Article Type: Clinical Article

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CLINICAL ARTICLE

Retrospective study of the effect of remifentanil use during labor on fetal heart rate patterns

Danne Boterenbrood 1*, Martine M. Wassen 1, Gerard H. A. Visser 2, Jan G. Nijhuis 3

1

Department of Obstetrics and Gynecology, Zuyderland Medical Center, Geleen, the

Netherlands 2

Department of Obstetrics and Gynecology, University Medical Center Utrecht,

Utrecht, the Netherlands 3

Department of Obstetrics and Gynecology, GROW-School for Oncology and

Developmental Biology, Maastricht University Medical Center+, Maastricht, the Netherlands

*

Corresponding author: Danne Boterenbrood

Dr. H. van der Hoffplein 1, 6162 BG Geleen, The Netherlands. Tel.: +31 64 932 8066; fax: +31 88 459 7463. E-mail address: [email protected]

ABSTRACT Objective: To investigate possible associations between remifentanil and the appearance of sinusoidal heart rate patterns in fetuses, and neonatal outcomes. This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/ijgo.12344 This article is protected by copyright. All rights reserved.

Methods: The present retrospective cohort study included data from patients at over

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37 weeks of singleton or multiple pregnancies attending Zuyderland Medical Center, Sittard, the Netherlands, in labor between June 1, and August 31, 2015. Patient data were stratified by whether remifentanil was administered during delivery (remifentanil group) or not (control group), and fetal heart rate tracings were reviewed to identify sinusoidal heart rate patterns. The neonatal outcomes compared were 5-minute Apgar scores and umbilical artery pH. Results: There were 119 patients included in the study; 60 in the remifentanil group and 59 in the control group. Tracings from 20 (33%) patients in the remifentanil group exhibited a sinusoidal heart rate pattern after remifentanil administration, compared with 5 (8%) patients in the control group (P=0.001). The median time before the onset of sinusoidal patterns after remifentanil administration was 12 minutes. No adverse neonatal outcomes were recorded in either group. Conclusion: Remifentanil use during labor was associated with the occurrence of sinusoidal heart rate patterns in the fetus; this was not associated with adverse neonatal outcomes.

Keywords: Neonatal outcome; Remifentanil; Sinusoidal heart rate pattern.

Synopsis: Remifentanil use during labor was associated with sinusoidal heart rate patterns in fetuses but not adverse neonatal outcomes.

1. Introduction Sinusoidal heart rate (SHR) patterns are a rare and still not completely understood fetal heart rate (FHR) pattern that are characterized as fixed uniform fluctuations in

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the FHR [1]. In 1982, Modanlou and Freeman [2] introduced several criteria that are

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still used to describe SHR patterns: (1) stable baseline heart rate of 120–160 beats per minute (bpm) with regular oscillations; (2) amplitude of 5–15 bpm; (3) frequency of 2–5 cycles/minute; (4) fixed or flat short-term FHR variability; (5) oscillation of the sinusoidal wave form above and below baseline; and (6) no areas of normal FHR variability or reactivity.

A true SHR pattern is rarely seen and is considered a sign of severe fetal jeopardy owing to its association with increased perinatal morbidity and mortality [1, 3, 4]; consequently, it is considered a pathological FHR tracing [5]. The pathophysiological mechanism of a true SHR pattern has still not been completely revealed, but it seems to be associated with prolonged or severe hypoxia causing dysfunction of the autonomic nervous system and rapid changes in arterial blood pressure [6, 7]. A true SHR pattern is best known for its association with fetal conditions that cause severe acute or chronic fetal anemia [1, 8–10] but it has also been recorded during fetal intrapartum asphyxia/hypoxia [11, 12].

In addition to the presence of a true SHR pattern during fetal jeopardy, other SHR patterns have been reported. These pseudo-SHR patterns are mostly transient, resolving spontaneously, and are associated with good fetal outcomes. The reported incidence during labor varies from 4.2% to 15% [13–15]. They have been related to different causes including fetal sucking movements and regular mouthing [16, 17]. Narcotic analgesics, administered to patients during labor have also been reported to be a potential cause [2, 13, 14, 18–21].

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Remifentanil is a narcotic analgesic agent used for pain relief. A recent review by

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van de Velde et al. [22] demonstrated that remifentanil is increasingly used for pain relief during labor. In the Netherlands, the percentage of patients who received opiates during labor in 2013 was 15.8% [23]. Remifentanil is a short acting, potent μ1-opioid receptor agonist that crosses the placental membrane without difficulty. Significant remifentanil-associated maternal respiratory adverse events have been reported and continuous monitoring of maternal vital functions and one-to-one obstetric care is important during its use [22].

During a short period of time, several occurrences of a SHR pattern after remifentanil administration were recorded at the study institution. Based on these cases, the aim of the present study was to investigate the possible associations between remifentanil administration and the appearance of a fetal SHR pattern and neonatal outcomes.

2. Materials and methods The present retrospective study investigated the effect of remifentanil administration on FHR patterns during labor. Nulliparous and multiparous patients with singleton or multiple pregnancies who were experiencing labor after 37 weeks of pregnancy between June 1 and August 31, 2015, at Zuyderland Medical Center, Sittard, the Netherlands, a non-university teaching hospital, were included. Patients needed to have at least 60 minutes of interpretable cardiotocography data available to be included. The study was approved by the institution medical ethics committee; informed consent was not considered necessary.

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Patients who had remifentanil (Ultiva; Glaxo Smith Kline, Zeist, Netherlands)

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administered during delivery (remifentanil group) were grouped and a control group of patients, matched for spontaneous or induced labor and for delivery type, who received no pain relief or epidural analgesia was included. Patients in the remifentanil group had remifentanil administered by a patient-controlled device that was programmed to deliver 28 μg of remifentanil (solution 40 μg/mL) on request with a lockout time of 3 minutes. In line with study institution protocol, remifentanil administration was stopped at the start of the second stage of labor.

All FHR patterns were assessed by two independent investigators (D.B. and M.M.W.), who were masked to remifentanil use. If there was uncertainty about the presence of a SHR pattern, the investigators discussed the pattern and disagreements were resolved with a third reviewer (J.N.) if necessary. Tracings from labor, starting from the beginning of the first stage (i.e. dilatation greater than 3 cm) were examined. A SHR pattern was identified using the criteria described by Modanlou and Freeman [2], with a minimum period of 10 minutes.

The primary outcome was the presence of a SHR pattern, with several components of the pattern recorded: delay until pattern onset following remifentanil administration, the presence of an intermittent or continuous pattern, the total duration of the pattern in relation to the total duration of remifentanil use, and the amplitude of oscillations. The secondary neonatal outcomes were 5-minute Apgar scores and umbilical artery pH; a 5-minute Apgar score below 7 or umbilical artery pH below 7.10 were considered to indicate poor neonatal outcomes.

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Data were entered in an Excel (Microsoft, Redmond, WA, USA) database and SPSS

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version 22 (IBM, Armonk, NY, USA) was used for statistical analyses. The independent t-test, χ2 test, and Mann–Whitney U test were used to compare baseline characteristics and assess associations between remifentanil administration and SHR patterns, and P25 bpm) would be associated with severe fetal hypoxia [12, 24, 25], which is in agreement with the present results.

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The underlying mechanism for SHR patterns is not yet known and needs to be

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investigated further. A possible explanation is the interference of opioids with the central nervous system. As described previously, autonomic nervous system dysfunction, resulting in an imbalance between the sympathetic and parasympathetic nervous system, could be responsible for a decrease in FHR variability. The etiology of the appearance of the typically sinusoidal waves needs to be revealed further [6, 7].

The present study had some limitations. Primarily, it had a retrospective study design and a relatively small sample size. However, despite these small numbers, a significant difference was found between the groups. The groups were matched for the onset of labor and the type of delivery in an attempt to rule out potential confounding variables; this was because the use of oxytocin [13] and the need to perform a vacuum extraction or cesarean delivery owing to fetal distress could influence the presence of a SHR pattern. The study of Murphy et al. [13] demonstrated a significantly higher incidence of SHR patterns after the start of epidural analgesia; because eliminating all patients with epidural analgesia from the control group would influence the basic characteristics of this group, the decision was made not to exclude these patients. Owing to the very low number of SHR patterns observed in the control group, it was not possible to confirm if there was a potential association between epidural analgesia and the appearance of a SHR pattern.

The possibility of underestimating the incidence of SHR patterns owing to shorter recording times was eliminated, given that there was no significant difference in the

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total duration of FHR traces between the groups. Additionally, to prevent selection

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bias, the patients with SHR patterns who stimulated the initial interest in the study were excluded because they were outside the inclusion period.

There have been several studies that have demonstrated narcotic analgesics to cause a reduction in heart rate variability and the appearance of a SHR pattern; butorphanol, alphaprodine, meperidine, and nalbuphine have previously been demonstrated to be associated with the appearance of a SHR pattern, with reported incidences of up to 75% [2, 13, 14, 18–21]. A relatively high incidence was recorded in the present study, corresponding with these previous results. Similar to the present study, the above mentioned previous studies also failed to demonstrate any adverse neonatal outcomes when a SHR pattern was recorded.

To the best of our knowledge, the present study was the first to demonstrate the potential effect of remifentanil on FHR patterns; this has important implications for daily clinical practice. This indicates that a SHR pattern observed after starting remifentanil administration, without other signs suggestive of fetal distress, does not warrant further fetal investigation. For clinicians, this knowledge is of crucial importance as identifying a SHR pattern could otherwise lead to unnecessary interventions and to unnecessary maternal anxiety.

Research into SHR patterns was largely restricted to the years immediately after its first description and additional studies are still necessary to further clarify this unusual pattern. Further research is recommended to gain more information about the pathophysiologic mechanisms and the implications of this pattern.

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Author contributions DB contributed to the design of the study, the acquisition and interpretation of data, and writing the manuscript. MMW contributed to the design of the study, the acquisition and interpretation of data, and revising the manuscript. GHAV contributed to the design of the study and revising the manuscript. JGN conceived the study, contributed to the design of the study, the acquisition and interpretation of data, and revising the manuscript.

Conflict of interest The authors have no conflicts of interest.

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Figure 1 FHR trace in a patient who exhibited a SHR pattern after administration of remifentanil. The patient was multiparous, aged 29 years, at full term, and 5–6 cm dilatation. A normal FHR pattern prior to the administration of remifentanil (A); paper speed 1 cm/min. The SHR pattern shortly following the administration of remifentanil (B); paper speed 1 cm/min. The grey line represents the maternal heart rate. Abbreviations: FHR, fetal heart rate; SHR, sinusoidal heart rate.

Figure 2 FHR trace in a patient who did not receive remifentanil and exhibited a SHR pattern that resolved spontaneously. The patient was multiparous, aged 33 years, and at 7 cm of dilatation. Paper speed 1 cm/min. The grey line represents the maternal heart rate. Abbreviations: FHR, fetal heart rate; SHR, sinusoidal heart rate.

Table 1 Patient characteristics. a Variable Remifentanil group (n=60) Control group (n=59) P value Age, y 30.9±5.3 30.0±3.7 0.018 BMI 26.0±5.3 25.4 ± 4.6 0.428 Parity 0.223 Nulliparous 18 (30) 24 (41) Multiparous 42 (70) 35 (59) Duration of pregnancy at delivery, wk 39.0 ± 1.3 39.6 ± 1.3 0.313 Onset of labor 0.344 Spontaneous 20 (33) 15 (25) Induced 40 (67) 44 (75) Type of delivery 0.917 Spontaneous vaginal 52 (87) 50 (85) Vacuum assisted 5 (8) 5 (8) Cesarean delivery 3 (5) 4 (7) Twin pregnancy 1 (2) 0 (0) 0.319 Use of epidural analgesia 0 26 (44)

Retrospective study of the effect of remifentanil use during labor on fetal heart rate patterns.

To investigate possible associations between remifentanil and the appearance of sinusoidal heart rate patterns in fetuses, and neonatal outcomes...
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