GB2562264A - Device for the determination of fertility status - Google Patents

Abstract

A process and device for indicating a fertility status of a woman comprises recording with an external conductivity measuring device 10 a conductivity value from a vulva mucus sample isolated on each day over a number consecutive days to yield a first series of conductivity values. A threshold value it then calculated from an average value of the first series of conductivity values using an algorithm within a processing unit. Further conductivity values of vulva mucus isolated on each day after calculation of the threshold value are then recorded to yield additional conductivity values, and wherein these values are compared to the threshold value using the processing unit. A signal is then sent to an indicator to indicate a fertility status when the one or more additional conductivity value exceeds the signal threshold value. The threshold value is preferably selected to equal at least 130%, 140% or 150% of the average value. The conductivity measuring means may further comprise a pair of electrodes located in a recess 5 formed in a flat surface of the device.

Description

Device for the determination of fertility status

The present invention relates to a process for determining and indicating a fertility status in a woman and a device enabling the same. The present invention relates particularly to a non-invasive process and device which provides a personal determination of fertility in a woman.

Background

The ability to time intercourse to achieve pregnancy is an important part of family planning. As the sperm only has a 1% probability of surviving more than 6.8 days it is usually assumed that an intercourse may result in a pregnancy if it occurs during the 6-day fertile window preceding the day of ovulation; the two highest fertility days being those immediately prior to ovulation.

However, this fertile window may occur during a broad range of days in the menstrual cycle. The clinical guidelines identify the period between days 10 and 17, but this is valid for only 30% of women. Predicting the fertile window with any accuracy can be difficult, even if the menstrual cycles are regular.

Unfortunately, determining the direct timing of ovulation by serial ultrasound examinations is highly impractical. Alternatively, the identification of a pre-ovulatory rise in oestrogens followed by a peak in luteinizing hormone (LH) concentration as determined by radioimmunoassay is a good indication of imminent ovulation. Several samples of blood, drawn at mid-cycle, can be analysed for luteinizing hormone concentration. These techniques are expensive, inconvenient and also require several visits to a hospital or medical laboratory having the appropriate analytical facilities and can miss the beginning of the fertile interval and even the most fertile days.

Therefore, techniques in non-clinical settings that help to pinpoint such a period would have immense practical value.

Ovulation is observed in 51.1% of cycles 1 day and in 43.2% of cycles 2 days after the surge in serum LH. Current commercially available hormonal ovulation timing systems are ovulation detection kits based on urinary LH, sometimes together with oestrogen levels. These methods are usually reliable, as the ovulation by ultrasound occurs within 3 days of the urine LH surge in 97% of cycles, but costly. Further, the situation can be complicated by the fact that some women may have a surge in the LH hormone without releasing an egg. This condition is known as Luteinized Unruptured Follicle Syndrome (LUFS). Other women may experience false small peaks in the LH hormone before it fully peaks, commonly seen in women with polycystic ovarian syndrome. This could mislead to time intercourse too early and thus such solutions are not always useful.

Further, several authors now consider that methods based on cycle monitoring by daily vaginal ultrasound and/or urinary LH detection are not informative about the probability of conception at a particular time in the fertile interval within an ovulatory cycle. A method of predicting ovulation accurately and which can be conveniently carried out in the privacy (of the home) would be very useful. Therefore, a range of alternative approaches to pinpoint the ovulation date and/or the most fertile period has been researched with the ultimate goal to establish day-specific probabilities of conception.

This task has been attempted mostly by observing or testing a variety of body-based measurements, including physiological parameters such as measuring basal body temperature, the levels of urinary metabolites of reproductive hormones, monitoring cervical mucus, saliva and/or vocal pitch.

Methods based on biochemical changes in various body fluids such as vaginal secretions, saliva, or urine have been proposed but the significant variation in the component being measured between individuals has led to a lack of consistency and/or reliability. For example, where the lactic acid concentration of vaginal secretions was used as an indicator of impending ovulation, the variability of its concentration between individuals was too great to be useful. Therefore, although such chemical or physical characteristics appear to be predictive of ovulation they often show such variations among individuals that any means of monitoring for its changes requires that tests be individually calibrated to each user which presents a further challenge.

More specifically, the physical/chemical characteristics of secretions, have been the focus of a number of researchers: one such example being saliva: when a woman is about to ovulate, her saliva begins to form a distinct crystal, fern-like pattern due to an increase in hormone levels. This "ferning" pattern begins to appear around 3 to 5 days prior to ovulation and hence considered to be a strong indicator. A further proposal concerns the visible change in the "quality" of mucus observed in vaginal discharge and the appearance - tackiness, colour etc. has been used to predict the onset and end of the fertile period for women using natural family planning (the Billings Ovulation Method). It has been suggested such a technique could help identify the days with the greatest likelihood of conception from intercourse both for normally fertile and sub-fertile couples and intercourse recommendable to occur on days with optimal mucus quality. However, assessing the quality of mucus is to a large degree subjective.

This might be one of the reasons why, using this method is uncommon among women trying to conceive and many clinicians still recommend hormonal ovulation-detection kits referred to above instead. One could assume that the LH kits may be preferred as they offer unambiguous readouts, but their applicability has been found to be limited during irregular cycles. For sub-fertile couples, the hormone kits may signal prematurely. These kits are also uneconomical and their tests cannot be repeated on the same day.

Further methods relying on qualitative measuring of such secretions have been developed: EP0177994 describes a device for determining the fertile and infertile phases of the menstrual cycle, which comprises making regular determinations of the electrical resistivity of the subject's saliva mid-cycle and indicating the onset of ovulation as a function of a peak resistivity measurement, which peak is followed by a nadir and subsequent sharp increase in said electrical resistivity measurement.

It is also known that one of the mucus properties which can be measured is conductivity. Conductivity of vaginal mucus is known to be correlated with the time of ovulation. In EP0177994 the technique uses electrical resistance readings of cervical mucus (taken using an intra-vaginal probe which rests on the base of the cervix whilst taking measurements) together with the saliva data in the calculation determining the fertile period. It is considered that the highest conductivity (lowest resistance) of the mucus indicates time of ovulation. Other sources indicate that the minimum in the electrical resistance of vaginal secretions occurs within 2 days of ovulation.

The present author believes that, due to the conductivity of the vaginal fluid and the tissue surrounding the probe, such a method does not permit an accurate reading of mucus conductivity itself and thus such methods may be limited in accuracy as well as being less convenient for the user (multiple testing and invasive procedures to obtain readings).

In EP0498303 means are provided to predict ovulation by monitoring changes in cervical mucus secretion by the use of a vaginal probe with two electrodes located close to the tip of the probe and thus near the entrance of the cervix. The two electrodes are covered during the measurement by the mucus secreted by the cervical glands which descends into the vagina. The authors propose a drop of 10 - 15% from the baseline measurement will give indication of at least 72 hours before ovulation.

Thus, both the solutions concerning cervical mucus measurement rely on use of an internal probe, which is not desirable for quick and easy testing. Further, ensuring a high standard of cleanliness and hygiene for the probe may be troublesome during everyday use. Other methods of the prior art which utilise mucus in their deductions either rely on cross referencing the resulting data with additional data taken from another sample type (e.g. saliva) or measurement type (e.g. viscosity or other physical parameter) or utilise characteristics associated with ovulation timing, such as changes in body basal temperature.

The present invention arises from the remaining need to provide a quick, easy, and reliable method as well as device for personal use to determine fertility status, and hence the optimum time for intercourse to achieve conception.

Summary

The inventors have therefore provided a non-invasive process for determining and indicating a fertility status in a woman, comprising: recording, post menstrual bleeding cessation, a conductivity value from vulva mucus sample isolated on each day, over at least 3 consecutive days with an external conductivity measuring device to yield a first series of conductivity values, calculating via an algorithm a threshold value based on average value of the first series of conductivity values using a processing unit, recording a further conductivity value of vulva mucus isolated on each day after calculation of the threshold value to yield one or more additional conductivity values, comparing said one or more additional values to the threshold value using the microprocessor; and sending a signal to indicate a fertility status when one or further conductivity value(s) exceed(s) the signal threshold value.

In some embodiments, the threshold value may be determined as 130%, 140% or 150% of an average value of the first series of conductivity values.

In some embodiments, the conductivity value from vulvar mucus sample may be isolated on each day, over at least 4 consecutive days. A non-invasive device is also provided for indicating a fertility status of a woman comprising: an external conductivity measuring device configured to record a series of conductivity values of isolated vulva mucus samples; a processing unit configured to determine an average value from the series of conductivity values, calculate a threshold value based on the average value via an algorithm, compare subsequently recorded conductivity values thereto and initiate a signal when any of the subsequently recorded conductivity values exceeds the threshold value; and an indicator configured to receive the signal from the microprocessor and communicate a fertility status. In some embodiments the threshold value may be determined as 130%, 140% or 150% of an average value of the first series of conductivity values.

In further embodiments the process of the invention is repeated for each fertility cycle to generate one or more further series of conductivity values, the threshold value is then adjusted by the algorithm according to the accumulated average over the one or more further series to create a personalised fertility determination for each cycle thereafter.

The method and device of the invention has a number of advantages which are not provided by the current solutions in the prior art:

The device calculates optimum fertility based on the woman's own measurements and thus serves as its own calibration system enabling an accurate and personal determination. Further, the device does not require in-vivo measurement, the sample is first obtained easily from the vulva and placed in the sample chamber of the device; no insertion of a probe or other instrument is necessary and the procedure is very quick. As a result, there is no need for a bulky apparatus as the device preferably uses an external power source in order to enable such measurements. Further, using the algorithm of the invention, the woman's own data has been sufficient to provide an accurate indication of fertility without the need for further cross referencing of other data from any other source. No knowledge about previous cycles is needed as a new baseline is established for each cycle based on the initial readouts.

In a preferred embodiment, the device further comprises a circuit and two electrodes; the electrodes are located in recess formed in surface of device, preferably wherein the surface is flat.

In the preferred embodiment, the device has a fertility indicator comprising an LED. In an additional, optional embodiment there may be an LCD in order to visually indicate more information about the fertility status to the user.

The device may comprise an internal power source such as a battery or preferably is powered by an external source, such as via a USB, mobile phone or solar charger. Any other variant for charging the device may be provided in an embodiment of the invention.

In one example, the device has information transfer connection means such as a port or USB connector in order to easily transfer data to or from the device. The device may have further capability to transfer or receive data to/from a remote server/location e.g. Bluetooth or Wi-Fi capability.

The device is preferably made or coated with a waterproof or water shielding material, such that contact with water-based fluids or samples does not interfere with the electronics. Further, this feature enables the device to be washed easily after use and helps maintain an acceptable level of hygiene.

The device is preferably portable and sized as such. In one embodiment the device is compact and/or cylindrical. The device may be no wider than 3cm but is not limited in this regard.

Brief description

Figure 1A shows an embodiment of the vulvar mucus conductivity measuring device of the invention;

Figure IB shows an embodiment of an optional device complimenting the invention;

Figure 2A shows graphical experiment results for woman A; and

Figure 2B shows graphical experiment results for woman B.

Detailed description

Figures 1A and IB illustrate examples of a device in accordance with the invention. The non-essential features herein described may be taken alone or in different combinations to yield various embodiments of a device within the scope of the invention.

Figure 1A shows a first device for indicating fertility status in accordance with the invention from side front and top viewing angles. The different features described below may be orientated or else positioned in any feasible way to enable use of the device. Their exact location is not intended to limit the scope of the disclosure herein.

The externally used device typically comprises a housing or casing 10, which may have a protective waterproofing layer or be made of a material providing resistance. The housing further includes a recess or cavity 3 for accessing a conductivity measuring unit and processor including two contacts and electronic circuit 5, housed within the casing. The cavity is easily cleanable by washing with water after use to remove the sample.

The recess may have a cover, lid, stopper or similar (not shown) and may temporarily positioned thereon and thus configured to protect the internal part of the device when access is not required; for example, during storage, to maintain hygiene when it is not in use. When a sample is contained therein, it is also useful to open and then releasably secure such cover or lid over the recess to retain the sample in the device and prevent spillage of the sample therefrom, particularly if the device is moved or turned over.

The device in this example further comprises a USB or other connector, which in this case is a male connector 9 but could equally, be a female port. Such a USB connector may be retractable within the casing or housing, or protected by a lid, cap or similar when not in use to maintain hygiene of the device and or maintain a compact shape of the device for portability. The USB can be used to power the device externally or transfer information from the processing unit which may store recorded measurements and information for external transfer and processing. In other embodiments, the USB can be a female port, in order to receive a connection thereto.

The device further incorporates a signal indicator in the form of an LED 7 which is visible to the user on the housing of the device.

In figure IB, an additional electronic component 11, such as a visual display component, for use with the device is shown, providing yet a further embodiment of the invention in which the component and device together provide an ovulation timing visualisation assembly.

Such a component comprises an LCD screen 12 to display detailed information about the fertility status; for example commands about the functional status of the device, including messages (error), quantitative data readings and/or other information helpful in the communication of the fertility status e.g. a value such as 1 or 2 meaning a relatively high or peak fertility status (or 0 meaning a low status). The LCD may also be a touch screen allowing the user to interact with the device via the visual display.

In this example, the component may also have an operating button 14 providing an on/off function. In such an embodiment, the component may comprise a battery (not shown) to externally power the device when connected to the visual display component. However, this is not essential. It is feasible that the port/connector of the device may be operatively connected to the component 11 via an electric wire there between; in particular the component may have a complimentary female 16 port to the counterpart male 9 connector, or such roles could be reversed. In some embodiments, the transfer of data to or from the visual component could be wireless.

Alternatively, an external mobile device with a display screen could be used as a power source and/or a visual component to transfer data to and from the device for further functionality, processing and display options. The interaction and data functionality can be accessed and/or operated using that mobile device, e.g. together with web-based or mobile applications designed to process and display the data.

Once the device is connected to a power source or charged, whether connected externally or switched on or activated, the user operates the device by opening the cover (if in place) to access the sampling cavity and inserts sample mucus, simply using a fingertip, on to the contacts connecting the circuit on the measuring component situated therein.

The measuring device then records a conductivity value for the isolated vulva mucus sample. This exercise is repeated daily and a series of conductivity measurements is recorded by the device.

The processing unit within the device is configured to determine an average value from the series of conductivity values and thereafter calculates a threshold value using pre-programed algorithm. Each subsequent day, the recorded conductivity value is compared to the threshold. An output is then relayed to initiate a signal if a subsequently recorded conductivity values exceeds the threshold value and the LED indicator receives the signal and communicates a fertility status to the user e.g. as a colour such as green (= fertile period). In addition, in the instance the visual component is connected, the LCD screen provides a further detailed visual indication of the status and/or may include other information helpful to the user.

The cavity is cleaned by washing with water and lightly drying or left to dry open. The cavity can be covered and the device stored conveniently for hygienic storage and transport.

Testing

The present authors have validated their method and device by comparing it with other commonly used methods and devices presently on the market, particularly urine hormone based testing devices.

Currently the most advanced hormone testing kit available commercially is Clearblue Digital Ovulation Test with Dual Hormone Indicator (CDOTDHI), which works by monitoring the changes in 2 key fertility hormones - luteinising hormone (LH) and oestrogen in urine. The rise in oestrogen in the days before the LH surge is interpreted as High Fertility status. The LH surge, which happens about 24-36 hours before ovulation, triggers the Peak Fertility readout. The manufacturer claims that the test is over 99% accurate in detecting the LH surge.

Recent research performed using Clearblue Easy Fertility Monitor™ (CBEFM), which measures urinary metabolites of oestrogen and luteinizing hormone, suggests that the peaks in fertility as determined by them and by self-assessment of cervical mucus are similar, although CBEFM failed to identify the onset of the fertile window approximately 40% of the time. There is a strong positive correlation between the LH surge and the peak of cervical-vulvar mucus.

Clinical Study

Two healthy female subjects (mean age 23 years), with regular menstrual cycles, participated in the study.

Each subject was provided with: a prototype vulvar mucus conductivity measuring device in accordance with the functionality of the invention (and conductivity reading attachment - COM-100 meter manufactured by HM Digital) with an explanation about the correct use of the prototype device; a Clearblue Digital Ovulation Test with Dual Hormone Indicator; a basal thermometer (model Braun PRT2000EU); and a flow sheet on which to record the conductivity measurements, hormone test readings (when test was performed) and basal body temperature (BBT).

The protocol of the study included the following: a) vulvar mucus conductivity measurement was taken in the morning of days when no bleeding was observed - a sample of the vulvar mucus was placed within the small groove containing two metal electrodes of the device and the device was closed

Conductivity was recorded each day on the attached COM-100 meter and the raw readings were divided by 100 so that they fall in the 0-10 range (and can be graphically displayed with the hormonal testing results) b) hormonal testing was undertaken using the manufacturer's kit and instruction and recorded

Low Fertility was assigned the value of 0, High Fertility the value of 1 and Peak Fertility the value of 2.

When Peak Fertility was reached no further hormonal testing was performed until the next cycle started c) BBT readings were taken from day 1 throughout the cycle (cycle day 1 was defined as the first day of bleeding - any amount) A total of 8 cycles from each subject were recorded and analysed.

The raw results are presented in the tables following:

Vulvar mucus conductivity measurements and fertility signals

Woman A

Vulvar mucus conductivity measurements and highest fertility signals

Woman B

*no more test strips available

The temperature measurements did not provide any useful information due to background noise.

Analysis

Graphical analysis corresponding with this data is presented in Figures 2A and 2B.

Figure 2A and Figure 2B show vulvar mucus conductivity with blue line (a) and hormonal readout in red line (b). Timing of the Peak Fertility signal is marked with a solid yellow line (c); the fertility signal given by vulvar mucus indicated with a yellow dotted line.

The patterns of mucus conductivity demonstrated the following: • low conductivity shown throughout the first days after menstrual bleeding cessation (amount of vulvar mucus available for testing was sometimes quite small) • The conductivity and amount of mucus stayed flat or slowly increased until Peak Fertility indicated by CDOTDHI, after which a sharp increase in conductivity and the amount of mucus was observed • The peaks in vulvar mucus conductivity occurred between 2 to 5 days after the Peak Fertility signal - average 3.1 days (the distance between the solid and dotted yellow lines)

The last period of woman B is an exception, where no Peak Fertility signal was obtained due to lack of testing strips

Normal couples

The difference between the Peak Fertility signal given by CDOTDHI and the signal provided by mucus conductivity measurements is negligible from the point of view of normal fertility couples since the pregnancy can be achieved as a result of an intercourse taking place up to 3 days before the conductivity peak. However, the implications for sub-fertile couples are significant.

Sub-fertile couples

Timing in the case of sub-fertile couples is more critical as the intercourse needs to occur from 1 day before to 1 day after the peak. In such cases, it is noted by the applicants that the hormonal-based kits may give a premature signal, particularly if the difference between the hormone peak and mucus conductivity peak is more than 2 days. Therefore, at least for sub-fertile couples, the present invention offers a better option for accurately determining and indicating the best moment for conception.

As a result of this testing the applicant has proposed an algorithm which can be applied to a process or device such that there is a new way of triggering the signal of fertility based on vulvar mucus conductivity measurements with improved accuracy.

The signal is triggered when the observed conductivity exceeds by 30% or more the average conductivity from the first 4 conductivity measurements after menstrual bleeding cessation. The trigger values and corresponding signals are shown in the last column of Tables 1 and 2 (Appendix). With only one exception (woman A on 26/4/2015) all the highest fertility signals occur exactly on the dates of the highest mucus conductivity after the hormone peak signals. The single case (woman A on 26/4/2015), when the conductivity signal triggered 3 days after the hormone signal and 1 day before the mucus conductivity peak, is still likely to offer a better chance of conception than following the hormone signal alone. It is in the remit of the invention that the threshold value will be dependent on the woman and thus may be at least 130%, 140% or even 150% or more of the average value based on the first series of data generated over the initial 3 or 4 day series.

While the timing of hormonal testing relies on the knowledge of the previous cycles, the vulvar mucus conductivity algorithm does not require any pre- stored information, as the baseline conductivity level is taken from the beginning of the cycle. This is particularly important for women with irregular cycles, as their use of hormonal testing can easily become uneconomic or even useless.

The investigations conclude that the measurement of vulvar mucus conductivity can be performed externally with ease and the readings are directly due to the conductivity of the mucus and not the surrounding tissues - the relationship between fertility peaks indicated by conductivity measurement of vulvar mucus and by hormonal testing.

The authors believe these experiments confirm that conductivity of vulvar mucus can serve as an indication of the best time for conception. According to this approach the highest fertility day actually occurs 2-5 days after the Peak Fertility indicated by CDOTDHI.

Further the measurements can be performed externally to provide data suitable for algorithmic processing and no knowledge about previous cycles is needed as a new baseline is established for each new cycle based on the initial readouts.

The device has further advantages since it is easy to clean and there is no risk of infection because it is not invasive; hence the device is widely applicable in less hygienic environments.

Claims (15)

Claims:

1. A device for indicating a fertility status of a woman comprising: an external conductivity measuring device configured to record a series of conductivity values of isolated vulva mucus samples; a processing unit configured to determine an average value from the series of conductivity values, calculate a threshold value using an algorithm, compare subsequently recorded conductivity values thereto and initiate a signal when any of the subsequently recorded conductivity values exceeds the threshold value; and an indicator configured to receive the signal from the processing unit and communicate a fertility status.

2. A device according to claim 1, wherein the device further comprises a circuit and two electrodes.

3. A device according to claim 2, wherein the electrodes are located in recess formed in a surface of device, preferably wherein the surface is flat.

4. A device according to any preceding claim, wherein the indicator comprises a fertility indicator such as an LED, and/or an LCD screen.

5. A device according to any preceding claim, wherein the device is powered by an internal battery or by external source.

6. A device according to any preceding claim, wherein the device further comprises information transfer connection such as a port or USB connector.

7. A device according to any preceding claim, wherein the device has wireless data transfer capability, such as Bluetooth or Wi-Fi and can send or receive conductivity data to/from a remote server/location.

8. A device according to any preceding claim, wherein the device is made or coated with a waterproof or water repelling material.

9. A device according to any preceding claim, wherein the device is configured to be portable.

10. A device according to any preceding claim, wherein the threshold value equals at least 130% of the average value.

11. A device according to any preceding claim, wherein the threshold value equals at least 140% of the average value.

12. A device according to any preceding claim, wherein the threshold value equals at least 150% of the average value.

13. A process for determining and indicating a fertility status in a woman, comprising: recording, post menstrual bleeding cessation, a conductivity value from vulva mucus sample isolated on each day, over at least 4 consecutive days with an external conductivity measuring device to yield a first series of conductivity values, calculating a threshold value from an average value of the first series of conductivity values using an algorithm within a processing unit, recording a further conductivity value of vulva mucus isolated on each day after calculation of the threshold value to yield one or more additional conductivity values, comparing said one or more additional values to the threshold value using the processing unit; and sending a signal to indicate a fertility status when the one or more additional conductivity value exceeds the signal threshold value.

14. A process for determining and indicating a fertility status in a woman according to Claim 13, wherein the threshold value equals at least 130%, 140% or 150% of the average value.

15. A process for determining and indicating a fertility status in a woman according to Claim 13 or 14, wherein the process is repeated one or more times to generate one or more further series of conductivity values for each fertility cycle and the threshold value is adjusted according to the accumulated average for further each series to create a personalised determination and indication of fertility status.