Essay: Preterm birth

1 Introduction
1.1 Preterm birth
Every year 135 million babies are born worldwide of which 14.9 million babies are born preterm. Preterm birth is defined by the world health organization (WHO) as all alive births before 37 completed weeks of gestation or fewer than 259 days since the first day of a woman’s last menstrual period. Sub-division of preterm birth is based on gestational age: extremely preterm (<28 weeks), very preterm (<32 weeks) and moderate to late preterm (32 to <37 weeks) (1). Overall, more than one million babies die due to complications of preterm birth. Numerous other health risks are associated with prematurity such as reduced growth, cardiovascular complications, respiratory, gastrointestinal and metabolic problems, neurodevelopmental and cognitive dysfunction and major difficulties in academic achievement (2). The exact cause of premature births is still unknown but different interventions are available. The two main interventions for prevention of preterm birth are cervical cerclage and tocolytics. A cervical cerclage is indicated when the risk of late miscarriage or preterm delivery is increased due to congenital or acquired weakness in the cervix. Although cervical cerclage might benefit women with short cervices who have previous preterm birth, the evidence is not conclusive and selection of the appropriate candidates for cerclage is uncertain (3, 4). Tocolytics are administered to delay delivery to allow transfer to a maternal intensive care unit where corticosteroids could be given to reduce neonatal morbidity and mortality. Corticosteroids are always given in combination with tocolytics and reduce the incidence of neonatal respiratory distress syndrome, intraventricular hemorrhage and perinatal death (4). Tocolytics are mainly agonists of the uterorelaxant pathway like magnesium, β-adrenergic receptor agonists, etc. or antagonists of the uterotonic pathways like progesterone, calcium channel blockers, etc. (5). The effects of tocolytic therapy in arresting preterm labor and preventing preterm birth are limited. This failure of the tocolysis might be because once preterm labor is finally diagnosed, any therapeutic benefit is already lost or becomes temporary. Therefore, the identification of woman at risk and early detection of labor are important factors in the prevention of preterm birth (6, 7).
1.2 Telemonitoring
In an effort to improve the early detection of preterm labor, telemonitoring can be an useful method for the detection of early uterine contractions without hospitalizing the patient. Telemonitoring is the remote monitoring of patients, including diagnosing, treating, or consultation, via telecommunications for a patient at a distance (8). Telemonitoring of patients is a novel technique in the medical care system. Since a few years it is possible to monitor patients at home. Various medical fields such as cardiology, endocrinology, nephrology, etc. are already using telemedicine for several years . However, telemonitoring in the field of obstetrics is a newly developing field . Although, telemonitoring for gestational diabetes is already used . The continuous care of the mother and the fetus are of primary importance, even in low-risk pregnancies. Several techniques are already used like the Home Uterine Activity Monitor (HUAM), the FETALGARD Lite-NIBP device and Sense4Baby. All these techniques are based on tocodynamometry for the measurements of uterine activity (9). Which results in an uncertain accuracy due to influences of different variables such as instrument placement, the tension of the belt, the amount of adipose tissue, etc. (6). Therefore, the uterine contractions sensor (stingray, Bloom technologies, San Francisco) is developed. The measurements with the stingray are based on electrohysterography (EHG), the uterine electromyography. The stingray sensor is a portable device which is applied to the mother’s abdomen and is able to measure uterine contractions and the maternal heartbeat. These data are displayed in a smartphone application and send to the hospital for reviewing.
1.3 The process of labor
Throughout the pregnancy different types of contractions can occur. These contractions can either be Braxton Hicks contractions or labor contractions. Braxton hicks contractions are also called practice contractions because they prepare the uterus for labor. They can begin early in the second trimester but are most commonly in the third trimester. The Braxton hicks contractions are irregular in intensity, infrequent, unpredictable and non-rhythmic. The contractions do not increase in intensity or frequency and are mostly experienced as uncomfortable rather than painful since they are beneath the pain threshold of 15-20 mmHg. Although for some women the contraction can be painful (12, 13). The Braxton hicks contractions increase towards the end of the pregnancy and evolve into true labor contractions. True labor contractions occur in two phases namely, the latent phase and the active labor phase
In the latent phase of labor, the contractions are somewhat irregular but increase progressively in intensity (50-60 mmHg) and become more oriented, more polarized and more frequent. The frequency of contractions can change from 5 to 30 minutes and will last for 30 to 45 seconds. Changes in the connective tissue of the cervix contribute to cervical softening, effacement and dilatation. The process of dilation will take approximately 8 hours (Figure 1), although definitions of the latent phase duration vary between researchers. The onset of the latent phase is often based on the woman’s report of painful contractions. The latent phase ends when a patient achieves a cervical dilation of two- three centimeter (11, 14).
During active labor the contractions increase in intensity, duration and frequency. The duration of the contractions will increase to 45-60 seconds and the rest phase between contractions will decrease to three to five minutes. The uterus will contract more orientated and synchronized. The dilation of the cervix occurs in three phases namely an acceleration phase, a phase of maximum slope and a deceleration phase. The duration of the acceleration phase has a significant degree of variation and is compatible with a cervical dilation of three to five centimeter. The phase of maximum slope has the most rapid rate of dilation during labor and the cervix will further dilate from five to eight centimeters. At last, the deceleration phase is identified when the rate of dilation decreases and maximum dilation is reached. This phase will last for about 30 minutes to 2 hours. The durations of contractions will further increase to 60-90 seconds with a resting phase of 30 seconds to 2 minutes (Figure 1). This phase is the hardest because the contractions are long, strong, intense and can even overlap (12, 15, 16).
Figure 1: The average dilation curve for nulliparous labor (15).
1.3.1 Dystocia
Dystocia is characterized by an abnormal slow progress of labor and can be due to problems related to the fetus e.g. large or a malposition of the fetuses, maternal reproductive tract abnormalities and primary or secondary uterine inertia. Uterine inertia is the absence of effective uterine contractions during labor and is the most common cause of dystocia. Poor functioning of the uterus may be due to incomplete polarization. Studies conducted to investigate the pattern of uterine contractions showed that the fall time (time it takes to return from its peak to its baseline) of a contraction in relation to its rise time (time to reach its peak) was longer in dystocia compared to normal progressing labor. Therefore, less contractions per hour are present in patients with dystocia which causes the slower progress of labor (17). Uterine electromyogram topography can be used to display dystocia. Dystocia can be managed medically, with uterotonic agents such as oxytocin and assisted fetal extraction, or surgically, with delivery through Cesarean section (17, 18).
1.4 Induction of labor
Induction of labor is defined as the artificial initiation of labor, before its spontaneous onset, for the purpose of delivery of the fetus and the placenta (19). Induction of labor is a common obstetric intervention which is usually undertaken for a clinical indication and widely practiced to improve the health outcome for women and their infants. Unfortunately, labor induction itself may cause problems especially when the cervix is not favorable (20). So labor induction should only be considered when it is felt that the benefits of vaginal delivery outweigh the potential maternal and fetal risks of awaiting spontaneous labor. The most common reasons for labor induction are post-term pregnancies, diabetes, hypertensive disorders and maternal request.
Methods of inducing labor include both pharmacological medication and mechanical approaches. Several factors may influence the choice of method for induction of labor including cervical and membrane status, parity, and patient and provider preference.
1.4.1 Pharmacological labor induction
The most common pharmacological medication used to induce labor are oxytocin and prostaglandin. Oxytocin is naturally synthesized in the hypothalamus and stored in the posterior pituitary. Sensory stimuli of the cervix, vagina and even the breasts causes the release of oxytocin. Maternal oxytocin levels are important in the second stage of labor but their role in the initiation of labor is still unclear. It may play a very important role in the initiation of parturition by paracrine interactions between fetal membranes and the myometrium involving the oxytocin receptor system. The most common side effect of oxytocin treatment is hyperstimulation of the uterus. Hyperstimulation is defined as a persistent pattern of >5 contractions/10 minutes, contractions lasting >2 minutes or contractions of normal duration occurring within 1 minutes of each other with or without fetal heart rate changes. The resulting prolonged and intense uterine contractions are beneficial during the third stage of labor, but potentially devastating if the drug is administered prior to delivery of the baby (19). Another method for labor induction is prostaglandins, which induces both uterine contractility and cervical dilation. Prostaglandins are produced by almost every tissue in the body and originate from the vesicular glands. Administration of prostaglandins is possible intravenous, extra-amniotic, oral and endocervical. However, the vaginal route is the most successful and is non-invasive. Hyperstimulation of the uterus with fetal heart rate changes is also a potential side effect of prostaglandins. Since prostaglandin is produced in every tissue in the body, administration for the purpose of inducing labor or ripening an unfavorable cervix is tempered by the effects in other systems, including the gut and brain (19, 21).
1.4.2 Mechanical labor induction
The most common mechanical approaches used for labor induction are balloon catheters and amniotomy. Balloon catheters, unlike pharmacological options, may ripen the cervix without leading to labor and a second agent, such as oxytocin or prostaglandins, is required. The Cook® double balloon catheter is often used for labor induction and requires transcervical placement with one balloon resting at the internal cervical os and the second balloon lying distal to the external os. Prostaglandin gels can be placed between the two balloon to optimize the results (19). Amniotomy, i.e. deliberate artificial rupture of the membranes, causes the release of endogenous prostaglandins which in turn results in cervical changes and spontaneous labor. To receive active labor, amniotomy is performed in combination with oxytocin or prostaglandins. This procedure is only possible if the membranes are physically accessible. Potential risk includes cord prolapse and when the membranes are ruptured, the fetal environment is vulnerable to ascending infection. Amniotomy is often used during labor for clinical reasons, such as failure to progress in the first stage of labor and need to assess the status of the liquor in the presence of fetal heart rate abnormalities (22).
1.5 Uterine contractions
Uterine contractions are the main forces throughout the process of labor and are defined as contractions of the uterus smooth muscles, resulting in an increase of intra-uterine pressure eventually leading to cervical dilation and delivery (10). Uterine contractions are expressed in frequency, duration and intensity and will increase throughout labor. The frequency and duration of contractions are expressed in minutes. Whereas the intensity of contractions is expressed in millimeter of mercury (mmHg). Which is also known as the intra-uterine hydrostatic pressure. The pressure at rest is usually five mmHg, but during pregnancy the intra-uterine pressure can increase to about 30 mmHg and during labor the intra-uterine pressure can increase even to 60-80 mmHg or more (11).
The smooth muscles cells of the uterus or myometrial cells can all individually contract or relax. Contraction and relaxation of the individual cells are not a feature of labor. It is a constant phenomenon during, but also outside pregnancy. Simultaneous contractions of all myometrial cells will lead to an increase in intra-uterine pressure. Only when the pressure increase is high enough, pregnant women will recognize this as a contraction. This process of contraction and relaxation of the myometrial cells results from the cyclic de- and repolarization of the muscle cell membranes. Intermittent bursts of spike-like action potentials result in spontaneous electrical discharges in the muscles of the uterus. A single electrical spike can initiate a contraction, but multiple, coordinated spikes are needed for forceful and maintained contractions. In order to obtain multiple, coordinated action potentials all through the myometrium, myometrial cells are coupled together electrically by gap junctions. Throughout most of the pregnancy, only a few gap-junctions are present indicating poor coupling and decreased electrical conductance. At term, however, the gap junctions increase and form an electrical network required for effective contractions. Estrogen and progesterone are essential in regulating the presence of gap junctions. During pregnancy, the myometrium is influenced by progesterone which inhibits the development of gap junctions. Therefore no coordinated contractions are present during pregnancy. Towards the end of pregnancy, the myometrium is more influenced by estrogen, gap junctions develop and the myometrium contracts simultaneous (6, 11). Estrogen not only influences the amount of gap junctions but also the density of oxytocin receptors on myometrial cells. Oxytocin is produced in the posterior pituitary gland and stimulates contractions of the myometrium by stimulating the entry of Ca2+ in the myometrial cells and inhibiting the Ca2+ efflux mechanisms (5). The oxytocin receptors will increase significantly during labor, thereby the myometrium is able to respond maximally to the endogenous oxytocin. The oxytocin receptors together with the increased gap junctions, the myometrium is able to contract intense and coordinated .
1.6 Monitoring uterine activity
Monitoring during labor is used to assess both uterine activity and fetal wellbeing. Fetal wellbeing is monitored based on the fetal heart rate pattern in relation to contractions. Whereas uterine contractions is evaluated based on the frequency and duration of contractions. Different monitoring methods can be used to measure contractions during labor. The cardiotocography is the most common method for assessing uterine contractility while the intrauterine pressure catheter is considered to be the gold standard. Since the two currently used methods have several disadvantages, an alternative method is in development. Uterine electromyography (EMG) is a promising method to perform accurately and reliable, non-invasive trans-abdominal surface measurements (6, 23, 24).
1.6.1 Cardiotocography
Fetal monitoring is typically assessed non-invasively with a cardiotocography (CTG). The CTG is used throughout the third trimester of pregnancy and during labor. Cardiotocography records the fetal heartbeat using Doppler ultrasound transducer (-cardio-) and the uterine contractions using a tocodynamometer or pressure transducer (-toco-). The Doppler ultrasound transducer and the pressure transducer are placed against the mother’s abdomen with an elastic belt (Figure 2). The Doppler ultrasound is used to measure moving structures as the heart, making is useful for monitoring fetal heart rate (FHR). Pressure transducers are external force measurement devices which detect changes in abdominal contours as an indirect indication of uterine contractions. The information provided by the FHR sensor are the baseline FHR ((usually between 110 and 160 beats per minute), accelerations (transient increases in the FHR), and decelerations (transient decreases in the FHR). Changes in FHR can be subtle and can be influenced by internal stimuli such as uterine contractions or external stimuli like movements of the mother. Therefore FHR pattern recognition, including the relationship between the uterine contractions and FHR decelerations, are fundamental to the use of continuous CTG monitoring (6, 24, 25).
Figure 2: Cardiotocography using a Doppler ultrasound transducer for fetal heart rate monitoring and a pressure transducer for contraction measurements.
The major limitation for CTG is the inability to assess the intensity of uterine contractions, which is crucial for labor management. Another limitation is accuracy since many different variables affect the measurement of FHR and/or uterine contractions, such as instrument placement, the amount of subcutaneous fat, and uterine wall pressure. CTG also prevents mobility and restricts the use of massage, different positions and/or immersion in water used to improve comfort, control and coping strategies during labor (6, 23, 25).
1.6.2 Intrauterine pressure catheter
The intrauterine pressure catheter (IUPC) is considered to be the gold standard for monitoring uterine contractions. It enables assessment of both the frequency and the intensity of contractions more accurately than cardiotocography. The newest type of IUPC is the Koala® IUPC (Clinical Innovations, Inc., Murray, Utah). The Koala® is a sensor-tipped IUPC that employs air-coupling technology from a distally mounted flexible balloon in the uterus to an external, reusable transducer in the monitor cable and connector. A sensing membrane near the tip of the catheter registers pressure readings which are transmitted through a sealed micro-column of air to a transducer remotely located in a reusable monitor cable. These intra-uterine pressure readings indicate the frequency and intensity of uterine contractions enabling the clinicians to evaluate labor and fetal wellbeing (6, 24, 26). To receive accurate readings the catheter needs to be placed in the amniotic place (Figure 3). To allow passage of the IUPC, the fetal membranes must be ruptured and the cervix must be sufficiently dilated at least one to two centimeters. Improper placement outside the amniotic membranes (extraovular-between the chorion and the endometrial lining) (Figure 3) will still provide a reading, but not the reading of the absolute intrauterine pressure. The risks for placental abruption and fetal distress will also increase especially during amnioinfusion (27). The use of an IUPC is also limited due to several other risk factors, such as infections, uterine perforation, fetal damage, etc. (24).
Figure 3: Placement of the intrauterine pressure catheter.
1.6.3 Electrohysterography
Electrohysterography uses a different modality for monitoring uterine activity. This method measures the electrical activity of the myometrium which is responsible for myometrial contractions. It utilizes surface electrodes applied to the maternal abdomen and a high-frequency, low-noise amplifier to measure the electrical activity. In addition, it also makes use of filtering technologies, as well as the powerful processing capabilities of currently available personal computing devices to analyze uterine smooth muscle contractions (23). EHG enables non-invasive evaluation of the beginning, time to peak, duration, frequency and intensity of uterine contractions (24). The frequency, amplitude and duration of contractions are determined, respectively, by the frequency of the action potential bursts, the total number of myometrial cells that are activated simultaneously, and the duration of each burst (6). Earlier studies showed that the EHG bursts correlate with changes in intrauterine pressure and that measuring EHG activity has a similar effectiveness of detection of uterine contractions to CTG (Figure 4) and even compared with an IUPC. Further, EHG is able to identify the transition from the non-labor to the labor state of the myometrium (28). Recent research investigated the propagation of the electrical signal in the myometrium. As mentioned before, the amount of gap junctions in the uterus increase close to delivery. The increasing number of gap junctions form an electrical network required for the coordination of effective contractions. This electrical network increases the propagation velocity of the electrical signal. Subsequently, EHG recordings can be used to assess the propagation velocity and thereby determine the stage of pregnancy (29). Consequently, labor, and subsequent term or preterm delivery, can be predicted successfully using non-invasive uterine EHG (6).
Figure 4: Correspondence between the electrical activity of the myometrium (EMG activity; top trace) and tocodynamometry (bottom trace). The numbers on the y-axis of the tocodynamometry trace are arbitrary units (28).
1.7 Aim of the study
Early diagnosis of preterm labor is an important factor in the prevention of preterm birth. The problem is that throughout the third trimester expecting mothers have different contractions. The identification of labor contractions at home depends on the subjective, unreliable self-diagnosis of the mother, since the currently used methods are not applicable at home. Therefore, the non-invasive, wearable stingray sensor is developed by Bloom technologies to obtain access to specific information, currently only available in hospitals. The stingray sensor is able to connect with an application (belli), especially developed for uterine contraction monitoring at home.
The first objective of this research project is to validate uterine activity measurements of the stingray sensor in the hospital. The validation of the stingray sensor will be done by comparing the EHG measurement of the stingray sensor with the CTG measurements. If possible the EHG measurements will also be compared with IUPC measurements. Due to the invasiveness of IUPC, these measurements are limited. Afterwards, the algorithms for the application are optimized based on the measurements in the hospital.
The second objective is a feasibility study of the belli application based on measurements at home. The results of the measurements at home are send to the hospital via an online platform. After delivery, the use of the application and the use of the patches is evaluated based on a questionnaire.