Abstract
Background
Several randomised controlled trials show that maintenance of labour epidural analgesia with programmed intermittent epidural bolus reduces the maternal motor block compared with maintenance with a continuous infusion. However, these trials were usually restricted to healthy nulliparous parturients. To assess the generalisability of these randomised controlled trials to ‘real-world’ conditions, we compared maternal motor function (modified Bromage score) over time between healthy nulliparous and parous women using routinely collected quality-control data.
Methods
After ethical approval, all parturients receiving programmed intermittent epidural bolus labour analgesia between June 2013 and October 2014 were included in this prospective cohort study. Bupivacaine 0.1% with fentanyl 2 μg ml−1 was used allowing for patient-controlled bolus every 20 min. The maternal motor function (primary outcome) was regularly assessed from insertion of the epidural catheter until delivery.
Results
Of the 839 parturients included, 553 (66%) were nulliparous and 286 (34%) were parous. The parous women had a shorter median duration of epidural analgesia (3 h 59 min vs 5 h 45 min) and a higher incidence of spontaneous delivery (66% vs 37%). The probability of being in a certain Bromage category at birth was similar in nulliparous and parous women in a general additive model adjusting for duration of epidural analgesia, number of rescue top-ups, and number of catheter manipulations (cumulative odds ratio: 1.18; 95% confidence interval: 0.98–1.41). Parous women required a higher time-weighted number and volume of rescue top-ups.
Conclusions
The results of the randomised controlled trials on a reduced motor block with programmed intermittent epidural bolus seem generalisable to parturients typically not included in these trials.
Keywords: analgesia, epidural, labour, obstetrics, patient controlled analgesia, randomised controlled trial
Editor's key points.
-
•
Epidural obstetric analgesia is common, although debate remains about the optimal approach for good analgesia without significant motor block.
-
•
Many trials exclude parous women, reducing generalisability to the obstetric population. This cohort study used routinely collected data of nulliparous and parous women to assess whether randomised controlled trial results may apply more widely.
-
•
There was no difference in motor block between nulliparous and parous women, although higher than in published randomised controlled trials.
-
•
Although labour was shorter in parous women, pain tended to be more severe. This needs to be considered in selecting dosing regimens.
Neuraxial analgesia is the most effective and common mode of pain relief during labour.1 Patient-controlled epidural analgesia (PCEA) combined with a low-dose background continuous epidural infusion (CEI) increases patient satisfaction compared with PCEA without background infusion, and also increases the volume of local anaesthetics.2 Previous RCTs have demonstrated that the substitution of the background infusion with programmed intermittent epidural bolus (PIEB) is able to decrease local anaesthetic consumption,3, 4, 5, 6 thereby reducing the incidence of maternal motor block,4 the incidence of breakthrough pain, and hence the need for manual rescue top-ups by the anaesthesiologist.4, 7, 8 Whether the observed decrease in motor block has a beneficial effect on the progress of labour is a matter of extensive debate.
Although RCTs are considered the gold standard for comparing treatment effects, the relevance of RCT results in daily clinical practice depends on their generalisability.9, 10, 11 Generalisability depends, amongst other things, on RCT inclusion and exclusion criteria, and on the performance of the treatment outside the controlled condition of a clinical trial. Moreover, RCTs are often insufficiently powered to assess side-effects. In all except one RCT on PIEB,3 inclusion was limited to healthy nulliparous women. Two observational studies relaxing the typical exclusion criterion of the RCTs were inconclusive whether the results of the RCTs on PIEB regarding maternal side-effects, such as maternal motor function, are generalisable.12, 13 Therefore, it remains unclear whether the results of these RCTs can be extrapolated to daily clinical practice and, namely, whether there is a differential effect in parous women typically excluded from RCTs.
In this study, routinely collected observational data of all parturients receiving epidural labour analgesia using PIEB were used to compare RCT-eligible nulliparous women with usually RCT-ineligible parous women. We investigated, in an explanatory analysis, whether there were differential effects in maternal motor function (primary outcome) or pain over time (first secondary outcome) between these two groups of parturients as a way of establishing generalisability of RCT results to real-world settings.
Methods
The regional Ethics Committee (Ethikkommission Nordwest-und Zentralschweiz [EKNZ]; EKNZ 2015-297) approved this prospective cohort study and waived the requirement for a written informed consent, as all data are routinely collected for quality-control purposes. We adhered to the guidelines for reporting observational studies using routinely collected data.14, 15, 16
In 2013, PIEB became the standard method for the maintenance of epidural labour analgesia in our hospital. The epidural space was identified on the L4–5 or L3–4 interspace using the loss of resistance to saline technique. A 20 G multi-orifice epidural catheter was inserted through an 18 G Tuohy needle, 5 cm into the epidural space and secured. After an initial epidural dose of 15–20 ml of the maintenance solution, consisting of bupivacaine 0.1% with fentanyl 2 μg ml−1, PIEB settings facilitated the delivery of 5 ml automated bolus every 60 min at 250 ml h−1. Additional PCEA boluses of 5 ml with a lockout time of 20 min were allowed. In case of a PIEB close to a PCEA bolus, the PIEB was postponed by 20 min. The parturient was instructed to demand a PCEA bolus whenever she felt uncomfortable.
The anaesthesiologist assessed motor function according to the modified Bromage score and a pain score on a verbal analogue scale (VAS) from 0 to 10 (0 = no pain to 10 = worst pain imaginable),17 every 60–90 min (scheduled assessments) or whenever breakthrough pain occurred (unscheduled assessments). If the parturient felt she had insufficient analgesia after activating the PCEA bolus, an anaesthesiologist administered a 5–10 ml rescue top-up of the maintenance solution. All parturients receiving PIEB labour analgesia were followed up until delivery, regardless of whether the epidural was successful or had to be pulled back or re-sited.
The characteristics of each parturient, cervical dilation, time and mode of delivery, withdrawal or resiting of the epidural catheter, and mode of delivery were also recorded. The satisfaction score of the parturient about the quality of PIEB labour analgesia was recorded postpartum on a VAS from 0 to 10 at the follow-up visit to remove the epidural catheter.
Definition of ‘RCT-eligible’ and ‘RCT-ineligible’ parturients
In RCTs on PIEB, nulliparous women with co-morbidities (i.e. ASA physical status [PS] >2) and all parous women were typically excluded. In our cohort, nulliparous ASA PS <3 parturients were, therefore, classified as RCT eligible, and all parous ASA PS <3 women as RCT ineligible. As the percentage of nulliparous women with co-morbidities was very low, we excluded all ASA PS >2 nulliparous and parous women from the analysis.
Statistical analysis
The primary outcome was analysed using a general additive model (GAM) for an ordered categorical response.18 Our model included co-variates considered most relevant a priori: the duration of epidural analgesia, number of rescue top-ups, and number of catheter manipulations (pulling back or resiting). With this model, we then predicted the modified Bromage score at the time of delivery for parturients not requiring manipulation or additional anaesthetics. When making predictions, we set the duration of epidural analgesia to the average for nulliparous and parous women, respectively. We plotted the percentage of all study parturients with a given Bromage score at the last assessment before birth against the predicted percentage of parturients with that score at birth (Supplementary Fig. S1). In our main model, we allowed average nulliparous and parous women to have a different decline in mobility over time and a different level of mobility at birth. In an alternative model, we forced average nulliparous and parous women to have the same decline in mobility over time and the same level of mobility at birth if starting analgesia at the same time. In this alternative model, the predicted Bromage score at birth could only differ between average nulliparous and parous women because of their different average durations of analgesia.
The secondary outcome, pain over time, was transformed to lie between 0 and 1 by dividing the VAS by 10. We then analysed the transformed outcome, a fractional response, using an overdispersed binomial GAM that included the same co-variates as before.19
We also used a logistic regression model to estimate the association between the modified Bromage score and the risk of an instrumental as opposed to a vaginal delivery without instrumental assistance. The model was adjusted for parity and the parturients' BMI, as the latter was observed to be associated with a higher incidence of instrumental delivery.20, 21
Baseline characteristics were summarised using mean (standard deviation), median (inter-quartile range [IQR]), or n (%) as appropriate.
The sample size of this explanatory analysis consists of a convenient sample of all parturients who received epidural labour analgesia between June 2013 and October 2014 at our hospital. This time period had been chosen to achieve reliable estimates from a multivariable regression analysis.22 The absence of a formal sample-size calculation does not allow to formally establish equivalence. However, the large convenient sample is still able to render any clinically relevant differences implausible.
Our GAMs were fit in R 3.3.1 (R Foundation for Statistical Computing, Vienna, Austria) using R package mgcv 1.8–12. We used Intercooled Stata version 14.1 for Mac (StataCorp, College Station, TX, USA) for other analyses and graphs.
Results
A total of 960 parturients received epidural labour analgesia between June 2013 and October 2014, of which 839 were included in the cohort study (Fig. 1). Only a small percentage was initiated with a combined spinal epidural (CSE) technique, or used a lower concentration of bupivacaine 0.0625% with fentanyl 2 μg ml−1. Women with a CSE technique, bupivacaine 0.0625%, ASA PS class >2, or incomplete documentation were excluded from data analysis. Before excluding parturients, every effort was made to look up missing values in the medical record or the obstetrics database.
Fig 1.
Flow diagram of study participants.
The average age of all parturients was similar in nulliparous and parous women (31 [IQR: 16–47] vs 33 [IQR: 21–45] yr; Table 1). The epidural catheter was inserted at a similar cervical dilation (Table 1) and with a similar initial epidural loading dose (median: 15 ml; IQR: 15–20 ml in both groups). Nevertheless, the time from insertion to delivery was shorter in parous women (median: 3 h, 58 min; IQR: 2 h, 37 min to 5 h, 36 min) than in nulliparous women (median: 5 h, 45 min; IQR: 3 h, 50 min to 8 h). Compared with nulliparous women, parous women had more spontaneous deliveries, with fewer instrumental and Caesarean deliveries (Table 2).
Table 1.
Patient characteristics. IQR, inter-quartile range.
| All, n=839 (100%) | Nulliparous women, n=553 (66%) | Parous women, n=286 (34%) | Missing, n (%) | |
|---|---|---|---|---|
| Age (yr), mean (range) | 32 (16–47) | 31 (16–47) | 33 (21–45) | — |
| BMI (kg m−2), median (IQR) | 28 (25–31) | 28 (25–30) | 28 (25–31) | 92 (11) |
| Gravidity (G), n (%) | ||||
| G1 | 418 (50) | 418 (76) | — | — |
| G2–G8 | 421 (50) | 135 (24) | 286 (100) | |
| Parity (P), n (%) | ||||
| P0 | 553 (66) | 553 (100) | — | — |
| P1 | 232 (28) | — | 232 (81) | |
| P2—P4 | 54 (6) | — | 54 (19) | |
| Cervical dilation at insertion of epidural catheter (cm), median (IQR) | 4 (3–6) | 4 (3–6) | 4 (3–5) | 202 (24) |
| Labour pain pre-epidural, VAS | 10 (8–10) | 10 (8–10) | 10 (8–10) | 230 (27) |
Table 2.
Characteristics of epidural analgesia and mode of delivery. IQR, inter-quartile range.
| All, n=839 (100%) | Nulliparous women, n=553 (66%) | Parous women, n=286 (34%) | Missing, n (%) | |
|---|---|---|---|---|
| Number of rescue top-ups per hour in those with rescue top-ups, median (IQR) | 0.27 (0.19–0.42) (n=456; 54%) | 0.25 (0.18–0.38) (n=303; 55%) | 0.31 (0.20–0.46) (n=153; 54%) | |
| Additional volume per hour in those with rescue top-ups, median (IQR) | 1.8 (1.1–2.7) (n=456; 54%) | 1.7 (1.0–2.5) (n=303; 55%) | 2.0 (1.4–2.9) (n=153; 54%) | |
| Modified Bromage score, last available assessment before birth | ||||
|
2 (0.24) | 2 (0.36) | — | 102 (12) |
|
16 (1.9) | 14 (2.6) | 2 (0.71) | |
|
31 (3.7) | 25 (4.6) | 6 (2.1) | |
|
118 (14) | 73 (13) | 45 (16) | |
|
529 (63) | 333 (60) | 196 (68) | |
|
41 (4.9) | 32 (5.8) | 9 (3.2) | |
| Labour pain, last available VAS before birth, median (IQR; range) | 3 (1–5; 0–10) | 3 (1–5; 0–10) | 3 (1–6; 0–10) | 135 (16) |
| Mode of delivery, n (%) | ||||
| Spontaneous | 394 (47) | 204 (37) | 190 (66) | — |
| Instrumental | 228 (27) | 187 (34) | 41 (14) | |
| Caesarean section | 217 (26) | 162 (29) | 55 (19) | |
Motor function
The motor function of nulliparous and parous women showed a similar decline over time (Fig. 2). Adjusting for the duration of labour analgesia and all the other co-variates, both groups of parturients had a similar motor block at birth. The model also suggested that an increased duration of epidural analgesia, and increased numbers of rescue top-ups and catheter manipulations were all associated with an increased motor block at delivery (Table 3).
Fig 2.
Modified Bromage score over time for nulliparous and parous women from initiation of labour analgesia until delivery.
Table 3.
General additive model of the modified Bromage score (as an ordered category) regardless of mode of delivery (21.6% of variation explained by this final model; Akaike information criterion 4843). Cumulative odds ratios (Cum OR) and 95% confidence intervals (95% CI) show the association between the probability of being in a higher category of the modified Bromage score and the parous vs nulliparous women, adjusted for the most relevant confounders. An OR >1 corresponds to a higher probability of being in a high Bromage category (i.e. corresponds to a greater mobility at birth). An OR <1 corresponds to decreased probability of being in a high Bromage category (i.e. corresponds to a lower mobility at birth).
| Cum OR (95% CI) | |
|---|---|
| Parous vs nulliparous women | 1.18 (0.98; 1.41) |
| Duration of epidural analgesia (per 1 h increase) | 0.58 (0.56; 0.61) |
| Manipulation on epidural catheter (per each additional pulling back) | 0.42 (0.31; 0.57) |
| Resiting of the epidural catheter (per each additional resiting) | 0.86 (0.55; 1.33) |
| Rescue top-up (per each additional top-up) | 0.98 (0.96; 1.00) |
The multivariable main model allowing nulliparous and parous women to have a different decline in motor function over time provided a marginally better fit to the motor-function data than the alternative model, in which nulliparous and parous women were forced to have the same average decline in motor function (21.6% vs 21.4% of the variation explained; Supplementary Table S1). In the main and alternative models, the predicted percentages of parturients with a certain modified Bromage score at birth were almost identical (Supplementary Table S2 and Fig. S1). As the goodness of fit and the predictions from the alternative model were very close to those of the main model, the only important difference between nulliparous and parous women was the duration of epidural analgesia in nulliparous women.
Instrumental delivery
Instrumental deliveries were significantly less frequent in parous than in nulliparous women. When parity was taken into account, our data did not provide evidence that parturients with a lower Bromage score at birth or parturients with a higher BMI had a higher incidence of an instrumental delivery as opposed to a spontaneous delivery (Table 4).
Table 4.
Influence of modified Bromage score on instrumental delivery (vacuum and forceps) compared with spontaneous delivery adjusted for parity and BMI (n=493, patients undergoing a Caesarean section are excluded). CI, confidence interval; OR, odds ratio.
| OR (95% CI) | |
|---|---|
| Bromage score (per 1 unit decrease) | 1.13 (0.87; 1.47) |
| Parous vs nulliparous women | 0.24 (0.16; 0.38) |
| BMI (per 1 kg m−2 increase) | 0.97 (0.93; 1.02) |
Pain
Pain scores at scheduled and unscheduled assessments were comparable between nulliparous and parous women (Table 2). In particular, the median pain score at the last assessment before birth was comparable in both groups. Compared with nulliparous women, parous women required a higher time-weighted number (mean difference: 0.1 bolus h−1; 95% confidence interval [CI]: 0.02–0.2; P=0.019) and volume of additional rescue top-ups (0.8 ml h−1; 95% CI: 0.1–1.5 ml h−1; P=0.017), and hence, a higher time-weighted number of additional visits by the anaesthesiologist (Table 2).
The high variability and lack of a clear pattern in our pain assessments over time meant we could not identify a useful GAM. Our multivariable GAM for pain was only able to explain 4.8% of the variation in these pain data.
Patient satisfaction
Postpartum patient satisfaction about the quality of PIEB labour analgesia was high and similar in nulliparous and parous women (median VAS: 10 in both; IQR: 8–10 in nulliparous and 9–10 in parous women). However, this information was missing for 223 parturients (26%).
Discussion
This large cohort study of nulliparous and parous women shows that the motor function under epidural PIEB labour analgesia shared a similar decline over time in both groups. The lower modified Bromage score at birth in nulliparous parturients was mostly because of the longer duration of epidural labour analgesia. This implies that the results from RCTs on PIEB regarding maternal motor function seem to be generalisable to parous women who were usually ineligible for these trials. The ineligible parturients in our cohort required a higher time-weighted number and volume of additional rescue top-ups, implying that pain may be more intense and resistant to labour epidural analgesia in parous than in nulliparous women.
Limitations
This cohort study is based on routine data prospectively collected for quality-control purposes. Although the assessments by the anaesthesiologist in charge were planned at fixed time intervals, clinical workload did not allow strict adherence to this schedule, and assessments frequently occurred in situations of breakthrough pain. This leads to higher pain scores than if a fixed time schedule was strictly adhered to and, as a result, limits the comparability of our pain assessment with assessments in RCTs that are typically recorded at scheduled intervals.3, 5, 23, 24, 25 Pain measurement at assessments prompted by breakthrough pain is likely to have contributed to the lack of discernible pattern in our pain data. However, the assessment of the motor block is not expected to be influenced by the irregular schedule of the anaesthesiologist, as motor block is thought to have a slower but steady increase with the duration of epidural analgesia.
A further limitation of routinely collected data is that they are usually of lower data quality compared with settings where a dedicated and trained study team collects the data. This explains the high number of missing values for some of the parameters. As the distribution of important characteristics did not differ between those with patients with a missing last record of the modified Bromage score (output not shown), we presume missing values occur randomly, except for some parturients with a very short duration of labour, in which no assessment was made after insertion of the epidural catheter. However, it is unlikely that such a short duration of labour leads to a pronounced motor block, especially as we do not use a dedicated test dose (using a local anaesthetic of higher concentration). Hence, the results of a complete case analysis can be considered to be unbiased.26
Parturients with co-morbidities and parturients receiving CSE anaesthesia or a lower concentration of bupivacaine were excluded from our analysis, as an extrapolation of the results based on a low number of observations would not be robust enough for claiming generalisability. Therefore, we can only conclude generalisability for healthy parous women.
Motor block
The incidence of motor block observed in our cohort was similar in parous and nulliparous women, but was higher than in published trials.4, 5 Only one of the RCTs comparing PIEB and CEI had maternal motor function as a primary endpoint.4 In this trial, motor block was defined as a modified Bromage score <6. The difference in incidence might be explained by a difference in assessment. In our daily clinical practice, we do not routinely request parturients to perform knee bends when assessing mobility. By definition, every woman who has not been mobilised out of bed is classified as a Bromage score <6. Amongst our parturients, 20% had a clinically relevant motor block, defined as a modified Bromage score ≤4, similar to the percentage seen in other studies.4, 23 In addition, parturients requesting supplemental analgesia are more likely to develop a motor block, but such women were often excluded from analyses in previous RCTs.7, 27 To avoid confounding, we adjusted our multivariable model for the number of epidural catheter manipulations and the number of rescue top-ups. However, the volume administered by the parturients using PCEA was not recorded, and hence, not adjusted for. Despite the unmeasured confounding by the higher volume in a shorter period of time, parous women were not more likely to have a relevantly higher motor block than nulliparous women.
Pain
We recorded breakthrough pain in 65% of parturients, a higher incidence than in previous studies. However, the time-weighted number and volume of additional rescue top-ups were relatively low (<1 bolus every 2 h). There might be several explanations for this. First, breakthrough pain was a reason for exclusion from further follow-up in some of the previous RCTs.7, 8 In our cohort, visits by the anaesthesiologist frequently occurred in situations of breakthrough pain, leading to an overestimation of the reported pain scores. Third, our cohort included nulliparous and parous women, and the latter suffered from more breakthrough pain, which was also observed in a survey by Ranta and colleagues.28 This suggests that residual pain during epidural analgesia is more intense and resistant to labour epidural analgesia in parous than in nulliparous women. Possible reasons for this finding might be that those parous women receiving epidural labour analgesia are characterised by additional risk factors for a more complicated and painful birth. Moreover, parous women seem to receive labour analgesia at a later stage, in which pain levels are already higher and more difficult to control.
Instrumental delivery
There is evidence, based on a limited sample size, that a high Bromage score allowing for ambulation in the second stage of labour was associated with a greater likelihood of a spontaneous delivery, whereas this association was not found for a high Bromage score in the first stage of labour.29 Our study provides no clear evidence of an association between instrumental and spontaneous delivery and motor block assessed shortly before delivery (i.e. certainly in the second stage of labour). However, the instrumental delivery rate was significantly lower in parous than in nulliparous women, consistent with other findings from the literature.30
Generalisability
As current medical practice focuses on personalised treatment, the applicability of the RCT results to the general population has been increasingly questioned.9 Two issues make it difficult to assess the external validity of past RCTs on PIEB.11 First, the inclusion criteria for most RCTs were restricted to healthy, term nulliparous parturients at an early stage of labour.4, 5, 7, 8, 23, 24, 25 This group represents only a subgroup of all parturients requiring epidural labour analgesia. Second, the total number of screened parturients is not clearly reported in many of the RCTs. Generalisability from these RCTs depends on the representativeness of those actually included amongst all eligible parturients. A general aim should be to establish real-world effectiveness in a broader population after having established solid evidence for efficacy in a restricted low-risk population.31
In the absence of such pragmatic trials, observational studies provide complementary insights by offering the opportunity establish generalisability and to assess side-effects.32 In this respect, our routine quality-control study provides data covering a heterogeneous population of parturients, from insertion of the epidural catheter until delivery, in a way that reflects daily clinical practice. Our group of nulliparous women was similar to the parturients included in past RCTs on PIEB, although we included all potentially eligible parturients in this group. (This may have also happened in some trials.) Our group of parous women consisted of women typically excluded from these RCTs. However, the same criteria were applied in nulliparous and parous women for offering epidural labour analgesia. The large sample size allowed us to control for confounding, the most serious disadvantage of observational data. Given that the current study findings of a similar course of motor block over time between nulliparous and parous women using PIEB for maintenance of labour analgesia, the reduced motor block observed with PIEB compared with CEI analgesia in nulliparous women in RCT is likely to be observed in parous women using PIEB analgesia. But, strictly speaking, we can only assess whether potentially eligible parturients are comparable with ineligible parturients under real-world conditions.
Conclusions
In conclusion, the results of the RCTs on PIEB seem generalisable to parous women who were usually excluded from such RCTs. Adjusted for the duration of epidural labour analgesia, the increase in motor block was comparable in nulliparous and parous women. The higher number and volume of rescue top-ups in parous women suggest that their labour is more intense and resistant to labour epidural analgesia, although shorter. This should be considered in the dosing scheme for PIEB labour analgesia in parous women. The awareness of the rapid progress of the more painful labour in parous women may allow for improved analgesia by the timely initiation of neuraxial analgesia and the administration of higher analgesic doses or shorter bolus dosing intervals than for nulliparous women.
Authors' contributions
Study conception: all authors.
Study design: LG, TG, SD.
Data collection: LG, SD.
Data interpretation: LG, JY, TG, SD.
Data analysis: JY, SD.
Drafting of manuscript: LG, SD.
Critical revising of manuscript: JY, IH, TG.
All authors agree to be accountable for all aspects of the work and approve the final manuscript.
Acknowledgements
The authors wish to thank Ramon Saccilotto who programmed and maintained the online database. Allison Dwileski's editorial assistance for the manuscript is gratefully acknowledged.
Handling editor: L. Colvin
Editorial decision: 02 February 2019
Footnotes
This article is accompanied by an editorial: Programmed intermittent epidural bolus technique for maintenance of labour analgesia: does it work for everyone? by Wong & Mercier., Br J Anaesth 2019:123:e190–e193, doi: 10.1016/j.bja.2019.02.008
Supplementary data to this article can be found online at https://doi.org/10.1016/j.bja.2019.02.016.
Declaration of interest
The authors declare that they have no conflicts of interest.
Funding
Foundation for Research and Education in Anaesthesia, University Hospital Basel, Switzerland.
Appendix A. Supplementary data
The following are the Supplementary data to this article:
Supplementary Fig S1.
Predicted and observed percentages of modified Bromage score at delivery in nulliparous and parous women.
References
- 1.Wong C.A. Advances in labor analgesia. Int J Womens Health. 2010;1:139–154. doi: 10.2147/ijwh.s4553. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Halpern S.H., Carvalho B. Patient-controlled epidural analgesia for labor. Anesth Analg. 2009;108:921–928. doi: 10.1213/ane.0b013e3181951a7f. [DOI] [PubMed] [Google Scholar]
- 3.Wong C.A., Ratliff J.T., Sullivan J.T., Scavone B.M., Toledo P., McCarthy R.J. A randomized comparison of programmed intermittent epidural bolus with continuous epidural infusion for labor analgesia. Anesth Analg. 2006;102:904–909. doi: 10.1213/01.ane.0000197778.57615.1a. [DOI] [PubMed] [Google Scholar]
- 4.Capogna G., Camorcia M., Stirparo S., Farcomeni A. Programmed intermittent epidural bolus versus continuous epidural infusion for labor analgesia: the effects on maternal motor function and labor outcome. A randomized double-blind study in nulliparous women. Anesth Analg. 2011;113:826–831. doi: 10.1213/ANE.0b013e31822827b8. [DOI] [PubMed] [Google Scholar]
- 5.Sia A.T., Lim Y., Ocampo C. A comparison of a basal infusion with automated mandatory boluses in parturient-controlled epidural analgesia during labor. Anesth Analg. 2007;104:673–678. doi: 10.1213/01.ane.0000253236.89376.60. [DOI] [PubMed] [Google Scholar]
- 6.George R.B., Allen T.K., Habib A.S. Intermittent epidural bolus compared with continuous epidural infusions for labor analgesia: a systematic review and meta-analysis. Anesth Analg. 2013;116:133–144. doi: 10.1213/ANE.0b013e3182713b26. [DOI] [PubMed] [Google Scholar]
- 7.Lim Y., Sia A.T.H., Ocampo C. Automated regular boluses for epidural analgesia: a comparison with continuous infusion. Int J Obstet Anesth. 2005;14:305–309. doi: 10.1016/j.ijoa.2005.05.004. [DOI] [PubMed] [Google Scholar]
- 8.Leo S., Ocampo C.E., Lim Y., Sia A.T. A randomized comparison of automated intermittent mandatory boluses with a basal infusion in combination with patient-controlled epidural analgesia for labor and delivery. Int J Obstet Anesth. 2010;19:357–364. doi: 10.1016/j.ijoa.2010.07.006. [DOI] [PubMed] [Google Scholar]
- 9.Bothwell L.E., Greene J.A., Podolsky S.H., Jones D.S. Assessing the gold standard—lessons from the history of RCTs. N Engl J Med. 2016;374:2175–2181. doi: 10.1056/NEJMms1604593. [DOI] [PubMed] [Google Scholar]
- 10.Kennedy-Martin T., Curtis S., Faries D., Robinson S., Johnston J. A literature review on the representativeness of randomized controlled trial samples and implications for the external validity of trial results. Trials. 2015;16:495. doi: 10.1186/s13063-015-1023-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Rothwell P.M. External validity of randomised controlled trials: “to whom do the results of this trial apply? Lancet. 2005;365:82–93. doi: 10.1016/S0140-6736(04)17670-8. [DOI] [PubMed] [Google Scholar]
- 12.Tien M., Allen T.K., Mauritz A., Habib A.S. A retrospective comparison of programmed intermittent epidural bolus with continuous epidural infusion for maintenance of labor analgesia. Curr Med Res Opin. 2016;32:1435–1440. doi: 10.1080/03007995.2016.1181619. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.McKenzie C.P., Cobb B., Riley E.T., Carvalho B. Programmed intermittent epidural boluses for maintenance of labor analgesia: an impact study. Int J Obstet Anesth. 2016;26:32–38. doi: 10.1016/j.ijoa.2015.11.005. [DOI] [PubMed] [Google Scholar]
- 14.von Elm E., Altman D.G., Egger M. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370:1453–1457. doi: 10.1016/S0140-6736(07)61602-X. [DOI] [PubMed] [Google Scholar]
- 15.Vandenbroucke J.P., von Elm E., Altman D.G. Strengthening the reporting of observational studies in epidemiology (STROBE): explanation and elaboration. PLoS Med. 2007;4:e297. doi: 10.1371/journal.pmed.0040297. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Benchimol E.I., Smeeth L., Guttmann A. The REporting of studies Conducted using Observational Routinely-collected health Data (RECORD) statement. PLoS Med. 2015;12:e1001885. doi: 10.1371/journal.pmed.1001885. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Breen T.W., Shapiro T., Glass B., Foster-Payne D., Orial N.E. Epidural anesthesia for labor in an ambulatory patient. Anesth Analg. 1993;77:919–924. doi: 10.1213/00000539-199311000-00008. [DOI] [PubMed] [Google Scholar]
- 18.Wood S.N., Pya N., Säfken B. Smoothing parameter and model selection for general smooth models. J Am Stat Assoc. 2016;516:1548–1575. [Google Scholar]
- 19.Papke L.E., Wooldridge J. Econometric methods for fractional response variables with an application to 401(k) plan participation rates. J Appl Econ. 1996;11:619–632. [Google Scholar]
- 20.Heslehurst N., Simpson H., Ells L.J. The impact of maternal BMI status on pregnancy outcomes with immediate short-term obstetric resource implications: a meta-analysis. Obes Rev. 2008;9:635–683. doi: 10.1111/j.1467-789X.2008.00511.x. [DOI] [PubMed] [Google Scholar]
- 21.Yeşilçiçek Çalik K., Korkmaz Yildiz N., Erkaya R. Effects of gestational weight gain and body mass index on obstetric outcome. Saudi J Biol Sci. 2018;25:1085–1089. doi: 10.1016/j.sjbs.2018.02.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Babyak M.A. What you see may not be what you get: a brief, nontechnical introduction to overfitting in regression-type models. Psychosom Med. 2004;66:411–421. doi: 10.1097/01.psy.0000127692.23278.a9. [DOI] [PubMed] [Google Scholar]
- 23.Fettes P.D.W., Moore C.S., Whiteside J.B., McLeod G.A., Wildsmith J.A.W. Intermittent vs continuous administration of epidural ropivacaine with fentanyl for analgesia during labour. Br J Anaesth. 2006;97:359–364. doi: 10.1093/bja/ael157. [DOI] [PubMed] [Google Scholar]
- 24.Wong C.A., McCarthy R.J., Hewlett B. The effect of manipulation of the programmed intermittent bolus time interval and injection volume on total drug use for labor epidural analgesia: a randomized controlled trial. Anesth Analg. 2011;112:904–911. doi: 10.1213/ANE.0b013e31820e7c2f. [DOI] [PubMed] [Google Scholar]
- 25.Salim R., Nachum Z., Moscovici R., Lavee M., Shalev E. Continuous compared with intermittent epidural infusion on progress of labor and patient satisfaction. Obstet Gynecol. 2005;106:301–306. doi: 10.1097/01.AOG.0000171109.53832.8d. [DOI] [PubMed] [Google Scholar]
- 26.Carpenter J., Kenward M.G. John Wiley & Sons; West Sussex: 2013. Multiple imputation and its application. [Google Scholar]
- 27.Chua S.M.H., Sia A.T.H. Automated intermittent epidural boluses improve analgesia induced by intrathecal fentanyl during labour. Can J Anaesth. 2004;51:581–585. doi: 10.1007/BF03018402. [DOI] [PubMed] [Google Scholar]
- 28.Ranta P., Spalding M., Kangas-Saarela T. Maternal expectations and experiences of labour pain—options of 1091 Finnish parturients. Acta Anaesthesiol Scand. 1995;39:60–66. doi: 10.1111/j.1399-6576.1995.tb05593.x. [DOI] [PubMed] [Google Scholar]
- 29.Wilson M.J.A., MacArthur C., Cooper G.M., Shennan A. On behalf of the COMET Study Group UK. Ambulation in labour and delivery mode: a randomised controlled trial of high-dose vs. mobile epidural analgesia. Anesth Analg. 2009;64:266–272. doi: 10.1111/j.1365-2044.2008.05756.x. [DOI] [PubMed] [Google Scholar]
- 30.Essex H.N., Green J., Baston H., Pickett K.E. Which women are at an increased risk of a caesarean section or an instrumental vaginal birth in the UK: an exploration within the Millennium Cohort Study. BJOG. 2013;120:732–742. doi: 10.1111/1471-0528.12177. [DOI] [PubMed] [Google Scholar]
- 31.Bullingham A., Liang S., Edmonds E., Mathur S., Sharma S. Continuous epidural infusion vs programmed intermittent epidural bolus for labour analgesia: a prospective, controlled, before-and-after cohort study of labour outcomes. Br J Anaesth. 2018;121:432–437. doi: 10.1016/j.bja.2018.03.038. [DOI] [PubMed] [Google Scholar]
- 32.Black N. Why we need observational studies to evaluate the effectiveness of health care. BMJ. 1996;312:1215–1218. doi: 10.1136/bmj.312.7040.1215. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.