Assessing the Risk of Spontaneous Premature Birth by Electrical Impedance Spectroscopy of the Cervix.

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.

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.

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.