Pulse Pressure and Post-epidural Fetal Heart Rate Changes: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pulse Pressure and Post-epidural Fetal Heart Rate Changes (NCT02565485), a randomized na study. The primary outcome is Incidence of New-onset Category II or III Fetal Heart Rate Tracings.

2. Clinical Question

The registry’s rationale begins with a clinical concern: epidural anesthesia can be accompanied by changes in maternal blood pressure and fetal heart rate. An intravenous fluid preload is described as standard practice before epidural placement, while the optimal volume is described as unknown. The study tested a risk-factor-based approach to preload volume rather than treating all patients as needing the same volume.

The comparison is specifically about the recorded fetal heart rate outcome after epidural placement. It does not, by itself, answer whether either fluid volume is preferable for every laboring patient or in other settings. The registry record also lists maternal hypotension, corrective interventions, and adverse events as secondary outcomes, which provide additional context about what was monitored.

3. Trial Design

NCT02565485, titled “Pulse Pressure and Post-epidural Fetal Heart Rate Changes,” is a completed randomized, single-masked, parallel-group trial sponsored by MetroHealth Medical Center. The registry lists an enrollment of 276. The study started on 2015-09-01, and primary completion was recorded on 2016-11-01. The phase is listed as NA.

The arms differed in the volume of Lactated Ringer’s administered before epidural placement. The Standard IV Preload arm received 500mL. The Volume Replacement IV Preload arm received 1500mL. The registry describes the 500mL preload as the standard intravenous preload used in Labor and Delivery at MetroHealth Medical Center. The trial’s stated purpose was to assess whether an increased preload among women with narrow pulse pressure was associated with a lower risk of new-onset fetal heart rate changes after epidural placement.

Random allocation and a parallel-group model are recorded, but the method used to generate the allocation sequence and the approach to allocation concealment are not reported in the registry record. The identity of the masked party is also not reported in the registry record. The registry does not report a detailed protocol, the original sample-size justification, or the planned statistical analysis procedures.

The primary outcome was recorded over the first 60 minutes following epidural placement. The registry describes assessments in 15 min increments after completion of epidural placement and initial dose administration, with a fetal heart rate category assigned for each increment. The posted comparison reports participant counts with the outcome by arm. The registry lists three secondary outcomes covering hypotension, interventions, and adverse events.

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 Incidence of New-onset Category II or III Fetal Heart Rate Tracings, measured over First 60 minutes following epidural placement.

The primary endpoint is the incidence of new-onset Category II or III fetal heart rate tracings during the first 60 minutes following epidural placement. The registry describes fetal heart rate tracings being evaluated in 15 min increments, beginning after completion of epidural placement and initial dose administration. ACOG Category I, II, or III was assigned to each increment. The posted primary result is a count of participants meeting the endpoint in each arm.

This endpoint was used to address the trial’s stated concern that fetal heart rate changes may occur after epidural placement, particularly among women selected for the study’s narrow-pulse-pressure rationale. Combining Category II and Category III into the posted endpoint gives a participant-level outcome indicating whether a qualifying tracing occurred during the observation period. It does not provide separate counts for Category II and Category III, the number of affected assessment increments, or details about the duration of any tracing.

The first-60-minute window anchors the result to the period specified by the registry. It should not be read as measuring fetal heart rate changes outside that window. Nor does the endpoint alone establish why a tracing changed or whether a change was attributable to the preload, epidural placement, or another factor.

7. Results Posted in the Registry

• Volume Replacement IV Preload: 38.0% (52/137) versus 51.8% (72/139) on control; risk difference -13.8 percentage points (95% CI -25.5 to -2.2), risk ratio 0.73 (0.56–0.96); unadjusted two-proportion z-test p = 0.021.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

New Onset Hypotension (>20% Decrease in Systolic and/or Diastolic Blood Pressure)

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Volume Replacement IV Preload: 10.2% (14/137) versus 34.5% (48/139) on control; risk difference -24.3 percentage points (95% CI -33.7 to -14.9), risk ratio 0.30 (0.17–0.51); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically lower for Volume Replacement IV Preload than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Interventions to Correct Maternal Hypotension or Fetal Heart Rate Abnormalities (Position Change, Supplemental Oxygen, Vasopressor Support, Emergent Operative Delivery)

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Volume Replacement IV Preload: 18.2% (25/137) versus 43.9% (61/139) on control; risk difference -25.6 percentage points (95% CI -36.1 to -15.2), risk ratio 0.42 (0.28–0.62); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically lower for Volume Replacement IV Preload than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary outcomes follow the same overall direction as the primary result: the volume replacement arm had fewer participants with each of the recorded outcomes than the standard preload arm. These outcomes address related but distinct aspects of the post-epidural period. Hypotension concerns maternal blood pressure, while the intervention outcome records responses to maternal hypotension or fetal heart rate abnormalities. The adverse-event outcome provides safety information within the categories recorded by the registry.

This pattern is consistent with the primary comparison in direction, but it should not be treated as a set of independent replications. The outcomes may be clinically or statistically related, and the registry does not report how their definitions or analyses were coordinated. The secondary results can add context to the primary finding, but they cannot establish that the same effect applies to unrecorded outcomes or periods.

The posted secondary p values are unadjusted. When several outcomes are tested, chance alone can contribute to apparently notable results across the set. Without a reported multiplicity strategy, the secondary comparisons carry less confirmatory weight than a prespecified primary result. The registry record does not report a hierarchy of secondary hypotheses or a separate formal analysis plan. Interpretation should therefore emphasize the shared descriptive pattern while retaining caution about the strength of evidence from individual secondary tests.

The interventions outcome is also a composite of different actions, including position change, supplemental oxygen, vasopressor support, and emergent operative delivery. A combined participant count does not show which component contributed to the result. The registry record does not provide component-specific counts, so it is not possible to determine whether the overall pattern was driven by any particular intervention.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• New Onset Hypotension (>20% Decrease in Systolic and/or Diastolic Blood Pressure)
• Interventions to Correct Maternal Hypotension or Fetal Heart Rate Abnormalities (Position Change, Supplemental Oxygen, Vasopressor Support, Emergent Operative Delivery)
• Adverse Events (Pulmonary Edema)

9. Statistical Interpretation

10. Statistical Methods Explained

For a binary outcome, each participant is classified according to whether the event was recorded. The primary result is a count of participants with a Category II or III tracing in the specified observation period. The arm-level counts are compared using a risk difference, which expresses the difference in the event proportions as a proportion-scale contrast. A negative value in this comparison means that the observed proportion was lower in the volume replacement arm.

What does the risk difference describe?

The posted risk difference is -0.138. It describes the absolute contrast between the arms, rather than a relative comparison. Its sign identifies the direction of the observed difference according to the comparison specified in the registry. The estimate is based on the observed participant counts and group sizes; it does not adjust for other variables. The registry also lists relative measures, but the risk difference is useful for describing the absolute separation between the observed proportions.

How should the p value be read?

A p value summarizes how unusual data at least as discrepant as those observed would be under a statistical model in which there is no between-arm difference, subject to that model’s assumptions. It is not the probability that the null hypothesis is true, nor does it measure the size or importance of the observed difference. The primary p value is 0.021 and is explicitly unadjusted. A p value should therefore be read alongside the estimated difference, its interval, the outcome definition, and the analysis context rather than as a stand-alone verdict.

What does the confidence interval add?

A confidence interval represents uncertainty around an estimate. In general, it shows a range of values that are reasonably compatible with the observed data under the method used to calculate the interval. A narrower interval indicates greater precision than a wider interval, while an interval extending across zero would include both directions of the risk difference. For the primary result, the reported interval runs from -0.255 to -0.022. The registry record does not state the confidence level or provide details of the interval method.

What does randomization contribute?

Random allocation is intended to make the assigned groups comparable on average, including with respect to factors that are measured and factors that are not measured. That general property supports interpreting a between-arm contrast as a comparison of assigned interventions. It does not guarantee that every relevant feature was balanced in a particular trial, and it does not replace careful reporting of the allocation procedure, missing data, or analysis population. Those methodological details are not reported in the registry record.

Why distinguish the posted result from a causal conclusion?

The result is a comparison of outcomes recorded in the trial arms. A causal interpretation depends on how the trial was conducted and analyzed, including whether participants were analyzed according to assignment, how missing observations were handled, and whether the outcome was assessed consistently. The registry identifies randomization but does not report those analysis details. The numerical comparison can be described directly, while broader claims should remain limited to what the record documents.

In general, binary outcomes can be summarized using absolute or relative measures. Absolute measures describe the difference in event proportions; relative measures describe one proportion in relation to the other. They answer different questions and should not be treated as interchangeable. The registry provides a risk difference and also lists risk-ratio and odds-ratio estimates. The primary interpretation above focuses on the absolute risk difference because it directly describes the observed separation in proportions.

In general, multiplicity arises when several outcomes or hypotheses are examined. If each test is treated as though it were the only test, the chance of at least one apparently notable result can increase across a family of tests. Statistical methods can address this, but the chosen approach depends on the study’s aims and analysis plan. No adjustment is reported for the posted p values, and a multiplicity plan is not reported in the registry record. This makes the primary outcome especially important to distinguish from secondary findings.

The registry presents participant counts rather than a model-based adjusted estimate. No adjustment variables or regression model are reported in the registry record. The posted comparisons should therefore be read as unadjusted contrasts derived from the arm-level summaries, not as estimates adjusted for baseline characteristics or other factors.

11. Confidence Intervals and Precision

The primary risk difference is -0.138, and its reported confidence interval extends from -0.255 to -0.022. The interval lies below zero, so the range of values reported by this analysis is in the direction of a lower observed proportion in the volume replacement arm. Its width also conveys that the estimate is not exact: the data are compatible with a range of effect sizes, not only the point estimate.

In general, a confidence interval is a way to express statistical uncertainty around an estimate. It is not a guarantee that the true value lies within the particular interval, and it does not account for sources of uncertainty omitted from the analysis, such as unreported missing-data procedures or model choices. The registry record does not specify the confidence level or calculation method, so those details cannot be assessed from the record.

The primary outcome counts are 72 of 139 in the standard arm and 52 of 137 in the volume replacement arm. The p value is 0.021 and is unadjusted. Taken together, the estimate, interval, and p value describe the observed contrast and its statistical uncertainty under the posted analysis. They do not establish precision for settings or populations that were not studied.

Precision is distinct from clinical importance. Whether a difference matters in practice depends on context beyond the statistical interval, and the registry record does not define a threshold for a clinically important difference. The interval also does not address the possibility of selective reporting or unreported analysis choices.

12. 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 planning figures for the primary comparison are participants per arm, not total events. They are illustrations based on the observed effect, rather than the assumptions used to design the trial. The registry record does not report the trial’s original sample-size justification or original design assumptions.

The planning illustration uses a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. It considers detecting the stated fraction of the observed effect. For planning for 100% of the observed effect, the figures are 202 participants per arm for 80% power and 270 participants per arm for 90% power. For planning for 75% of the observed effect, the figures are 362 and 484 participants per arm, respectively. For planning for 50% of the observed effect, the figures are 818 and 1,094 participants per arm, respectively.

In plain terms, the 80% power column represents the planned chance of detecting the assumed effect under the stated statistical assumptions if that effect were present. The 90% column represents a higher planned chance of detection for the same assumed effect, which requires a larger planned sample. Smaller effects require more participants because they are harder to distinguish from random variation. These figures are planning illustrations, not observed power.

13. 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, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.518; treatment proportion p₁ = 0.380; average p̄ = 0.449.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.7034 = 1.3786.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6965 = 0.5862.
4. n = (1.3786 + 0.5862)² / (-0.1384)² = 201.5, rounded up to 202 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
p0 <- 0.517985611510791                          # control proportion
p1 <- 0.37956204379562                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^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 (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(2565485)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 202 (80% power), 270 (90% power)
 75% of observed effect: n per arm = 362 (80% power), 484 (90% power)
 50% of observed effect: n per arm = 818 (80% power), 1,094 (90% power)
power.prop.test: 201.5 
Simulated power at n = 202 per arm: 0.801 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-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.

14. Multiplicity, Missing Data and Analysis Populations

The registry identifies a primary endpoint and lists secondary outcomes, but it does not report a statistical plan describing how multiple outcomes or comparisons were to be handled. No multiplicity adjustment is reported for the posted p values. The primary result should therefore be distinguished from secondary findings, which are more appropriately treated as supporting or exploratory evidence rather than as separate definitive tests.

The registry record does not report whether a hierarchy among the secondary outcomes was prespecified, whether any interim analyses were conducted, or whether stopping rules were used. It also does not report the original statistical analysis plan. These are unknowns in the registry record, not evidence that a particular procedure was or was not used.

Missing-data handling is not reported in the registry record. The posted arm summaries list 139 participants for the standard preload arm and 137 for the volume replacement arm, but the record does not explain whether those counts represent all randomized participants with outcome information, an analysis subset, or another analysis population. It does not state how missing endpoint assessments were classified or whether any participants were excluded from the analysis.

The analysis population is not reported in the registry record. In particular, the record does not say whether participants were analyzed according to randomized assignment, whether any per-protocol or other population was used, or how departures from assigned treatment were handled. The randomization design is relevant to interpretation, but the absence of these details limits assessment of the analysis process.

These reporting gaps matter because multiplicity, missing outcomes, and analysis-population choices can affect the interpretation of uncertainty. They do not change the posted counts or estimates, but they make it harder to evaluate how closely the posted analysis followed the intended design and how robust the result may be to alternative reasonable choices.

15. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

The registry lists zero serious adverse events in the Standard IV Preload arm and zero in the Volume Replacement IV Preload arm. It also lists zero other adverse events and zero deaths in each arm. The reported at-risk counts are 139 for the standard arm and 137 for the volume replacement arm. No serious adverse event terms are listed.

These entries mean that no events in the recorded categories were reported for the trial arms in the registry record. They do not show that the risk of an event is zero, and they do not establish that the two preload volumes have identical safety profiles. With no recorded events, the registry cannot provide an event-based comparison of the frequency or types of serious adverse events.

The listed adverse-event information should also be read within the registry’s reporting scope. The record does not provide further detail about event ascertainment, follow-up beyond the stated reporting, or how events were classified. The absence of listed events is therefore a limited safety description, not a guarantee that no harm occurred.

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

The posted primary result shows fewer participants with new-onset Category II or III fetal heart rate tracings in the volume replacement arm than in the standard preload arm during the first 60 minutes after epidural placement. The estimated risk difference is -0.138, with a reported interval from -0.255 to -0.022 and an unadjusted p value of 0.021. This describes the trial’s observed comparison; it should not be restated as proof that one preload volume works or does not work.

The result applies to the trial’s comparison of 1500mL and 500mL Lactated Ringer’s preloads in the study context described by the registry, with women targeted on the basis of narrow pulse pressure. The record does not establish whether the same pattern would be seen in people outside that context, at other sites, or with different care practices. It also does not show the mechanism that might explain the observed difference.

The primary outcome combines Category II and Category III tracings at the participant level. It does not tell readers how many events occurred in each category, how long tracings lasted, or what occurred after the first 60 minutes. The secondary intervention outcome also combines several different actions, so its overall count does not identify which response was used.

Finally, a statistical result does not by itself determine clinical importance. The registry record does not state a threshold for a meaningful difference, and its reporting does not include enough information to assess missing-data handling, the analysis population, or multiplicity procedures. Those limits should accompany any interpretation of the point estimate and its uncertainty.

17. Why This Trial Matters Statistically

This trial is statistically notable because it evaluates a targeted approach to a common treatment decision: whether preload volume should vary according to a proposed risk marker. The registry’s rationale identifies narrow pulse pressure as a potential indicator of lower intravascular volume and possible vulnerability to post-epidural fetal heart rate changes. The randomized comparison makes the central question explicit: whether a larger preload is associated with a different recorded outcome from the standard preload in the selected study context.

The primary outcome is time-bounded and participant-based, which gives a clear frame for interpreting the posted counts. The risk difference communicates the absolute direction and size of the observed contrast, while its confidence interval makes uncertainty visible. Reading both together is more informative than relying on the p value alone.

The trial also illustrates why supporting outcomes and safety reporting need careful interpretation. Secondary results point in the same direction, but they are unadjusted and involve related outcomes. The zero adverse-event entries are relevant to the record but do not prove absence of risk. Clear distinctions among primary, secondary, and safety findings help prevent stronger claims than the data support.

Finally, the record highlights the value of complete methods reporting. Allocation, masking, analysis populations, missing data, multiplicity, and the original design assumptions all affect how readers judge a trial. Several of those details are not reported in the registry record, limiting methodological appraisal despite the availability of arm-level outcome counts and comparisons.

18. 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 registry record contains several limitations specific to evaluating this trial. Although it identifies a randomized, single-masked, parallel design, it does not identify who was masked or describe the random-sequence generation and allocation-concealment procedures. The record also does not report the protocol or original sample-size justification, so it is not possible to assess whether the planned enrollment was based on a prespecified effect or variance assumption.

The primary endpoint is recorded across 15 min increments, but the posted result is a participant count for the combined Category II or III outcome. Separate counts by category, event duration, and the number of qualifying increments are not reported in the registry record. The result therefore cannot describe the distribution or persistence of the tracing changes.

Analysis details are limited. Missing-data procedures, analysis populations, treatment adherence, and any covariate adjustment are not reported in the registry record. The registry also does not report a multiplicity plan for the primary and secondary outcomes. These gaps constrain assessment of how the posted estimates were produced and how sensitive they may be to analysis choices.

The secondary intervention outcome combines multiple types of care, and component-specific results are not reported. Safety reporting lists no events in the recorded categories, but the registry does not provide further detail about ascertainment or follow-up. The results should be understood within these reporting limits and the population and observation window described in the record.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Pulse Pressure and Post-epidural Fetal Heart Rate Changes — NCT02565485.
• Registry record last updated 2018-07-09; status last verified 2018-06.
• Results first posted 2018-06-08.
• 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.

22. Record Summary

NCT02565485 is a completed randomized, single-masked, parallel-group trial sponsored by MetroHealth Medical Center. It compared a 500mL standard Lactated Ringer’s preload with a 1500mL volume replacement preload before labor epidural placement. The registry lists enrollment of 276 and focuses on women with narrow pulse pressure.

The primary endpoint was new-onset Category II or III fetal heart rate tracings during the first 60 minutes after epidural placement. The posted comparison favored the volume replacement arm in observed event proportion, with a risk difference of -0.138 and an unadjusted p value of 0.021. The registry also reports secondary outcomes and zero recorded serious adverse events, other adverse events, and deaths in each arm.

The record does not report the original sample-size justification, analysis population, missing-data procedures, or multiplicity plan. Those omissions are relevant when weighing the reported comparisons.