being sponsored in part by the government's Chief Scientist Office.

Practicing obstetrics and gynecology is completely different today than it was only 10 to 20 years ago. In 2004, making babies in vitro is commonplace; preimplantation genetic diagnosis rarely makes headline news; and ultrasound scanning is routine. Minimally invasive surgery has now replaced many major surgical procedures and has moved to outpatient surgery centers; compact imaging devices that are capable of making sophisticated analysis in small clinics have changed the structure of patient referral to hospitals, and heavy-duty scanners such as MRI, PET, and CT, are moving from one parking lot to another.

The future looks even more exciting as surgical procedures become better controlled and documented, and patients' medical data are better managed and communicated electronically. Israel is one of several countries at the forefront in this technological adventure. We have developed an "incubator" system here that supports innovative ideas with seed funding. Each project is granted partial funding by the government's Chief Scientist Office, and most projects are located in remote regions to stimulate and support growth on the periphery.

Each site focuses on 10 to 15 projects/companies, and following a careful review process, seed funding to cover up to 80% of costs is granted for a period of 2 to 3 years.

This kind of creative atmosphere has even triggered development of innovative medical devices by groups that are not funded by the government-supported incubator system.

My goal here is to highlight some of the potentially useful ob/gyn devices that have come out of this supportive environment. Some of the devices remain investigational and are undergoing pre-approved clinical trials. Others are further along in the pipeline. Of course, as Dr Isaacson pointed out in last year's Technology issue: "Just because we can, doesn't mean we should."¹ With that in mind, we expect that careful clinical trials will have to be done before most of the products discussed below are put into widespread clinical use.

Computerized labor monitoring

There haven't been any significant changes in this field since the introduction of electronic monitoring of pregnancy and delivery some 30 years ago. Nonstress test (NST) and cardiotocography (CTG) are still the gold standards for collecting information on the well-being of the fetus—and some experts even question the importance of these tools.² But new tools currently under development and clinical evaluation may change our ability to predict pregnancy outcomes, including fetal ECG monitoring, computerized labor monitoring, and home telemedicine.³

Despite advances in modern childbirth technology, it is still impossible to obtain accurate measurements of cervix dilatation and the progress of the fetal descent through the birth canal. The imprecise manual methods currently used to estimate these factors can cause mothers hours of unnecessary suffering, increase the risk of infection for mother and fetus, substantially increase the rate of labor complications, and waste hospital resources.^4-6 In contrast, objective detection of these parameters can prevent labor complications, shorten the delivery process, mitigate the risk of malpractice, and deliver significant cost savings.

Preliminary data suggest that Barnev's Computerized Labor Monitoring system (CLM) will enable obstetricians to base decisions on accurate and timely information (Figure 1). CLM uses ultrasound technology to calculate the distance between the device's sensors. The system monitors cervical dilatation by transmitting ultrasonic waves from transducers placed on the abdomen to receivers affixed safely and painlessly to the mother's cervix. Thus, cervical dilatation is accurately monitored continuously and automatically, reducing the need for manual examinations.

Similarly, sensors affixed to the fetal crown and at external anatomical locations enable accurate monitoring of fetal head descent. In most hospitals, the attachment of an electrode to the crown of the baby's head (as soon as it is accessible) to detect heart rate or even ECG is common and the CLM sensors can be incorporated within this protocol.

Data from the CLM system provide the staff with what they need to determine normal labor progression, which may allow simple and cost effective labor management for most deliveries. Fewer vaginal examinations may reduce the infection rate, which of course has been correlated with the number of vaginal examinations performed during labor.

The system's ongoing data collection may also help the medical team to improve their decision-making process and allow an early and objective evaluation of the lack of labor progress. The system records and archives cervix dilatation and head station and provides valuable documentation for any future litigation.

To date, the system has been used successfully in over 120 births, and is currently being clinically tested at two major United States institutions (IDE granted and IRB approved).

Home fetal monitoring and telemedicine

The PMG/Nano Medica's Babycom, which is based on piezo-micromechanics technology, enables pregnant patients to keep track of fetal heart rate at home. Unlike the diagnostic devices offered to professionals for diagnostic or imaging purposes, the device is relatively inexpensive. It's also mother-friendly: It weighs about 10 oz and has a built-in scanner with a wide-angle ultrasound beam that allows patients to detect beats quickly and easily (Figure 2).

The exact role of this device in patient management has yet to be defined, but preliminary experience shows that whenever a pregnant woman has any doubt regarding the welfare of her fetus, she can use it at her own convenience and get in touch with her ob/gyn if she has concerns. The FHR is visible on a digital display.

Because the device generates ultrasound waves that are six times lower than permitted limits, it's safe for patients to use and is FDA-approved for use with a doctor's prescription.

"Smart" fetal monitoring

PMG Medica has also developed a "smart" monitor, likewise based on the company's piezo-micromechanics technology. Weighing only 0.4 kg, this low-cost device is one of the most lightweight PC-based fetal monitors currently available (Figure 3). The fully computerized monitor with high-performance U/S scanning technology can be used in the patient's home, in the office or hospital, for ambulatory monitoring, and for home telemedicine as a wireless system. The company says that it contains a high-performance proprietary scanning probe with options to include additional clinical parameters such as oxygen concentration.

The concept of remote sensing of uterine contractions to prevent premature labor was tested several years ago, and was abandoned. This new concept, which offers complete NST from the patient's home, may be integrated with other home telemedicine services to monitor high-risk patients who otherwise would have to be admitted to an antenatal clinic for observation. The device may also be of value during home births, which are usually performed without maternal/fetal monitoring. The system can be hooked up to any desk or laptop computer.

Changes in minimally invasive gynecologic surgery

Intrauterine and cervical procedures are currently being performed by traditional blind techniques, based on the surgeon's experience and his or her "feel" through manual manipulation of surgical instruments over the uterine walls. Curettage or evacuation of the uterine cavity for diagnostic and/or therapeutic purposes, endometrial tissue sampling, and removal of an endometrial polyp all fall into this category. Unfortunately, if the surgeon incorrectly assesses the position or size of the uterus, uterine perforation can occur.

Safe-T-Choice (STC), developed by Ron-Tech Medical, couples a transvaginal ultrasound probe with a specially designed cervical holder (tenaculum) by means of a disposable adaptor (Figure 4). This enables real-time ultrasound imaging and guidance of various intrauterine surgical procedures. STC mates the vaginal probe in a long-axis projection, connects the cervix holder and the transvaginal U/S transducer to form a single coupled device, and allows the free movement required during surgical maneuvers.

The sonographic field of view shows continuous real-time images of the uterus during all stages of the surgical procedure. The device allows the physician to perform the procedure with the help of U/S monitoring.

In a recent study, the STC system was used to guide various surgical intrauterine procedures in 45 patients, performed by nine gynecologists at NYU hospital.⁷ The procedures were completed successfully without any complication. Between 83% and 90% of the surgeons involved in the experiment felt the technique increased safety and accuracy for the parameters that were evaluated. Fewer intrauterine instrument manipulations were required, and in 85% of the cases, the exact surgical site was more accurately detected. The authors concluded that the Safe-T-Choice made the operation safer by providing high-resolution images of the cervical canal and the uterine cavity during all stages of the procedure, and by improving visualization of the precise surgical site.

Getting surgeons to change their habits is no easy task, but the conversion from "blind" to "visible" likely will sway many of them to take up this new approach. The new system is FDA-approved and is currently being tested in various sites in the US, Europe, and Israel.

Active vaginal tampons

Rostam Ltd., in collaboration with a group of scientists and clinicians from the Hebrew University and Hadassah Medical School in Jerusalem, has developed a novel bi-functional tampon. The tampon absorbs menstrual discharge like any other conventional menstrual tampon but also uses controlled-release drug delivery technology to deliver various natural active substances by means of polymeric strips. The tampon's appearance and mechanism of action are the same as any other regular plastic applicator tampon.

The first product using this novel technology is a pH tampon that neutralizes the elevation in vaginal pH that normally occurs during menstruation. As menstrual fluid is absorbed, the strips in the tampon release a mixture of citric and lactic acids. The safety and efficacy of the new tampon was demonstrated in two double- blind, placebo-controlled clinical trials that enrolled 30 healthy volunteers in each study.⁸ Among women using a regular tampon, mean vag-inal pH increased during menstruation from 4.76 to 5.08 (P=0.0011). In a second unpublished study, mean vaginal pH in the active tampon users was maintained at 4.5 (elevated from pre-menses value of 4.1) while the mean vaginal pH in the regular tampon users increased from 4.1 premenstrually to 5.2 during menstruation (P=0.02). None of the subjects had significant reactions to the pH tampon in either trial.

Determining the cause of vaginal discharge

There is no specific test to distinguish between vaginal discharge, amniotic fluid, urine, or leakage from other causes, and hospitals usually don't have simple devices to continuously monitor for intermittent amniotic leaks. Two recently developed diagnostic pantiliner kits called VI-SENSE and AL-SENSE are available from a company called Common Sense (Figure 5).

Both kits are based on a yellow indicator strip, which indicates abnormal pH of vaginal fluids. The VI-SENSE stains blue whenever pH is elevated above normal or the buffer capacity is low. A very fine-tuned dynamic range of reaction to the two acidity parameters results in more than 90% sensitivity in detecting bacterial and parasitic infections. The test strip has a specificity of 84%.⁹

The AL-SENSE stains blue whenever the pH of the fluid exceeds 5.2, which can help identify amniotic leaks. Urine wetness causes a blue-green stain, which vanishes completely after drying for 10 minutes, thus acting as a negative control, and resulting in 100% sensitivity to amniotic leaks that reach the indicator.

The core technology is based on four unique features of the polymers: (a) the plasticizer component maintains high elasticity and negligible leaching; (b) another additive prevents the drift of the color changes, and keeps them stable for over 48 hours; (c) the permeability is calibrated to react to low-buffer capacities, so that a stain will be created at a range of pH levels and buffer capacities; (d) the unique composition of the polymer matrix causes any stain created by fluids with a high concentration of ammonia to reverse within 10 minutes of drying.

A total of 109 valid cases were enrolled in a clinical study to evaluate the effectiveness of the VI-SENSE. Results for the new device were compared with those of conventional vaginal swabs for Trichomonas and Candida from the same women. The clinical study found that the VI-SENSE's acidity parameters resulted in more than 90% sensitivity and 84% specificity in detecting bacterial and parasitic infections.

Once the regulatory process has been completed, these new polymer-based pads may assist clinicians in detecting bacterial and parasitic infections, as well as distinguishing between amniotic fluid leakage, urine, or infectious discharge.

A new approach to stress urinary incontinence

Among the conservative approaches to SUI are absorbents and pelvic floor physiotherapy. Unfortunately, patient compliance with these regimens is poor and there are insufficient follow-up data. Devices that block the urethra (internally or externally) also are available, but they can be invasive. Most vaginal pessaries that are supposed to lift the bladder neck are large and intrusive, they need to be inserted by a medical practitioner, and are intended for prolonged re-use.

ConTIPI Ltd. has developed a novel approach: a disposable device that is inserted into the vagina with an applicator, similar to the one used for the regular tampon (Figure 6). The device, which is awaiting a patent, anchors itself after insertion, expands, and supports the mid-urethra in a tension-free manner, (similar to the effects of tension-free vaginal tape) for several hours. Pulling its string causes the device to shrink in size, allowing for easy removal and disposal. The device is inserted vaginally by the patient. A woman may insert it before a stressful event (e.g., dancing) or use it over a prolonged period (8–12 hours daily).

The TIPI tampon has been found to be comfortable, easy to insert and remove, and it does not interfere with urination, defection, walking, or posture changes. A large-scale premarketing controlled study, (including 50 patients for 35 days) is in progress. In a clinical study of 20 patients, researchers employed a 1-hour pad test, followed by 5 hours of routine daily work with and without the device. The ConTIPI pad reduced leakage by about 90% on average during the 1-hour test and by about 81% by the end of 6 hours.

In summary

The new techniques and devices described here are just the tip of the iceberg. Of course, as new diagnostic and therapeutic solutions surface, it can become more difficult for clinicians to choose an option. In the treatment of uterine fibroids, for instance, there was a time when the only options were hysterectomy and myomectomy. Now we also have uterine artery embolization and GnRH analogues. Experimental approaches that are emerging include high-focused U/S and thermal myolysis. At our Uterine Fibroid Center for Excellence, preliminary data even suggests that acupuncture may be of some benefit.¹⁰

The regulatory process that such devices must go through continues to become more demanding with each passing year, but such scrutiny not only protects the public and profession from unrealistic expectations, it helps serve up the most useful clinical tools from the most creative minds in biomedical technology.

REFERENCES

1. Isaacson K. Just because we can, doesn't mean we should. Contemporary OB/GYN. 2003;48:6.

2. Freeman R. Intrapartum fetal monitoring—a disappointing story. N Engl J Med. 1990;322:624-626.

3. Arulkumaran S, Lilja H, Lindecrantz K, et al. Fetal ECG waveform analysis should improve fetal surveillance in labour. J Perinat Med. 1990;18:13-22.

4. Phelps JY, Higby K, Smyth MH, et al. Accuracy and interobserver variability of simulated cervical dilatation measurements. Am J Obstet Gynecol. 1995;173:942-945.

5. Low JA. Intrapartum fetal surveillance. Is It worthwhile? Obstet Gynecol Clin North Am. 1999;26:725-739.

6. Friedman EA. Cervimetry: an objective method for the study of cervical dilation in labor. Am J Obstet Gynecol. 1956;71:1189-1193.

7. Timor-Tritsch IE, Masch RJ, Goldstein SR, et al. Transvaginal ultrasound-assisted gynecologic surgery: evaluation of a new device to improve safety of intrauterine surgery. Am J Obstet Gynecol. 2003;189:1074-1079.

8. Breziniski A, Stern T, Arbel R, et al. Society for Gynecologic Investigation (SGI), Washington, DC (Abstract 8). March, 2003.

9. Bornstein J, Geva A, Kaplan B, et al. A novel approach to detection of vaginal infections - "VI-Sense Pantiliner," ISSVD World Congress, Brazil, October 2003.

10. Tadir Y, Siterman S, Soriano D, et al. Acupuncture for the treatment of fibroid uterus. Presented at the Macabee (Tivii) Complementary Medicine, Annual Scientific Meeting. Israel, Nov. 2003

References of inventors and developers:

Barnev - labor monitoring: Yossi Machtey [yossi@barnev.co.il]

PMG - Fetal monitoring: Yona Zumeris PhD [pmg2@netvision.net.il]

Ron-Tech Medical. Tepper Ronnie MD [tepper_r@inter.net.il]

Rostam- Menashe Levy PhD [Mlevy@rostam.co.il]

Common Sense: Menashe Terem [menashe@cs-commonsense.com]

ConTIPI: Stress incontinence: Elan Ziv MD [zivelan@netvision.net.il]

Laser Microscopy: D H Douglas-Hamilton [dhdh@hamiltonthorne.com]

DR. TADIR is Professor of Obstetrics and Gynecology, and Director of Clinical Research at the Beckman Laser Institute, University of California, Irvine, and Tel Aviv University, (Israel) ytadir@bli.uci.edu.

Laser for assisted hatching and pre-embryo genetic diagnosis following IVF

During the summer of 1988, I joined a team of scientists at the Beckman Laser Institute on the campus of the University of California Irvine to evaluate the use of laser microbeams in in vitro fertilization (IVF).

Following several experiments with a large number of laser beams, tested on various types of eggs and embryos, the optimal system was defined.^1,2 The new "solution" looked for "appropriate problems" to be solved, and while IVF became an established treatment, the laser gamete system became an ideal tool for accurate manipulations.

The possibility of improving pregnancy rates in selected infertile patients with a different kind of manipulation was defined by Cohen and colleagues as assisted hatching, and the need to remove single blastomeres for genetic testing prior to the transfer into the uterus created another demand for such a computer-controlled precise manipulating device.^3,4 Several companies realized the potential of this tool for the IVF market (Figure A).

A preliminary article described the principles of this technique at length, and several articles have been published since then describing the potential clinical use of the laser in human IVF.⁵ Children born after diode laser-assisted hatching have been followed, and collected data on karyotypes, congenital malformations, and growth parameters were similar to non-IVF-born children.⁶

REFERENCES

1. Tadir Y, Wright WH, Vafa O, et al. Micromanipulation of gametes using laser microbeams. Hum Reprod. 1991;6:1011-1016.

2. Rink K, Delacretaz G, Salathe RP, et al. 1.5 µm diode laser microdissection of the zona pellucida of mouse oocytes. Biomed Optics. 1994;2134A-2153.

3. Cohen J, Alikani M, Trowbridge J, et al. Implantation enhancement by selective assisted hatching using zona drilling of human embryos with poor prognosis. Hum Reprod. 1992;5:685-691.

4. Han TS, Sagoskin AW, Graham JR, et al. Laser-assisted human embryo biopsy on the third day of development for preimplantation genetic diagnosis: two successful case reports. Fertil Steril. 2003;80:453-455.

5. Tadir Y. Ten years of laser-assisted gamete and embryo manipulation. Contemporary OB/GYN. 1998:43:126-150.

6. Kanyo K, Konc J. A follow-up study of children born after diode laser assisted hatching. Eur J Obstet Gynecol Reprod Biol. 2003;110:176-180.

 

Yona Tadir. What's in the technology pipeline? Contemporary Ob/Gyn Apr. 15, 2004;49:20-32.