METHODS AND DEVICE FOR DETERMINING EFFICIENCY OF LACTATION

Abstract

The invention generally concerns methods and devices for determining inadequate lactation in female subject.

Claims

1-28. (canceled)

29. A method for determining inadequate lactation in a female subject, the method comprising: determining an expression of a physicochemical parameter of a breast milk sample obtained from the subject at a time point after delivery, and determining whether the subject is inadequately lactating by comparing the expression of the physicochemical parameter of the breast milk sample with an expression of the physicochemical parameter of breast milk sample(s) obtained from adequately lactating subjects at the same time point after delivery or by comparing a change in expression of a physicochemical parameter of two or more breast milk samples obtained at two or more time points, with a change of an expression of the physicochemical parameter of breast milk sample(s) obtained from adequately lactating subjects, at the two or more time points; wherein inadequate lactation comprises or is associated with reduced lactation efficiency, delayed lactogenesis II (DLII), inadequate lactogenesis III or reduced milk production.

30. The method of claim 29, comprising: determining an expression of the physiochemical parameter of breast milk sample(s) obtained from adequately lactating subjects at the time point, and determining whether a subject is inadequately lactating,  by comparing the expression of the physicochemical parameter of the breast milk sample with an expression of the physicochemical parameter of breast milk sample(s) obtained from adequately lactating subjects at the time point or by comparing a change in expression of a physicochemical parameter of two or more breast milk samples obtained at two or more time points, with a change of an expression of the physicochemical parameter of breast milk sample(s) obtained from adequately lactating subjects, at the two or more time points, wherein when the expression of the physicochemical parameter measured for the breast milk sample and the expression of the physicochemical parameter predetermined for the control population at the same time point after delivery are not the same, the female subject has inadequate lactation.

31. The method of claim 30, wherein when the expression of the physicochemical parameter measured for the breast milk sample and the expression of the physicochemical parameter predetermined for the control population are same, or the physicochemical parameter for the breast milk sample is within 1.285SD (standard deviation) of the expression of the same physicochemical parameter predetermined for the control population for the same time point, the female subject has adequate lactation.

32. The method of claim 30, wherein if the expression of the physicochemical parameter of the breast milk sample obtained from the subject is different from the expression of the same physicochemical parameter of breast milk sample(s) obtained from the control population, the female subject is regarded as having or having likelihood of developing reduced lactation efficiency, delayed lactogenesis II (DLII), inadequate lactogenesis III or reduced milk production.

33. The method of claim 29, comprising computing a milk maturation index calculated on the breast milk sample, said milk maturation index is used for comparison with a milk maturation index obtained from the control population.

34. The method according to claim 29, comprising obtaining at least one breast milk sample from a female subject, obtaining at least one breast milk sample from one or both breasts of the female subject

35. The method according to claim 29, comprising obtaining multiple milk samples from the subject at different time points, optionally wherein at least some of the multiple samples obtained at different time points are obtained from either or both breasts of the female subject.

36. The method according to claim 29, comprising measuring the physicochemical parameter of the milk sample obtained from the female subject at a time point between delivery and 14 days after delivery.

37. The method according to claim 29, wherein the physicochemical parameter is at least one of (i) electrical resistivity, (ii) electrical conductivity, (iii) an amount of an electrolyte, (iv) an amount of a protein and (v) an amount of a sugar.

38. The method according to claim 37, wherein the at least one physicochemical parameter is electrical resistivity or electrical conductivity.

39. The method according to claim 29, for early diagnosis of at least one of inadequate lactation, reduced lactation efficiency, delayed lactogenesis II (DLII), inadequate lactogenesis III or reduced milk production, the method comprising determining an expression of at least one of electrical resistivity or electrical conductivity of a breast milk sample obtained from the subject at a time point between delivery and 14 days after delivery, and determining whether the subject is suffering or having likelihood of developing from at least one of reduced lactation efficiency, delayed lactogenesis II (DLII), inadequate lactogenesis III or reduced milk production, by comparing the expression of at least one of electrical resistivity or electrical conductivity of the breast milk sample with an expression of at least one of electrical resistivity or electrical conductivity of breast milk sample(s) obtained from adequately lactating subjects at the time point, wherein when the expression of least one of electrical resistivity or electrical conductivity measured for the breast milk sample and the expression of the of least one of electrical resistivity or electrical conductivity predetermined for the control population are not the same, the female subject is suffering from or having likelihood of developing at least one of reduced lactation efficiency, delayed lactogenesis II (DLII), inadequate lactogenesis III or reduced milk production

40. The method according to claim 29, for early diagnosis of at least one of inadequate lactation, reduced lactation efficiency, delayed lactogenesis II (DLII), inadequate lactogenesis III or reduced milk production, the method comprising determining an expression of at least one of electrical resistivity or electrical conductivity of a breast milk sample obtained from the subject at a time point between delivery and 5 days after delivery, and determining whether the subject is suffering from or having likelihood of developing at least one of reduced lactation efficiency, delayed lactogenesis II (DLII), inadequate lactogenesis III or reduced milk production, by comparing the expression of at least one of electrical resistivity or electrical conductivity of a breast milk sample with an expression of at least one of electrical resistivity or electrical conductivity of breast milk sample(s) obtained from adequately lactating subjects at the same time point, wherein when the expression of the at least one of electrical resistivity or electrical conductivity measured for the breast milk sample and the expression of the at least one of electrical resistivity or electrical conductivity predetermined for the control population are different, or the physicochemical parameter for the breast milk sample is outside a range defined by a standard deviation value of 1.285SD of the expression of the same physicochemical parameter predetermined for the control population, the female subject is suffering from or having likelihood of developing at least one of reduced lactation efficiency, delayed lactogenesis II (DLII), inadequate lactogenesis III or reduced milk production.

41. The method according to claim 29, wherein the female subject is suffering or having likelihood of developing from breast pain, swelling or fever wherein the method is for determining whether the pain, swelling or local fever are associated with inflammation or inadequate lactation.

42. The method according to claim 29, for determining the likelihood of developing inadequate lactation or breast inflammation in a female subject, the method comprising: determining an expression of a physicochemical parameter of a breast milk sample obtained from the subject at a time point after delivery and after the development of pain, swelling or fever, and determining whether the subject is likely to develop inadequate lactation or inflammation by comparing the expression of the physicochemical parameter of the breast milk sample with an expression of the physicochemical parameter of breast milk sample(s) obtained from adequately lactating subjects not suffering from pain, swelling or fever, at the same time point after delivery.

43. A device for carrying out a method according to claim 29, by measuring at least one physicochemical parameter in a breast milk sample, the device comprising a chamber configured for holding a breast milk sample, a detector for determining an expression of at least one physicochemical parameter of the breast milk sample, a signal transmitting module, a processor for carrying the comparison to control population and a user interface for delivering the results, indication of adequate/inadequate lactation, and insights.

44. The device according to claim 43, wherein the at least one physicochemical parameter is at least one of (i) electrical resistivity, (ii) electrical conductivity, (iii) an amount of an electrolyte, (iv) an amount of a protein and (v) an amount of a sugar.

45. The device according to claim 43, comprising an electrical sensor comprising at least one electrode assembly and a reader, wherein the electrode assembly is operably connected to a measurement compartment or any component thereof in a manner that allows transmission of signals between the electrode assembly and the reader and wherein the electrode assembly is configured to measure electrical conductivity or electrical resistivity.

46. A system for determining inadequate lactation in a female subject, the system comprising a device according to claim 44, a data processing unit and a data interface unit, wherein the data processing unit is configured for data communication with the device and the data interface unit being in data communication with the data processing unit; wherein the data processing unit comprising data relating to at least one expression of at least one of electrical conductivity or electrical resistivity at various time points after infant birth and is adapted to receiving from the device information relating to at least one expression of electrical conductivity or electrical resistivity of a breast milk sample obtained at the various time point, and provide an indication of lactation efficiency or inadequate lactation.

47. The device according to claim 43, for calculating milk maturation index and presenting said milk maturation index on the user interference.

48. The device according to claim 43, for determining and presenting on the user interface whether the subject is likely to develop breast inflammation.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0137] In order to better understand the subject matter that is disclosed herein and to exemplify how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:

[0138] FIGS. 1A-1C are graphs showing the correlation between sodium concertation in breast milk samples and the conductivity measured in these samples, FIG. 1A shows the correlation between sodium in de-fatted breast milk (referred to as milk serum) and conductivity tested in whole milk by lab-grade conductivity meter, FIG. 1B shows the correlation between conductivity measured in low volume hand-held conductivity meter device according to the invention and conductivity measurements in a lab-grade conductivity meter for the same sample of breast milk. FIG. 1C shows the correlation between sodium in de-fatted breast milk (referred to as milk serum) and conductivity measured in low volume hand-held meter.

[0139] FIG. 2 is a graph showing the correlation between sodium concertation, conductivity and day post delivery. In the graph, the darker the dot is, the higher is the sodium concentration.

[0140] FIG. 3 shows classification of conductivity values vs. day from birth, based on measured milk sodium levels, in samples associated with breastfeeding pain (circle markers), and samples not associated with breastfeeding pain (square and triangle markers) using a cutoff value of 16 (a referenced indicator for delayed lactogenesis) such that square markers correspond to sodium concentration above 16, triangle markers correspond to sodium concentration below 16, and breast pain, black circles correspond to sodium concentration above 16 (and reported pain) and gray circles correspond to sodium concentration below 16 (and reported pain), data was obtained from 70 milk samples at different days post-delivery, samples were collected and tested in laboratories by conductivity scanner and validated laboratory test for milk sodium.

[0141] FIG. 4 is a graph showing breast milk maturation index as a function of time after delivery.

[0142] FIGS. 5A-5D show individual mother's milk dynamic analysis; FIG. 5A are representative graphs from different mothers with 2 consecutive measurements with various time periods between the measurement, FIGS. 5B and 5C are examples of measurements of two individual mothers with repeated measurements along several weeks, each breast monitored separately, FIG. 5D shows a correlation in the same mother as shown in FIG. 5C, between pain intensity (upper panel) and the computed value (lower panel).

[0143] FIGS. 6A-6D are graphs showing the accuracy of prediction of lactation status using the developed algorithm, breast milk samples from over 400 mothers were collected at various day post delivery processes and analyzed to obtain milk maturation %, samples are classified into four groups based on lactation consultant and mothers' report: (i) exclusive breastfeeding, (ii) non-exclusive breastfeeding, (iii) predominant mothers milk but lactation problem and (iv) predominant mothers milk, no reported problems (OK), FIG. 6A. shows milk maturation % classified into two group in breast milk samples collected up to 1 year post delivery, FIG. 6B. same classification as in FIG. 6A limited to samples up to 50 days post delivery, FIG. 6C. shows milk maturation % classified into four group in breast milk samples collected up to 1 year post delivery, FIG. 6D. same classification as in FIG. 6C limited to samples up to 25 days post delivery.

[0144] FIG. 7 shows a schematic representation of a device in accordance with some embodiments.

DETAILED DESCRIPTION OF EMBODIMENTS

Non-Limiting Examples

Example 1: Measurements of Conductivity and Sodium Concentration in Human Milk

[0145] As shown in FIGS. 1A-1C, there is a linear correlation between the conductivity in human milk and the concentration of sodium of whole unprocessed milk samples. this correlation does not depend on the milk source (whole breast milk vs. de-fatted breast milk (centrifuge separated, referred to as “milk serum”), data not shown, and the type of the conductivity measurement.

[0146] FIG. 2 shows a correlation between sodium concentration (Z axis, opacity), conductivity (Y axis) and day post delivery (X axis). As can be seen, there is a correlation between sodium levels, and milk conductivity and a dynamics across days postpartum.

Example 2: Determination of Lactation Status

[0147] Human breast milk samples at different days post-delivery were collected and tested in laboratory by hand held low volume milk sensing conductivity scanner and validated laboratory milk sodium human milk was also obtained.

[0148] The measured milk sodium levels were classified using a cutoff of 16 mmol/L, previously report to be a cutoff for assessing delayed lactogenesis on day 3 postpartum (Morton 1994), and breast pain symptom reported by maternal report.

[0149] As can be seen in FIG. 3, conductivity of human milk is dynamically changing and can be determined based on exact day post delivery, and delayed lactogenesis can be identified based on conductivity. Pain is another condition that was shown here to be differentiated by conductivity of human milk in certain cases.

[0150] Based on the above, it can be suggested that breast milk conductivity as measured in a certain day after birth, can be used to determine breastfeeding and lactogenesis status, and pain can be further differentiated based on milk conductivity

Example 3: Prediction of Lactation Status

[0151] Based on the conductivity data and time elapsed from an event (set as delivery time in this example), an algorithm based on milk index table was developed and was clinically assessed to predict breastfeeding success and milk supply based on mother own milk sample. Relative normalized conductivity was measured by lactation consultants at the point of care or mothers' home, the system computed breastfeeding adequacy (% maturation, predicted age of milk, color).

[0152] System sensitivity, efficiency and accuracy relative to the clinical evaluation by face-to-face meeting with lactation consultant was assessed retrospectively on the dataset in 124 women post delivery. The women were assed at 4 days to 3 month with 88% of the women assed within first month up to a total of one year.

[0153] The computed milk maturation index alerts (output of the developed algorithm,) was compared to score of a lactation consultant after face-to-face evaluation of suspected low milk supply, and/or pain beyond 5 days postpartum, and/or reported non-exclusively breastfeeding.

[0154] The computed milk maturation alerts preliminary analysis revealed sensitivity of 73% (true positive identification) and specificity of 80% (true negative), with a positive predictive value (PPV) of 92%.

[0155] Positive is identification of at least one of low milk supply, and/or pain beyond 5 days postpartum, and/or reported non-exclusively breastfeeding, PPV is a statistic measure in clinical diagnostics—how many of the positively identified by the system are true positives.

[0156] All in all, The system was tested about 500 women after birth. Conductivity measurements were obtained from the women at different days post delivery, ranging from 1 day after birth to 350 days after birth using the device described herein. For each milk sample, a milk maturation % was calculated using the developed algorithm.

[0157] FIG. 4 shows the algorithm behavior in breast milk samples that were collected from exclusive breastfed women, with no breastfeeding problems, at various stages after delivery. The Y axis corresponds to computed milk maturation index that was calculated based on milk raw data by conductivity sensor and presented as percentages on the full range from early colostrum (0%) to mature milk (100%) conductivity.

[0158] For some of the tested women, more than a single sample was obtained and hence intra-subject information can be obtained between different time point (e.g. slope between points). As shown in FIG. 5A. It was suggested that a model integrating such inter-subject data can be used for increasing sensitivity and specificity for prediction power. The data from the two breast is shown for two different women in FIGS. 5B and 5C.

[0159] FIG. 5C shows that at day 7 after delivery only in one of the breasts there is a slight decrease in the model output and this was correlated to the mother condition, i.e. pain. As can be seen in FIG. 5D, an increase in pain was observed at the same time point as the decrease observed in FIG. 5C. these data indicate the ability to identify pain that was attributed by a lactation specialist to a transient inflammatory process, identified by the minor differentiation between-breast of dynamics of the maturation index calculated based on milk conductivity measured and computed by the system on days 6-8 postpartum, that was resolved by day 8-9 postpartum.

[0160] FIGS. 6A-6D depict maturation % and classification made by in accordance to feeding type and complications report by lactation consultants, using the following four criteria:

(i) Exclusive OK—Exclusive breastfeeding correspond to breastmilk samples obtained from mothers with no particular breastfeeding concerns (dark circle, grey),
(ii) Formula—significant formula feeds introduced (x, light grey), at least 30% Intermediate conditions:
(iii) predominant but problems—predominant breastfeeding with reported breastfeeding problems
(iv) Exclusive but problems—Exclusive breastfeeding with reported breastfeeding problems
(v) predominant OK—predominantly about 80% breastfeeding with some formula introduced without reported breastfeeding problems.

[0161] FIG. 6A shows calculated milk maturation % for two groups (i) exclusive breastfeeding and (ii) significant formula feeding in breast milk samples collected up to 1 year post delivery, FIG. 6B is the same figure as in FIG. 6A limited to 50 days post delivery.

[0162] FIG. 6C shows calculated milk maturation % for four groups detailed above in breast milk samples collected up to 1 year post delivery, FIG. 6D is the same figure as in FIG. 6C limited to 25 days post delivery.

[0163] As can be seen, milk maturation as calculated can differentiate between significant formula of over 30% of feeds in breastfeeding mothers, such mothers with reported breastfeeding problems and exclusive breastfeeding without reported problems. The intermediate cases can be further classified based on maturation calculated, to resemble any of the aforementioned groups.