Effect of Preemptive Epidural Analgesia in Labor on Cytokine Production: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Effect of Preemptive Epidural Analgesia in Labor on Cytokine Production (NCT00361712), a randomized phase 4 study. The primary outcome is Maternal Cytokine IL-10 Levels of pg/ml Upon Enrollment.

2. Clinical Question

3. Trial Design

The registry describes a randomized, parallel-group trial with no masking. It is listed as phase 4 and completed. Enrollment is recorded as 41. The trial started and reached primary completion in July 2006; the sponsor is Rabin Medical Center. Obstetric pain is the listed condition.

The two assigned strategies differed in when epidural analgesia was initiated. In the preemptive group, the epidural was to be given immediately upon arrival in the labor ward before painful contractions. In the standard-care group, it was to be given as soon as possible after cervical dilatation and painful labor. The registry labels the groups “Randomized to Early Epidural Analgesia” and “Randomized to Epidural Analgesia Upon Request.” The posted primary outcome summaries contain 20 participants in the early group and 21 in the upon-request group.

Random allocation can support a comparison of assigned strategies, but details about how the sequence was generated or concealed are not reported in the registry record. Masking is listed as none. The record does not describe adherence, crossovers, or whether the analysis followed assignment regardless of treatment received. Other eligibility criteria, participant characteristics, and the trial's original design assumptions are not reported in the registry record.

The primary outcome is maternal serum IL-10 measured right after enrollment. There are three outcome measures recorded, but no secondary outcome results are posted. The record lists no analyses. This leaves the posted group summaries as the main available numerical description of the primary measure.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Maternal Cytokine IL-10 Levels of pg/ml Upon Enrollment, measured over Right after enrollment.

The primary endpoint is maternal serum IL-10 concentration, expressed in pg/ml, measured right after enrollment. IL-10 is a cytokine. The registry's summary describes cytokines as inflammatory mediators whose production increases during labor, and notes that higher concentrations of certain cytokines have been linked to adverse maternal and neonatal outcomes. That context explains why cytokine production was of interest; it does not establish that this endpoint predicts an outcome in this trial.

The endpoint is continuous, and the registry reports the mean and standard deviation for each group. A mean describes the group's average measured concentration; a standard deviation describes the spread of individual measurements around that average. These are different aspects of the data: similar averages do not imply that individual values were tightly clustered, and a spread measure is not a confidence interval for the mean.

The stated measurement time is right after enrollment. The registry does not clarify the timing of blood collection in relation to randomization or epidural administration, nor does it report a later maternal IL-10 measurement for this primary endpoint. The endpoint should therefore be read as a group comparison at the recorded time point, not as a reported change from baseline. It is a laboratory measure, not a direct report of maternal or newborn clinical outcomes.

7. Results Posted in the Registry

• Randomized to Epidural Analgesia Upon Request: mean 14.20 versus 12.70 on control; difference 1.50 (95% CI -2.09 to 5.09), standardized effect d = 0.25; z-test p = 0.412.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous: a concentration measured in pg/ml. For a continuous outcome, a common way to summarize each group is with its mean and standard deviation. The mean conveys the central average, while the standard deviation conveys how dispersed the observed measurements are within the group. The standard deviation does not express uncertainty in the estimated mean; the confidence interval for the group contrast addresses uncertainty in that contrast.

What does the mean difference represent?

The comparison is oriented as the mean in the epidural-upon-request group minus the mean in the early-epidural group. The reported estimate is 1.5 pg/ml. Under that orientation, a positive estimate means the posted average was higher in the upon-request group. This is a difference in group averages, not a ratio and not a comparison of every individual participant. Since the endpoint is recorded right after enrollment, the estimate should not be interpreted as a change from baseline.

How should the confidence interval be read?

A confidence interval gives a range of values compatible with the estimate under the statistical method and assumptions used to construct it. The reported 95% interval for the mean difference runs from -2.085 to 5.085 pg/ml. Its inclusion of zero means that a zero difference is among the values compatible with these data under that method. The interval also permits a negative or positive difference. A confidence interval is not a probability statement that the true value has a particular chance of falling inside this particular interval.

What does the p-value add?

The unadjusted p-value is 0.412. In general, a p-value measures the compatibility of the data with a specified null hypothesis, using the assumptions of the test. It does not give the probability that the null hypothesis is true, and it does not show whether an effect matters clinically. The registry record lists no analyses, and the test details are not reported in the registry record. The posted p-value is therefore associated with the unadjusted recalculation from summary statistics, not a documented analysis plan.

The recalculated standard error for the group means is 1.006 in the early group and 1.528 in the upon-request group. A standard error describes the sampling uncertainty in an estimated mean, rather than the spread of individual observations. The reported pooled standard deviation is 5.916. A pooled spread combines within-group variation for purposes of a two-group comparison under assumptions about how the groups' variability is represented. It is distinct from the standard error and from the confidence interval.

Why can variation affect precision?

General statistical explanation: greater variation among measurements tends to make a group mean less precise when the amount of information is otherwise similar. In a comparison of means, the uncertainty depends on variability within both groups and on the amount of information in each. This is why the observed group standard deviations should be read alongside the mean difference and its confidence interval, rather than as evidence about the direction of the contrast.

General statistical explanation: over-dispersion means that the observed variability is greater than a model assumes. If a model understates variability, its standard errors can be too small and its intervals too narrow. The registry does not report an over-dispersion assessment or a model-based analysis, and the available comparison is a simple recalculation from summary statistics. Over-dispersion is therefore a general consideration, not a reported finding about this trial.

Randomization is intended to make assigned groups comparable on average, including with respect to factors not measured by investigators. It does not guarantee that every baseline characteristic is balanced in a small trial. The registry does not report baseline characteristics beyond the primary outcome summaries, and it does not describe an adjusted analysis. No adjustment for covariates should be inferred from the posted contrast.

In general, an intention-to-treat analysis compares participants according to their randomized assignments, while a per-protocol analysis applies eligibility or adherence rules after randomization. The registry record does not identify the analysis population or explain how participants who deviated from assignment, if any, were handled. Neither approach should be attributed to the trial based on the record. Missing outcome data, imputation, and sensitivity analyses are likewise not described.

Finally, the measurement time is important for the interpretation of the estimand, the quantity the comparison is meant to estimate. The record names an IL-10 level right after enrollment but does not specify its timing relative to treatment initiation. It also does not give a fuller endpoint definition, assay procedures, or a protocol for repeated measurements. Those omissions limit how specifically the numerical contrast can be tied to a treatment-timing effect.

10. Confidence Intervals and Precision

The mean difference estimate is 1.5 pg/ml, with a 95% confidence interval from -2.085 to 5.085 pg/ml. The interval is the key indicator of precision for the reported group contrast: it spans values below and above zero, so the data do not tightly determine either the direction or the size of a difference. Its width reflects uncertainty in the estimate under the recalculation's assumptions.

The confidence interval should not be read as a range containing every participant's IL-10 level. It concerns the estimated difference between group means. The group standard deviations, 4.5 pg/ml and 7.0 pg/ml, describe individual-level variation and are not substitutes for the interval. Similarly, the p-value of 0.412 does not summarize precision as directly as the interval does.

Precision is affected by both variability and the amount of information. Here, the posted group summaries include 20 participants in the early group and 21 in the upon-request group. The registry does not report how many measurements were missing, whether these counts represent all randomized participants with available outcome data, or whether any adjustment was made. The interval is based on a simple unadjusted recalculation of the posted summaries, so it should not be treated as an adjusted trial estimate.

The interval permits a range of possible differences, including a small difference and differences in either direction. It does not establish that all values in the interval are equally plausible, and it does not show which differences would matter clinically. The registry does not report a threshold for a clinically important IL-10 difference. Thus, the numerical precision can be described, but clinical importance cannot be determined from the interval alone.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The sample-size figures are planning illustrations based on the observed effect, not the trial's original design assumptions. They report participants per arm, not total event counts. The registry record describes the calculation assumptions as two-sided significance level 0.05, equal allocation between the two arms, and a normal approximation. The assumed effect to detect is the stated fraction of the observed effect. The trial's own design assumptions and sample-size justification are not reported in the registry record.

The 80% power column gives the planned number of participants per arm under the stated assumptions for a design with an 80% chance of detecting the assumed effect if that effect is real. The 90% power column gives the corresponding planning count for a design targeting a 90% chance. These are design probabilities under a model, not guarantees for a future study. The rows consider planning for 100%, 75%, and 50% of the observed effect. Smaller assumed effects require more participants per arm to achieve the same target power, which is why the counts increase as the assumed fraction decreases.

These calculations use an effect estimated from this trial's posted summaries, so they are sensitive to uncertainty in that estimate. The confidence interval is broad and includes zero, making the observed point estimate an uncertain basis for planning. The figures are not observed power: observed power is not a useful substitute for interpreting the estimate and its confidence interval. A planning calculation also does not establish that a study with a particular count would be adequate under different assumptions, outcome definitions, or analysis methods.

The record does not report the original sample-size target, anticipated effect, or design-stage power calculation. The planning illustrations should therefore be read as hypothetical calculations based on the observed contrast, separate from the trial's enrollment and from any claim about its original design.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 1.500; pooled standard deviation σ = 5.916.
2. n = 2 × (1.96 + 0.842)² × 5.916² / 1.500² = 244.1, rounded up to 245 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- 1.5                      # observed difference in means
sigma <- 5.91553799274333                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(361712)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 245 (80% power), 327 (90% power)
 75% of observed effect: n per arm = 435 (80% power), 582 (90% power)
 50% of observed effect: n per arm = 977 (80% power), 1,308 (90% power)
power.t.test: 245.1 
Simulated power at n = 245 per arm: 0.800 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The registry records three outcome measures, but no secondary outcome results are posted. The primary outcome is identified as maternal IL-10 measured right after enrollment. The other outcome measures are not detailed in the available record. No analysis record is listed, and no multiplicity strategy is reported in the registry record.

Multiplicity arises when several outcomes, time points, groups, or statistical comparisons are examined. In general, making many inferences can increase the chance of at least one apparently unusual result. Researchers may address this through prespecified primary outcomes, adjustment procedures, or a clear hierarchy of tests. The registry identifies a primary outcome, but it does not report whether the trial used any such procedure or how multiple comparisons were handled. It would be inappropriate to infer an adjustment or to treat the posted unadjusted p-value as multiplicity-adjusted.

Information about missing data is also not reported in the registry record. The record does not say whether every randomized participant had an IL-10 measurement, why measurements might be missing, how missing values were handled, or whether any imputation or sensitivity analysis was performed. The posted outcome group counts alone do not establish the complete-case status or missing-data method.

The analysis population is not identified. The record does not say whether the numerical summaries include all participants as randomized, only participants who received their assigned strategy, or another defined group. It also does not describe adherence, crossover, exclusions after randomization, or protocol deviations. Those details matter because different analysis populations can answer different questions.

The registry does not report the statistical analysis plan, the test underlying the comparison, covariate adjustment, or any interim analysis. These are unknowns, not evidence that a particular method was or was not used. Consequently, the result is most transparently described as an unadjusted recalculation of the posted summary statistics, with the limitations that follow from the lack of analysis and missing-data documentation.

14. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0.00% reporting threshold.

Most frequent non-serious adverse event terms

The adverse-event record lists serious adverse events as 0 in the early-epidural group and 0 in the epidural-upon-request group. The corresponding numbers at risk are 20 and 21. These are the posted serious-event counts; the registry does not provide serious-event terms. A zero count in these groups does not prove that serious events cannot occur, particularly when the available trial is small.

For other adverse events, the registry lists 9 in the early group and 0 in the upon-request group, with 20 and 21 at risk, respectively. These counts are not identified with event descriptions in the record, and the registry does not clarify whether they refer to participants with at least one event or to event occurrences. The counts therefore should not be treated as a complete account of event types, severity, timing, or attribution.

Death information is not reported in the registry record. The absence of posted serious-event counts does not establish the absence of all harms, and the other-adverse-event figures alone cannot establish a causal relationship to the assigned strategy. The record does not provide follow-up duration or detailed safety methods, which limits interpretation of these figures.

15. What the Result Does, and Does Not, Mean

The registry's primary outcome summaries show maternal IL-10 means of 12.7 pg/ml in the early-epidural group and 14.2 pg/ml in the epidural-upon-request group. The unadjusted mean difference, oriented as upon-request minus early, is 1.5 pg/ml. Its 95% confidence interval, from -2.085 to 5.085 pg/ml, includes zero and permits differences in either direction. This is evidence about the posted measurements and the precision of their comparison, not a definitive statement about a treatment effect.

The result does not show whether preemptive epidural analgesia changes cytokine production over time. The endpoint is a single maternal IL-10 level recorded right after enrollment, and the record does not clarify its timing relative to the intervention. The comparison also does not establish a difference in other cytokines or in maternal and newborn outcomes. Although the registry's background explains the biological interest in cytokines, no clinical outcome effect can be inferred from this laboratory measure alone.

The unadjusted p-value of 0.412 does not prove that the groups are equivalent or that no difference exists. Equivalence requires a prespecified margin and an analysis designed to evaluate whether differences lie within that margin; neither is reported in the registry record. Conversely, the numerical difference in group means does not establish a clinically important or causal effect.

Interpretation is further limited by the lack of a posted analysis record, unclear analysis population, and unreported missing-data handling. The observed spreads differ, and the confidence interval is broad. The record also does not provide a clinical threshold for an important IL-10 difference. Taken together, the posted result is an imprecise, unadjusted description of a measured biomarker in a randomized comparison, with important details needed for stronger interpretation not reported in the registry record.

16. Why This Trial Matters Statistically

This trial is statistically interesting because it compares two timings of the same broad labor analgesia strategy while focusing on a biological marker rather than a direct clinical endpoint. The randomized parallel-group design gives a framework for comparing assigned approaches, and the continuous IL-10 measure can be summarized as a difference between group means. That makes the distinction between an estimated effect and its uncertainty especially important.

The observed mean difference is modest relative to the uncertainty expressed by its 95% confidence interval, which extends from -2.085 to 5.085 pg/ml. The interval includes zero and allows effects in both directions. The p-value of 0.412 cannot resolve that uncertainty or tell readers whether any possible difference would be clinically meaningful. Reporting the estimate together with its interval is therefore more informative than relying on a threshold-based reading of the p-value alone.

The record also illustrates how registry completeness shapes statistical interpretation. It identifies a primary measure and posts group summaries, yet lists no analyses and gives no details about missing observations, analysis populations, or multiplicity handling. These omissions leave readers unable to determine whether the posted comparison reflects the trial's planned analysis. The measurement's relation to intervention timing is also unclear, which affects the question the endpoint can answer.

Finally, the planning illustrations demonstrate a general design principle: aiming to detect smaller effects requires more participants under otherwise fixed assumptions. In this case, those figures are based on an uncertain observed effect, and they are not the trial's original design calculation. The statistical value of the record lies in showing both what can be estimated from the posted summaries and how much uncertainty remains.

17. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The principal endpoint's timing is described as right after enrollment, but the record does not clarify whether the blood sample was taken before or after the assigned epidural strategy began. This prevents a clear interpretation of the estimate as a treatment effect at a defined post-intervention time. No change-from-baseline result is posted.

The registry provides no participant characteristics beyond the outcome summaries, and further eligibility criteria are not reported in the registry record. Details of random-sequence generation and concealment are also absent. Although allocation is identified as randomized, the record does not permit assessment of these design features or how well the groups were balanced on relevant characteristics.

The trial is small, and the confidence interval for the mean difference is broad. The posted comparison is an unadjusted recalculation from summary statistics; no sponsor analysis, adjustment method, or statistical analysis plan is described. The analysis population and missing-data handling are not reported, so it is unclear whether the summary counts reflect all randomized participants with outcome data or another subset.

The registry lists three outcome measures but posts no secondary results, and does not report how multiplicity was handled. It also does not provide assay details, a clinically important difference threshold, or detailed follow-up information. Safety reporting gives counts but no adverse-event descriptions for the other-event entries, and death information is not reported in the registry record. These limits restrict conclusions to the posted summaries and prevent a fuller assessment of the biomarker's clinical significance or the trial's safety findings.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Effect of Preemptive Epidural Analgesia in Labor on Cytokine Production — NCT00361712.
• Registry record last updated 2018-04-09; status last verified 2018-03.
• Results first posted 2018-03-12.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

21. Record Summary

NCT00361712 is a completed, randomized, unmasked, parallel-group phase 4 trial sponsored by Rabin Medical Center. The registry records enrollment of 41 and a start and primary completion in July 2006. The comparison is between early epidural analgesia and epidural analgesia upon request.

The primary outcome is maternal serum IL-10 in pg/ml, measured right after enrollment. The posted group means are 12.7 and 14.2 pg/ml, and the unadjusted recalculated mean difference is 1.5 pg/ml, with a 95% confidence interval from -2.085 to 5.085 pg/ml and p = 0.412. No analysis record or secondary outcome results are posted. Details about analysis populations, missing data, and the original sample-size assumptions are not reported in the registry record.