ST-analysis of the fetal electrocardiogram (ECG) (STAN ® ) combined with cardiotocography (CTG) for intrapartum fetal monitoring has been developed following many years of animal research. Changes in the ST-segment of the fetal ECG correlated with fetal hypoxia occurring during labor. In 1993 the first randomized controlled trial (RCT), comparing CTG with CTG + ST-analysis was published. STAN ® was introduced for daily practice in 2000.
To date, six RCTs have been performed, out of which five have been published. Furthermore, there are six published meta-analyses. The meta-analyses showed that CTG + ST-analysis reduced the risks of vaginal operative delivery by about 10% and fetal blood sampling by 40%. There are conflicting results regarding the effect on metabolic acidosis, much because of controveries about which RCTs should be included in a meta-analysis, and because of differences in methodology, execution and quality of the meta-analyses. Several cohort studies have been published, some showing significant decrease of metabolic acidosis after the introduction of ST-analysis.
In this review, we discuss not only the scientific evidence from the RCTs and meta-analyses, but also the limitations of these studies.
In conclusion, ST-analysis is effective in reducing operative vaginal deliveries and fetal blood sampling but the effect on neonatal metabolic acidosis is still under debate. Further research is needed to determine the place of ST-analysis in the labor ward for daily practice.
Highlights
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Five RCTs compared CTG + ST-analysis to CTG only.
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Fetal blood sampling and standardized “STAN clinical guidelines” were used.
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Fetal blood sampling and vaginal operative delivery was significantly reduced.
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The effect on metabolic acidosis differs in the published studies.
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The learning curve was not taken into account in any RCT.
Introduction
Electronic fetal heart rate (FHR) monitoring is a widely used method for assessing fetal status during labor. It aims to enable clinicians to identify hypoxic fetuses at risk for deterioration and provide prerequisites for a decision to intervene, and to deliver either vaginally or by cesarean section, thereby avoiding neonatal and long-term injury due to intrapartum asphyxia. Although little evidence exists regarding its efficacy, monitoring through cardiotocography (CTG) continues to be the method of choice in modern labor and delivery units in developed countries . Despite this, there has been no significant reduction in the incidence of long-term neurologic morbidity (including cerebral palsy) and research has been stimulated by the low true positive predictive value of CTG for metabolic acidosis, which often results in unnecessary interventions and a significant increase in the cesarean section rate during the last 40 years due to concerns during labor. The addition of fetal blood sampling (FBS) is believed to hamper this effect; however, systematic reviews report no evidence of benefit in reducing the operative interventions . Furthermore, FBS has also been shown to have a poor positive predictive value for intrapartum hypoxia . This is probably due to the fact that performance of FBS requires expertise, is invasive, and must be repeated with persisting CTG abnormalities, and thus is often not performed when indicated .
Other tools for fetal surveillance, for example, fetal pulse oximetry, have not been successful maybe due to the well-known challenge lying in developing new and emerging technologies, related not only to the need to provide basic physiology data but also to meet requirements of data acquisition, signal processing, and data presentation . Furthermore, any method in the fetal monitoring area requires understanding and compliance to clinical guidelines as well as a positive attitude toward changes of practice, a truly challenging perspective in such a medico-legally loaded field. Other important aspects related to evaluating the effect of medical technology are the choice of outcome parameters, the study design, the clinical setting of a trial, the ownership of the technique, as well as financial support available for its development. Moreover necessary clinical trials are expected to meet evidentiary standards that were never applied to existing technologies.
ST-analysis of the fetal electrocardiogram (ECG; STAN ® ) was introduced in the labor wards in 2000, after many years of research, starting with experimental animal research. Early animal studies observed that changes in the ST-segment of the fetal ECG correlated with fetal hypoxia occurring during labor . The ST analyzer (STAN ® monitor; Neoventa Medical, Goteborg, Sweden) was developed to combine traditional CTG with automatic analysis of the ST-segment of the fetal ECG. Changes in the shape of the ST-segment are noted automatically and an ST event is generated for a significant ST-change ( Fig. 1 ). Guidelines have been developed defining whether intervention is required according to changes occurring in the CTG in combination with ST-changes of the fetal ECG ( Table 1 ) .
| Classification of cardiotocographic patterns according to FIGO guidelines | |||
|---|---|---|---|
| Cardiotocographic classification | Baseline heart frequency | Variability Reactivity | Decelerations |
| Normal | 110–150 beats/min | 5–25 beats/min | Early decelerations |
| Accelerations | Uncomplicated variable decelerations with a duration of <60 s and a beat loss of <60 beats/min | ||
| Intermediary a | 100–110 beats/min | >25 beats/min without accelerations | Uncomplicated variable decelerations with a duration of <60 s and a beat loss of >60 beats/min |
| 150–170 beats/min Short bradycardia episode | <5 beats/min for >40 min | ||
| Abnormal | 150–170 beats/min and reduced variability | <5 beats/min for >60 min | Repeated late decelerations |
| >170 beats/min | Sinusoidal pattern | Complicated variable decelerations with a duration of >60 s | |
| Preterminal | Total lack of variability and reactivity with or without decelerations or bradycardia | ||
| ST-changes that prompt clinical intervention such as delivery or solving a cause of fetal distress | ||
|---|---|---|
| Intermediary CTG | Abnormal CTG | |
| Episodic T/QRS rise (duration < 10 min) | Increase >0.15 from baseline | Increase >0.10 from baseline |
| Baseline T/QRS rise (duration ≥ 10 min) | Increase >0.10 from baseline | Increase >0.05 from baseline |
| Biphasic ST (a component of the ST-segment below the baseline) | Continuous >5 min or >2 episodes of coupled biphasic ST type 2 or 3 | Continuous >2 min or >1 episode of coupled biphasic ST type 2 or 3 |
a Combination of several intermediary observations will result in an abnormal CTG.
Protocols to guide the use of a medical device have to be assessed and approved by the company responsible for the technology as part of the CE-marking process and by the FDA before any use in the United States. This implies that a change of guideline is limited by regulations similarly to change of an indication in relation to drugs. The premarketing approval (PMA) process, required for any new methodology, is the most stringent process that requires full documentation, including basic pathophysiology, signal processing, data presentation, control of device design, production, and software and adequate clinical data to support its safe and efficient use. On the basis of all these data and years of efforts, marketing approval is granted based on specific indications and method of use, and is enforced by law. Thus, it is not just the availability of a specific technology that allows a clinician to apply it, but the limit up to which it is approved for use.
The technique
The STAN ® concept is based on the association between changes of the ST-interval of the fetal ECG and the function of the fetal myocardium during hypoxia. The changes in fetal ECG associated with fetal distress are either an increase in T-wave amplitude, quantified by the ratio of T-wave amplitude to QRS-amplitude (T/QRS ratio), or a biphasic ST-segment. An increase in T-wave amplitude and subsequently in T/QRS ratio has been associated with a catecholamine surge, activation of β -adrenoreceptors, myocardial glycogenolysis, and metabolic acidosis . A biphasic shape of the ST-segment is related to two situations: (1) it may occur when the fetal heart is exposed to acute hypoxic stress, whereby it has had no time to respond to hypoxia, or (2) when the fetal heart has a reduced capacity to respond, due to (chronic) stress situations and lack of or already used resources. Biphasic ST-changes of the fetal ECG have been associated with disturbances in heart muscle function, infection, or malformations.
The STAN ® concept is based on a combined interpretation of CTG and ST changes . The relevance of an ST-change depends on the visual assessment of the CTG that, according to the criteria of the International Federation of Gynecology and Obstetrics (FIGO), is classified as “normal,” “intermediary” (or “suspicious”), “abnormal” (or “pathological”), and “(pre)terminal” . If a CTG is normal, any ST-change on the STAN ® monitor can be ignored. When a CTG is (pre)terminal, immediate intervention is advised, irrespective of ST-changes as is the case where the fetus has been assessed to be nonreactive or not found to be in a steady state at onset of the recording. In case of an intermediary or abnormal CTG, the STAN ® guidelines indicate intervention in relation to ST-changes. Depending on the clinical circumstances, the intervention could be delivery, FBS, or alleviation of a possible cause of fetal distress, for example, uterine hypertonus or maternal hypotension. The STAN ® guidelines can be used from a gestational age of 36 weeks onward.
The technique
The STAN ® concept is based on the association between changes of the ST-interval of the fetal ECG and the function of the fetal myocardium during hypoxia. The changes in fetal ECG associated with fetal distress are either an increase in T-wave amplitude, quantified by the ratio of T-wave amplitude to QRS-amplitude (T/QRS ratio), or a biphasic ST-segment. An increase in T-wave amplitude and subsequently in T/QRS ratio has been associated with a catecholamine surge, activation of β -adrenoreceptors, myocardial glycogenolysis, and metabolic acidosis . A biphasic shape of the ST-segment is related to two situations: (1) it may occur when the fetal heart is exposed to acute hypoxic stress, whereby it has had no time to respond to hypoxia, or (2) when the fetal heart has a reduced capacity to respond, due to (chronic) stress situations and lack of or already used resources. Biphasic ST-changes of the fetal ECG have been associated with disturbances in heart muscle function, infection, or malformations.
The STAN ® concept is based on a combined interpretation of CTG and ST changes . The relevance of an ST-change depends on the visual assessment of the CTG that, according to the criteria of the International Federation of Gynecology and Obstetrics (FIGO), is classified as “normal,” “intermediary” (or “suspicious”), “abnormal” (or “pathological”), and “(pre)terminal” . If a CTG is normal, any ST-change on the STAN ® monitor can be ignored. When a CTG is (pre)terminal, immediate intervention is advised, irrespective of ST-changes as is the case where the fetus has been assessed to be nonreactive or not found to be in a steady state at onset of the recording. In case of an intermediary or abnormal CTG, the STAN ® guidelines indicate intervention in relation to ST-changes. Depending on the clinical circumstances, the intervention could be delivery, FBS, or alleviation of a possible cause of fetal distress, for example, uterine hypertonus or maternal hypotension. The STAN ® guidelines can be used from a gestational age of 36 weeks onward.
Randomized clinical trials
Five RCTs, which included 15,365 patients, have been performed since 1993, all comparing continuous CTG-only monitoring with continuous CTG monitoring with ST-analysis . Details of the studies are shown in Table 2 . All trials used FBS in both arms.
| Authors/Year | Number of obstetric units/country | N | Main results |
|---|---|---|---|
| Westgate J et al. 1993 | 1/UK | 2434 | Trend to decrease in metabolic acidosis (OR 0.38, 95%CI: 0.13–1.07) Decrease in operative vaginal delivery rate (by 46%; p < 0.001) Trend to decrease in low 5-min Apgar score (OR 0.62, 95%CI: 0.35–1.08) |
| Amer-Wåhlin I et al. 2001 | 3/Sweden | 4966 | Decrease in metabolic acidosis (by 53%; p = 0.02) Decrease in operative vaginal delivery rate (by 17%; p = 0.047) No difference in rate of fetal blood sampling |
| Ojala K et al. 2006 | 1/Finland | 1483 | No difference in metabolic acidosis No difference in operative delivery rate Decrease in fetal blood sampling (by 56%; p < 0.001). |
| Vayssière C et al. 2007 | 2/France | 799 | No difference in neonatal outcome a No difference in operative deliveries Decrease in FBS by 56% (RR 0.44, 95%CI 0.36–0.52). |
| Westerhuis M et al. 2010 | 9/The Netherlands | 5681 | No decrease in UA metabolic acidosis in ECF Decrease in UA metabolic acidosis in blood by 39% (RR 0.63, 95%CI 0.42–0.94) No difference in operative deliveries No difference in low Apgar score and neonatal HIE Decrease in FBS by 48% (RR 0.52, 95%CI 0.46–0.59) |
a incl. acidosis, metabolic acidosis, low Apgar score, neonatal morbidity, and neonatal death.
Westgate et al. published the first randomized controlled trial (RCT) on the effect of intrapartum fetal ECG . In this trial of 2434 women monitored with CTG or CTG + ST-analysis during labor, absolute values of T/QRS and visually verified trends of increase in T/QRS were used rather than automatically detected T/QRS changes, as developed during later trials and described in the current STAN clinical guidelines. In this first trial, the CTG + ST arm of the study showed a 46% decrease in the rate of operative vaginal deliveries and a trend toward less metabolic acidosis. Given these encouraging results, a second RCT was performed with a further development of the technique, including computerized ST-analysis ( Table 2 ) and using guidelines based on the experience . A significant decrease in neonatal metabolic acidosis demonstrated in the second RCT was not supported by findings in the following three RCTs . These trials were not all powered to obtain a significant result and differed in the way metabolic acidosis was calculated (base deficit in blood giving considerably higher rates of metabolic acidosis compared with base deficit in extracellular fluid). Furthermore, one of the trials used abnormal CTG as inclusion criteria, without checking for baseline fetal status, thereby, in fact, violating the STAN guidelines, which state that ST-analysis should be started as early in labor as possible, preferably with a normal CTG .
The results of the five published STAN trials are summarized in Table 2 . As can be observed, their results are quite different.
A large National Institute of Child Health and Human Development (NICHD)-driven multicenter trial (NCT01131260) in the United States presented its results recently at the Society for Maternal-Fetal Medicine (SMFM) 2015. There are some important differences between the study designs of the European trials and the US trial. In the FDA-approved US trial, a simplified approach with a 3-category CTG classification system was chosen, thus assessing nonreassuring FHR (NRFHR grade 1) in one category instead of separating them into intermediary and abnormal as in the European 4-category guidelines. The aim was to simplify the interpretation of CTG + ST changes and reduce the risk for ambiguous data interpretation. However, major changes occurred in the US user guidelines affecting the decision to act based on ST-waveform changes as an adjunct to CTG analysis. The most obvious is that a 60′ rule has been included, stating that in case of an NRFHR for >60′ but no ST event, direct physician assessment of fetal state was required with intrauterine resuscitation, and if no improvement was observed, expeditious delivery was performed.
The statement in the US study protocol that could cause ST-analysis to be completely ignored was a paragraph stating the following: Do not rely solely on the appearance of an ST event marker to signal the need for obstetrical intervention. If you suspect, on the basis of FHR-only and/or clinical data that the fetus is experiencing severe hypoxia, you should manage the patient accordingly despite the absence of an ST event marker. As a consequence, one would assume unnecessary interventions, especially in 2nd stage with the risk of neonates being affected due to emergency operative procedures. Furthermore, the following statement was also added in the US study protocol:
In the presence of maternal fever and related infection, the fetus may have a blunted or no response to hypoxia, and ST events may fail to appear. Therefore, if the maternal temperature reaches 38.0°C (100.4 F) or greater, management should be related to the FHR and the clinical situation.
Thus, the USRCT study protocol was substantially altered from the protocol approved by the FDA, and the guidelines at some decisive points different from those used in the previous STAN RCTs, making comparisons problematic.
Meta-analysis of the RCTs
Six meta-analyses , including these five RCTs, have been performed, of which one is an individual patient data meta-analysis (IPDMA) and one is a “correction” of errors performed in the first five meta-analyses . Details are shown in Table 3 . The IPDMA offers numerous statistical and clinical advantages over an aggregate data meta-analysis as it increases the power to detect differential treatment effects across individuals in RCTs. The IPDMA showed that CTG + ST-analysis of the fetal ECG reduces the risk of metabolic acidosis in the extracellular fluid (RR 0.76; CI 95% 0.53–1.10) compared with CTG alone, although the reduction was not statistically significant. The numbers of FBS (RR 0.49; CI 95% 0.44–0.55) and instrumental vaginal deliveries (RR 0.90; CI 95% 0.83–0.99) were significantly reduced by CTG + ST-analysis. Furthermore, CTG + ST-analysis reduced the incidence of metabolic acidosis calculated in blood, arterial pH < 7.15, arterial pH < 7.05, arterial pH < 7.00, NICU admissions, hypoxic–ischemic encephalopathy, need for intubation, seizures, and a composite of adverse perinatal outcome, although not statistically significant. The cesarean section rate was comparable in both groups (RR 0.99; CI 95% 0.91–1.09). For the other secondary outcomes, no substantial differences were found between CTG + ST-analysis and CTG alone. In addition, CTG + STAN reduced the incidence of neonatal intensive care admission for infants born after 41 weeks of gestation (RR 0.61; CI 95% 0.39–0.95).
| References of RCTs included | RR (95% CI) metabolic acidosis | RR (95% CI) Operative delivery | RR (95% CI) Fetal blood sampling | |
|---|---|---|---|---|
| Neilson | 10,11,12,13,14 | 0.78 (0.44–1.37) a | 0.89 (0.81–0.98) b | 0.61 (0.41–0.91) |
| 0.99 (0.91–1.08) c | ||||
| Becker | 10,11,12,13,14 | 0.72 (0.43–1.19) | 0.88 (0.8–0.97) b | 0.59 (0.44–0.79) |
| 1.03 (0.67–1.21) c | ||||
| Potti | 10,11,12,13,14 | 0.80 (0.44–1.47) | 0.99 (0.91–1.08) b | NM |
| 0.89 (0.83–0.97) c | ||||
| Salmelin | 11,12,13,14 | 0.96 (0.49–1.88) | 0.93 (0.80–1.08) d | 0.55 (0.40–0.76) |
| Schuit | 11,12,13,14 | 0.76 (0.53–1.10) | 0.90 (0.83–0.99) b | 0.49 (0.44–0.55) |
| 0.99 (0.91–1.09) c | ||||
| Olofsson | 10,11,12,14 | 0.61 (0.41–0.91) | 0.88 (0.81–0.95) b | 0.64 (0.47–0.88) |
| 1.00 (0.91–1.11) c |
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