Assessing the Risk of Spontaneous Premature Birth by Electrical Impedance Spectroscopy of the Cervix.
Lead Research Organisation:
University of Sheffield
Department Name: Human Metabolism
Abstract
The timing of birth is crucial to reproduction. About 6-13% of babies are born prematurely at annual costs to the NHS of £1 billion more than for term babies. The cost of care in the first year of life for the surviving premature baby is 10-fold higher than for the term baby. Preterm birth (PTB) also accounts for the majority of deaths of structurally normal babies. A quarter of babies born before 28 weeks suffer handicap, with socio-economic burdens on families, many parents often having to give up work to care for their child. Prevention of PTB is limited by lack of accurate prediction of risk. Our group has been exploring the technique of electrical impedance spectroscopy (EIS) for assessing cervical tissue composition by recording its electrical "resistivity" - cervical impedance - to the injection of a small electrical current. Our thinking is that if we can detect the changes which occur in the cervix several months before labour starts we can predict women who will go into premature labour.
To test out this theory we recently conducted a small pilot study. In a small group of women at risk of premature birth (because they have had premature births before), we recently showed that EIS holds promise for accurately predicting premature delivery - women who delivered before 37 weeks, as well as those who delivered before 34 weeks, had lower cervical impedance between 20 and 28 weeks than those who did not. We now propose to confirm these preliminary findings by larger studies. Firstly, we will improve the measuring device for EIS by standardising its contact to the cervix and improving its hardware and software. We will then undertake a large experimental study measuring cervical impedance in two groups of pregnant women - 250 women with risk factors for preterm birth - at two time points during pregnancy (22 and 26 weeks). We will seek to confirm the use of EIS in clinical care will improve our ability to predict, prevent, and treat preterm labour and birth. We will compare EIS to current screening methods such as the fibronectin test and cervical ultrasound. We will also undertake some preliminary cost analysis of its introduction into clinical care and determine whether it may prove cost-effective compared to standard current care.
It has been well recognised that spontaneous PTB is often associated with uterine infection and inflammation but the mechanism and pattern of this association is unclear. Using modern techniques of profiling bacteria in the vagina we will explore whether the bacterial pattern in vaginal discharge of women who deliver preterm differs significantly from that of women who deliver at term. By finding this out we may be able to market a diagnostic kit which detects the pattern most associated with subsequent PTB which, combined with cervical EIS measurement, may improve our prediction of PTB. Prompt and improved identification of PTB risk by our studies will enable better care. This is possible through the administration of drugs such as the hormone progesterone, or others within the family of pain relief medication, known to prolong pregnancy. It may also help us to identify the "weak" cervix, a condition that continues to defy accurate diagnosis, so that a stitch can be more appropriately inserted round the cervix of those that truly need this, and avoided in those that do not need this. For women with symptoms of preterm labour cervical EIS may well identify those who are more likely to progress to birth than others, so that treatments to prepare the baby's lungs for birth, delay the birth, or ensure that birth occurs in an appropriately staffed and equipped health care facility can be provided. Most preterm births occur in women with no risk factors. At present there is no accurate method of screening all women. We therefore propose to measure cervical EIS at 22 week in 250 low risk women also, to determine whether it can be used for routine screening of all pregnant women for risk of PTB.
To test out this theory we recently conducted a small pilot study. In a small group of women at risk of premature birth (because they have had premature births before), we recently showed that EIS holds promise for accurately predicting premature delivery - women who delivered before 37 weeks, as well as those who delivered before 34 weeks, had lower cervical impedance between 20 and 28 weeks than those who did not. We now propose to confirm these preliminary findings by larger studies. Firstly, we will improve the measuring device for EIS by standardising its contact to the cervix and improving its hardware and software. We will then undertake a large experimental study measuring cervical impedance in two groups of pregnant women - 250 women with risk factors for preterm birth - at two time points during pregnancy (22 and 26 weeks). We will seek to confirm the use of EIS in clinical care will improve our ability to predict, prevent, and treat preterm labour and birth. We will compare EIS to current screening methods such as the fibronectin test and cervical ultrasound. We will also undertake some preliminary cost analysis of its introduction into clinical care and determine whether it may prove cost-effective compared to standard current care.
It has been well recognised that spontaneous PTB is often associated with uterine infection and inflammation but the mechanism and pattern of this association is unclear. Using modern techniques of profiling bacteria in the vagina we will explore whether the bacterial pattern in vaginal discharge of women who deliver preterm differs significantly from that of women who deliver at term. By finding this out we may be able to market a diagnostic kit which detects the pattern most associated with subsequent PTB which, combined with cervical EIS measurement, may improve our prediction of PTB. Prompt and improved identification of PTB risk by our studies will enable better care. This is possible through the administration of drugs such as the hormone progesterone, or others within the family of pain relief medication, known to prolong pregnancy. It may also help us to identify the "weak" cervix, a condition that continues to defy accurate diagnosis, so that a stitch can be more appropriately inserted round the cervix of those that truly need this, and avoided in those that do not need this. For women with symptoms of preterm labour cervical EIS may well identify those who are more likely to progress to birth than others, so that treatments to prepare the baby's lungs for birth, delay the birth, or ensure that birth occurs in an appropriately staffed and equipped health care facility can be provided. Most preterm births occur in women with no risk factors. At present there is no accurate method of screening all women. We therefore propose to measure cervical EIS at 22 week in 250 low risk women also, to determine whether it can be used for routine screening of all pregnant women for risk of PTB.
Technical Summary
The timing of birth is crucial to reproduction. 8-13% of babies are born prematurely at annual costs to the NHS of £1bn more than for term babies. Preterm birth(PTB) accounts for > 2/3 of deaths of babies, and contributes huge costs to hospital services during the first 5 years of life. A quarter of babies born <28 weeks suffer handicaps, with socioeconomic burdens on society, parents often having to give up work to care for their child. Prevention of PTB is limited by the lack of accurate prediction of risk. Electrical impedance spectroscopy(EIS) is a technique which may enable prediction of PTB risk. It involves the use of sensing electrodes to assess tissue impedance following the injection of a small electrical current. In 40 women at risk of PTB we recently showed that cervical impedance(CI) between 20 and 28 weeks gestation predicts PTB before 34 wks [sensitivity 100%, specificity 90%, PPV 63, NPV 100, LR+ 9.7, LR- 0.0,P < 0.0001] and 37 weeks [sens 85%, spec 85%, PPV 60%, NPV 96, LR+ 5.8, LR- 0.17,P < 0.0001]. We aim to: a)improve the accuracy of the device by standardising the contact pressure on the cervix, improving the device firmware and online spectral quality checks(Phase 1); b)determine the accuracy of CI-based prediction of PTB in 250 high-risk women studied at 20-22 and 26-28 wks, and 250 women with no risk factors, comparing CI to cervix length and the fibronectin test used in some clinical settings, and assessing whether determining vaginal microbiota using global array technology would prove a screening tool for PTB secondary to CI (phase 2); c)assess the cost-effectiveness & acceptability of CI, and design a study incorporating CI into current PTB screening pathways (Phase 3). A patient group held an inaugural meeting recently, proffered advice on this application and will inform the entire research project. Prompt identification of PTB risk by CI will enable prevention, better hospital bed utilisation, and care in appropriate centres.
Planned Impact
Approximately 12.9 million (9.6%) births worldwide, are preterm. With such global incidence rates, over 130 million pregnancies worldwide may potentially benefit from accurate cost-effective screening for preterm birth annually. Even if the impedance device proves useful for accurately screening only women at high risk of PTB (a previous history of PTB), there is still a potential screening target population of more than 10 million pregnant women worldwide per year. CI measurement may also enable better decision-making regarding women who present in hospital with symptoms of preterm labour, as only 20% will deliver preterm, and >25% of in utero transfers to other hospitals for suspected preterm labour remain undelivered after transfer. Accurately identifying women likely to deliver preterm would enable more prompt preventive therapy, facilitate their transfer to more appropriate care facilities and ensure provision of surgical cervical support (cerclage) if insufficiency is suspected.
We estimate that > 10 million women may become end-users globally annually. If the technique proves of value in low-risk as well as high-risk women, the technique could become adopted for routine screening for PTB during pregnancy, thus forming the basis for treatment interventions such as progesterone to prolong gestation, dexamethasone to accelerate fetal lung maturation, cervical cerclage for possible cervical weakness and in utero transfers to more appropriate neonatal facilities. Being a non-invasive technique, we anticipate high rates of acceptability. Our simultaneous health economic analysis will boost penetration rates if we are to establish low production and training costs.
Our findings are likely to impact the organisation and funding of antenatal services and screening for preterm birth, should we demonstrate clinical utility, high acceptability of this assessment amongst service users, and significant evidence of cost-utility. We envisage that our data will attract a lot of interest within such bodies as the National Institute for Health and Clinical Excellence (NICE), the Health Technology Assessment programme of the NIHR, as well as the Royal Colleges of Obstetricians and Paediatricians and similar professional societies and groupings. Health care commissioners as well as stakeholders in Primary care will benefit from our findings, particularly if we demonstrate that CI assessment may be employed in screening low risk women for PTB risk, since this would enable the adoption of universal screening for preterm birth as part of a strategy for primary prevention of spontaneous preterm birth. Taken together our work has the potential to substantially impact health care policy and planning, not just in the United Kingdom but potentially across Europe, the Americas and even the developing world in the long run.
We estimate that > 10 million women may become end-users globally annually. If the technique proves of value in low-risk as well as high-risk women, the technique could become adopted for routine screening for PTB during pregnancy, thus forming the basis for treatment interventions such as progesterone to prolong gestation, dexamethasone to accelerate fetal lung maturation, cervical cerclage for possible cervical weakness and in utero transfers to more appropriate neonatal facilities. Being a non-invasive technique, we anticipate high rates of acceptability. Our simultaneous health economic analysis will boost penetration rates if we are to establish low production and training costs.
Our findings are likely to impact the organisation and funding of antenatal services and screening for preterm birth, should we demonstrate clinical utility, high acceptability of this assessment amongst service users, and significant evidence of cost-utility. We envisage that our data will attract a lot of interest within such bodies as the National Institute for Health and Clinical Excellence (NICE), the Health Technology Assessment programme of the NIHR, as well as the Royal Colleges of Obstetricians and Paediatricians and similar professional societies and groupings. Health care commissioners as well as stakeholders in Primary care will benefit from our findings, particularly if we demonstrate that CI assessment may be employed in screening low risk women for PTB risk, since this would enable the adoption of universal screening for preterm birth as part of a strategy for primary prevention of spontaneous preterm birth. Taken together our work has the potential to substantially impact health care policy and planning, not just in the United Kingdom but potentially across Europe, the Americas and even the developing world in the long run.
Publications
Amabebe E
(2016)
Identifying metabolite markers for preterm birth in cervicovaginal fluid by magnetic resonance spectroscopy.
in Metabolomics : Official journal of the Metabolomic Society
Amabebe E
(2018)
The Vaginal Microenvironment: The Physiologic Role of Lactobacilli.
in Frontiers in medicine
Amabebe E
(2022)
Mechanistic Insights into Immune Suppression and Evasion in Bacterial Vaginosis.
in Current microbiology
Amabebe E
(2016)
Cervicovaginal Fluid Acetate: A Metabolite Marker of Preterm Birth in Symptomatic Pregnant Women.
in Frontiers in medicine
Amabebe E
(2020)
Female Gut and Genital Tract Microbiota-Induced Crosstalk and Differential Effects of Short-Chain Fatty Acids on Immune Sequelae.
in Frontiers in immunology
Amabebe E
(2021)
Spectral binning of cervicovaginal fluid metabolites improves prediction of spontaneous preterm birth and Lactobacillus species dominance.
in Reproduction & fertility
Amabebe E
(2022)
A Combination of Cervicovaginal Fluid Glutamate, Acetate and D-Lactate Identified Asymptomatic Low-Risk Women Destined to Deliver Preterm: a Prospective Cohort Study.
in Reproductive sciences (Thousand Oaks, Calif.)
Amabebe E
(2021)
The transmembrane G protein-coupled CXCR3 receptor-ligand system and maternal foetal allograft rejection.
in Placenta
Amabebe E
(2018)
Psychosocial Stress, Cortisol Levels, and Maintenance of Vaginal Health.
in Frontiers in endocrinology
Description | NIHR Invention for Innovation Scheme |
Amount | £792,753 (GBP) |
Funding ID | II-LB-0216-20001 |
Organisation | National Institute for Health Research |
Sector | Public |
Country | United Kingdom |
Start | 02/2017 |
End | 01/2020 |
Title | Highligh report October 2014 |
Description | This is the most recent of the quarterly reports for this project. |
Type Of Material | Model of mechanisms or symptoms - human |
Provided To Others? | No |
Impact | This is still being used to develop the measurement device and has therefore had no impact yet. |
URL | http://ecclippx.group.shef.ac.uk |
Title | Informal report NIHR i4i Jan 15 2014 |
Description | This is an update regarding the development of proposed engineering device for assessing the human cervix |
Type Of Material | Technology assay or reagent |
Provided To Others? | No |
Impact | This just demonstrates that the project is on schedule and targets are being met. |
URL | http://ecclippx.group.shef.ac.uk |
Title | The Sheffield Mark 5 Electrical Impedance Measurement Device |
Description | As per the terms of the grant we have successfully developed the next Impedance Measurement device prototype which will inform forthcoming clinical experimental trials |
Type Of Material | Physiological assessment or outcome measure |
Provided To Others? | No |
Impact | This is required for the successful attainment of Milestone one as stated in the research plan for this grant |
URL | http://www.ecclippx.group.shef.ac.uk |
Title | Cervicovaginal fluid biorepository |
Description | The study has enabled the generation and collection of cervicovaginal fluid data from women at various gestational time points for biomarker discovery studies and translational investigations. |
Type Of Material | Database/Collection of data |
Year Produced | 2016 |
Provided To Others? | No |
Impact | Publication of new findings. |
Description | The pre-term birth dialogues: to develop an interdisciplinary research group to improve prediction and management of preterm birth in LMICs. |
Organisation | University of Cape Town |
Department | Institute of Infectious Disease and Molecular Medicine (IIDMM) |
Country | South Africa |
Sector | Academic/University |
PI Contribution | I am a co-PI on a GCRF Networking Grant by the Academy of Medical Sciences co-written with University of Cape Town |
Collaborator Contribution | University of Cape Town is the overseas partner in a GCRF Networking Grant awarded us by the Academy of Medical Sciences, UK |
Impact | A multi-disciplinary partnership that has resulted in a GCRF Networking Grant. SA also included in my recently successful NIHR Global Health Grant (~£1.9 million) under discussion for contracting. |
Start Year | 2017 |
Title | APPARATUS AND METHODS FOR DETERMINING FORCE APPLIED TO THE TIP OF A PROBE |
Description | An apparatus capable of determining the force applied to the tip of an electrical impedance spectroscopy probe comprises: • an elongate probe comprising a probe tip attached to a handle, the probe tip having a substantially planar distal end for contacting human or animal tissue; • a load cell located in said handle and capable of measuring a force Fload cell applied axially along a longitudinal axis when said probe tip is in contact with said human or animal tissue; • an accelerometer located in the handle for measuring a gravity vector Aaxial; • processing means for compensating for the mass of the probe tip using said measured force and gravity vector to produce a calibrated measurement of force F applied to said probe tip. |
IP Reference | WO2017109481 |
Protection | Patent application published |
Year Protection Granted | 2017 |
Licensed | No |
Impact | None yet |
Title | Developing the Everybaby Cervical Impedance Probe for predicting preterm birth. |
Description | Everybaby limited is Developing the Cervical Impedance Probe for predicting preterm birth and aims to undertake multicentre and multi-country trials by the beginning of 2023. |
Type | Diagnostic Tool - Non-Imaging |
Current Stage Of Development | Late clinical evaluation |
Year Development Stage Completed | 2022 |
Development Status | Actively seeking support |
Impact | The device will be a new point of care test for pregnancy risk assessment for preterm birth. |
Company Name | EVERYBABY LIMITED |
Description | Company to develop and commercialise the cervical electrical impedance device funded by my MRC Grant |
Year Established | 2019 |
Impact | The company is concluding the next version of the cervical probe for application for regulatory approvals across the UK, Europe, USA, The Middle East and Asia |
Description | Public engagement via media interviews and press releases relating to the technology |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | This was a Press Release by the STHFT and the UoS relating to the work and new grant funding. This was also published in the Telegraph Newspaper which attracted international readership: http://www.satprnews.com/2017/03/01/next-generation-device-could-herald-breakthrough-in-prediction-of-preterm-birth/ and http://www.telegraph.co.uk/news/2017/02/25/premature-babies-smart-pen-save-nhs-1bn-year-revolutionising/ |
Year(s) Of Engagement Activity | 2017 |
URL | http://www.telegraph.co.uk/news/2017/02/25/premature-babies-smart-pen-save-nhs-1bn-year-revolutionis... |
Description | Publicity newsletter for the next generation EIS device following successful licensing and spin-out of company to commercialise the impedance probe |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Born too soon: novel device improves prediction of preterm birth - the newsletter raised awareness about the technology and the technical team including the new CEO of Everybaby Ltd who will commercialize the device. |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.medicaldevice-network.com/analysis/eis-everybaby/ |
Description | University of Sheffield Festival of the Mind |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | The project stimulated thought-provoking discussions by the Sheffield and regional community on the rising global incidence of preterm birth (PTB) and what we are doing to address this health challenge. We reflected on the local and global burden of PTB bears and the need for better diagnostic and preventive tools. To achieve these goals, we created a pregnancy-animated timeline using a multimedia portfolio of 2D and 3D pregnancy scans and combining these visual components with extracts from interviews with parents in Sheffield and around the world who have experienced PTB (thanks to the ongoing collaborations between the ECCLIPPxTM team and researchers in South Africa, Bangladesh, Nigeria and Argentina). During the Festival of the Mind, the video presentation was supported with a talk by our research group and members of our Preterm Birth PPI team about how current research in Sheffield can help prevent preterm birth or its consequences. Our project raised awareness about the importance of doing research on PTB and encouraged members of the public to participate in our studies by financially supporting such work, joining the PPI team or becoming co-applicants on future grant applications. |
Year(s) Of Engagement Activity | 2018 |
URL | http://festivalofthemind.group.shef.ac.uk/born-too-early-too-soon-a-story-across-gestations/ |