Cardiac and Cerebral Hemodynamics With Umbilical Cord Milking Compared With Early Cord Clamping: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Cardiac and Cerebral Hemodynamics With Umbilical Cord Milking Compared With Early Cord Clamping (NCT03621956), a randomized na study. The primary outcome is StO2 in the First 10 Minutes of Life.

2. Clinical Question

The primary endpoint is StO2 in the first 10 minutes of life, reported as a mean with standard deviation. A secondary outcome is heart rate at 10 minutes. The registry record describes a randomized trial and lists these two procedures, but it does not report participant-level data, a detailed allocation procedure, or a fuller clinical profile of the enrolled infants. Those omissions limit how closely the posted group summaries can be connected to particular clinical circumstances.

3. Trial Design

The registry record describes a randomized study with a parallel model and no masking. Its official title calls it a randomized cluster crossover trial, while the listed design model is parallel. The record does not explain how clustering or crossover was implemented, how sites or participants were assigned, or how the two design descriptions relate. It is therefore not possible to infer the allocation unit or the analysis implications from the title alone.

The study is marked completed and lists enrollment of 34. The recorded start date is 2019-01-07 and the primary completion date is 2021-06-01. Three clinical sites enrolling in the primary MINVI trial are described as collecting NIRS data in a subset of 200 non-vigorous term and near-term infants. The record does not reconcile that subset description with the enrollment figure for this study, so the distinction between a planned subset and the number represented in the posted results is not clear.

The two procedures are umbilical cord milking and early cord clamping. For cord milking, the cord is grasped and blood is pushed toward the infant four times before clamping; the record says this can be done in 15-20 seconds. For early clamping, the cord is clamped within 30 seconds of delivery. The primary measure is StO2 during birth to 10 minutes of life, and heart rate at 10 minutes is listed as a secondary outcome.

The registry record does not report the original sample-size justification, the detailed randomization method, the handling of any cluster or crossover structure, or a prespecified statistical analysis plan. It also does not describe an intention-to-treat or per-protocol analysis population. These details matter when judging whether the reported summaries and comparisons reflect the design as intended.

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 StO2 in the First 10 Minutes of Life, measured over birth to 10 minutes of life.

The primary endpoint is StO2 in the first 10 minutes of life, reported in percent as a mean and standard deviation. The registry describes it as cerebral oxygenation derived from skeletal muscle oxygen saturation and measured by near-infrared spectroscopy. After delivery, the assigned procedure, and stabilization during resuscitation, a NIRS sensor is placed on the newborn’s right forehead within 10 minutes of placement on the resuscitation bed. The endpoint timeframe is birth to 10 minutes of life.

NIRS provides a non-invasive way to monitor oxygenation during a short period immediately after birth. A group mean can summarize the average recorded value, while the standard deviation describes how spread out the observations are around that average. Those summaries can help characterize the measured oxygenation in each group, but they do not show each infant’s measurement or how the values changed over time.

The record does not specify the exact timing of each individual reading within the measurement window, how multiple readings were combined, or how unusable or missing measurements were handled. It also does not report a clinically important threshold for interpreting a difference in StO2. The posted comparison should therefore be read as a difference in the reported group means, not as a complete account of individual oxygenation trajectories or clinical significance.

7. Results Posted in the Registry

• Early Cord Clamping: mean 74.50 versus 70.00 on control; difference 4.50 (95% CI 0.75 to 8.25), standardized effect d = 0.90; z-test p = 0.019.

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.

Heart Rate at 10 Minutes

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Early Cord Clamping: mean 160.00 versus 152.00 on control; difference 8.00 (95% CI -0.71 to 16.71), standardized effect d = 0.62; z-test p = 0.072.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Early Cord Clamping and the control. The interval gives the range of effects that remain compatible with the data.

The posted secondary outcome is heart rate at 10 minutes. Its group means are higher in the early-clamping group, in the same direction as the primary mean StO2 comparison. However, the heart-rate confidence interval includes zero, and its unadjusted p-value is 0.072. The secondary result therefore provides a less precise and less conclusive comparison than the primary result; similarity in direction does not make the outcomes interchangeable.

StO2 and heart rate measure different aspects of the immediate post-birth period. A pattern in one measure does not validate or explain a pattern in the other. The registry does not report a prespecified relationship between the endpoints, a combined outcome, or an analysis testing whether changes in one measure corresponded to changes in the other. The results should be considered separately rather than treated as mutually confirming evidence.

Unadjusted secondary results carry less weight because multiple outcomes can create more opportunities for apparently notable findings, even when no true difference exists. General statistical practice may address this through prespecification or multiplicity adjustment, but the registry record does not report whether either approach was used. The single posted secondary outcome does not reveal whether additional outcomes were considered in the study’s analysis plan.

The secondary finding can be read as descriptive evidence about the reported group summaries, with uncertainty reflected in its interval. It should not be used alone to infer a clinically meaningful effect or to overturn the interpretation of the primary endpoint. Nor does an interval that includes zero demonstrate equivalence. The registry record does not report an equivalence margin or a non-inferiority framework for this outcome.

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

• Heart Rate at 10 Minutes

9. Statistical Interpretation

10. Statistical Methods Explained

What does a mean difference describe?

A mean is the arithmetic average of the recorded values within a group. A mean difference compares the two group averages, and its direction depends on which group is subtracted from which. In this study, the registry identifies cord milking as the control, and the displayed comparisons give early cord clamping relative to cord milking. Thus, a positive reported difference means that the early-clamping group had the higher average on that measure. The comparison is a summary of group-level data, not a statement about every participant.

The standard deviation describes the spread of individual observations around a group mean. It is different from the standard error, which describes uncertainty in an estimated mean. The primary outcome standard deviations are 7.15 for cord milking and 2.17 for early clamping. The heart-rate standard deviations are 12.76 and 12.99, respectively. Differences in spread can affect how precisely group means are estimated; similar group sizes alone do not determine precision.

What does a confidence interval convey?

General statistical explanation: a confidence interval gives a range of values compatible with the data and the method used to construct it. It communicates uncertainty about an estimated quantity, not the range of individual measurements and not a guarantee that the true value lies within the reported bounds. For a difference between means, an interval that includes zero is compatible with no group difference under the analysis, while an interval that excludes zero indicates that zero is not among the values supported by that interval’s construction. The interval does not establish clinical importance or prove causation.

How should a p-value be read?

General statistical explanation: a p-value describes how unusual data at least as inconsistent with a specified null hypothesis would be if that hypothesis and the analysis assumptions were true. It is not the probability that the null hypothesis is true, nor the probability that chance alone produced the result. The registry gives unadjusted p-values of 0.019 for the primary measure and 0.072 for heart rate. Because the values are unadjusted, they do not account for any multiplicity correction. The record does not report a detailed testing plan or enough analysis detail to determine whether other adjustments were made.

The reported p-value should be considered with the estimated difference and its confidence interval. A p-value does not communicate the size of the difference, and a small value does not by itself establish importance. Likewise, a result that is not statistically distinguishable from zero does not prove that there is no difference; its confidence interval may still allow effects in either direction.

What role does the study design play?

Randomization can help create comparable groups on average, but interpretation relies on knowing what was randomized and how the data were analyzed. The record labels the study randomized, gives a parallel model, and uses “cluster crossover” in the official title. It does not report whether sites, clusters, or individuals were assigned, nor how crossover periods or within-cluster relationships were handled. If observations are correlated within a cluster, treating every observation as independent can understate uncertainty. This is a general statistical concern; the record does not establish whether such a correction was needed or used in this study.

The record reports group means, standard deviations, group counts, mean differences, confidence intervals, and unadjusted p-values. It does not state the specific inferential procedure, model terms, or assumptions used to produce the comparisons. The figures should therefore be interpreted as posted summaries, without attributing them to a particular test or model that the registry does not describe.

Why can over-dispersion matter?

General statistical explanation: over-dispersion occurs when the observed variability is greater than a model expects. If it is present and not accounted for, estimated uncertainty can be too small and confidence intervals can be too narrow. It is particularly relevant to count or clustered data, but the record does not describe an over-dispersion assessment or identify a model for these outcomes. The primary endpoint is continuous, so the available information does not support claiming that over-dispersion was present or affected the results.

More generally, the validity of a mean comparison depends on the design, the distribution of observations, independence assumptions, and the handling of missing values. The posted group summaries do not let readers check those assumptions at the participant level. No individual observations, distribution plots, or missing-data accounting are reported in the registry record.

What does the standardized effect add?

General statistical explanation: a standardized effect expresses a difference relative to a measure of variability. This can help compare effects measured on different scales, but it is less directly interpretable in the original measurement units. Any standardized effect should be read alongside the original mean difference and its confidence interval. The record includes standardized comparison information, but does not explain a prespecified interpretation threshold or its role in the trial’s own analysis.

The statistical summaries are useful descriptions of the posted data, but they cannot resolve the unreported features of allocation, clustering, crossover, endpoint processing, or missingness. Those design and analysis details are necessary to assess how well the uncertainty estimates reflect the actual trial structure.

11. Confidence Intervals and Precision

The primary mean difference is 4.5 percentage points, with a confidence interval reported from 0.752 to 8.248. The interval lies above zero, so the posted interval is consistent with a higher mean StO2 in the early-clamping group than in the cord-milking group. Its width also indicates that the data remain compatible with a range of difference sizes. The estimate is not exact, and the interval should not be read as a range containing most individual infants’ measurements.

The primary groups were small: 15 infants in the cord-milking group and 19 in the early-clamping group. Small groups generally provide less information about group averages than larger groups, although precision also depends on variability and design. The observed standard deviations differed between the groups, which is relevant context for the mean estimates. The registry does not report participant-level values or enough detail about clustering and crossover to assess whether the stated interval fully reflects the study structure.

For heart rate, the mean difference was 8.0 beats per minute, and the reported interval was -0.707 to 16.71. Because this range includes zero, the result is compatible with no difference as well as with a positive difference for early clamping. The interval is also compatible with a small difference in the opposite direction. The unadjusted p-value of 0.072 is consistent with this uncertainty, but neither the interval nor the p-value establishes that the groups were equivalent.

Confidence intervals quantify statistical uncertainty under the method used; they do not incorporate every uncertainty about the study. Missing information about the design implementation, analysis plan, missing observations, and clinical importance remains relevant. The registry does not report a threshold for a clinically important difference in either outcome, so statistical precision cannot be translated into a judgment about clinical importance.

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 are participants per arm, not a total across both arms and not total events. They are illustrations based on the observed effect, using a two-sided significance level of 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. These are planning assumptions for the illustration; the original trial-design assumptions are not reported in the registry record.

The 80% power column gives the number of participants per arm that the illustration estimates would be needed to have an 80% chance of detecting the assumed effect under those assumptions, if that effect were real and the statistical model’s assumptions held. The 90% power column describes the corresponding planning target for a 90% chance. Power is a design-stage probability, not a guarantee that a particular study will produce a statistically significant result.

The entries use the full observed effect and smaller fractions of that effect. Planning for 75% of the observed effect requires more participants per arm than planning for the full observed effect; planning for 50% requires more still. This reflects a general principle: smaller effects are harder to distinguish from random variation, so they usually require more information. For example, the primary-outcome planning entries range from 20 participants per arm for the full observed effect at 80% power to 78 per arm for half the observed effect at that power. At 90% power, the corresponding entries range from 26 to 104 per arm.

These calculations are not observed power. They are not evidence that the completed study had a particular probability of detecting its result, and they are not a substitute for the trial’s original sample-size rationale. The registry record does not report that rationale, nor does the planning illustration describe adjustments for a cluster or crossover structure.

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, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 4.500; pooled standard deviation σ = 5.001.
2. n = 2 × (1.96 + 0.842)² × 5.001² / 4.500² = 19.4, rounded up to 20 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 <- 4.5                      # observed difference in means
sigma <- 5.00148477954297                     # 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(3621956)
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 = 20 (80% power), 26 (90% power)
 75% of observed effect: n per arm = 35 (80% power), 47 (90% power)
 50% of observed effect: n per arm = 78 (80% power), 104 (90% power)
power.t.test: 20.4 
Simulated power at n = 20 per arm: 0.794 (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.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists two outcome measures: the primary StO2 measure and heart rate at 10 minutes as a secondary outcome. The posted comparisons include unadjusted p-values. The record does not report whether a multiplicity strategy was prespecified, whether the primary endpoint was the sole confirmatory test, or whether any adjustment was applied beyond the unadjusted comparisons. When several outcomes or analyses are examined, the chance of at least one apparently unusual result can increase; how much that matters depends on the full analysis plan, which is not reported.

The record does not report a detailed statistical analysis plan, an interim-analysis schedule, stopping rules, or the timing of analysis decisions. It also does not describe a primary analysis population such as intention-to-treat, modified intention-to-treat, or per-protocol. Without those details, readers cannot determine how deviations from assigned procedures, exclusions, or incomplete measurements were handled.

Missing-data information is not reported in the registry record. There is no posted count of missing NIRS or heart-rate observations, no description of why data might have been missing, and no account of imputation or sensitivity analyses. Missingness can affect a comparison if the probability of having a measurement differs between groups or is related to the outcome. The group counts attached to the outcome summaries do not by themselves explain whether all enrolled participants contributed data or how those counts were determined.

The title’s cluster-crossover description and the listed parallel model raise an additional question about the unit of assignment and dependence among observations. The registry record does not explain whether the analysis accounted for clustering, crossover periods, or any correlation structure. Those details can affect standard errors and confidence intervals. It would be inappropriate to assume that a particular correction was used or that the posted estimates are invalid; the implementation is simply not reported in the registry record.

These gaps do not erase the descriptive group results, but they limit assessment of how the reported inferential statistics were obtained and whether all planned analyses are represented.

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 0% reporting threshold.

The registry reports zero serious adverse events among 15 participants at risk in the umbilical cord milking group and among 19 at risk in the early cord clamping group. It also reports zero other adverse events in both groups and zero deaths in both groups. These counts describe what was recorded for the participants at risk in the registry entry.

Zero observed events is not proof that the risk is zero. With limited group counts, uncommon events may not appear in a study even if they can occur. The record does not provide event definitions, a detailed surveillance period, further event descriptions, or longer-term safety follow-up. The absence of listed events should therefore be read as a descriptive finding for this record, not as a guarantee of safety or as a comparison precise enough to rule out differences in rare harms.

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

The posted primary data show that mean StO2 was higher in the early-clamping group than in the cord-milking group, with a reported mean difference of 4.5 percentage points. The primary confidence interval excludes zero, and the unadjusted p-value is 0.019. This supports a difference between the observed group averages under the reported comparison. It does not establish that the procedure caused the difference or that the difference is clinically important.

The study record identifies randomization, but does not explain how the assignment worked alongside the cluster-crossover title and parallel model. The record also does not report the statistical analysis plan, missing-data handling, or analysis population. Those omissions leave uncertainty about how closely the posted estimates and intervals reflect the design and the full set of participants.

The heart-rate result has a different level of precision: its interval includes zero. That does not show that the groups are the same, just as a higher observed mean in one group does not prove a reliable difference. It means the posted data do not pin down the secondary group difference as precisely as the primary comparison.

The safety entry reports no serious adverse events, other adverse events, or deaths in either group. These zero counts are limited to the recorded participants and follow-up described by the registry; the record does not give enough safety detail to rule out uncommon events or longer-term outcomes.

These results concern short-term measurements in the described study population. They do not establish effects outside that population, explain individual infants’ outcomes, or settle broader questions about the procedures. The registry does not report a clinical-importance threshold for StO2 or heart rate. Statistical evidence about group averages should therefore be kept distinct from judgments about clinical meaning.

17. Why This Trial Matters Statistically

This trial is statistically informative because it places a short-window physiologic measure at the center of a randomized comparison of two delivery-room procedures. The primary endpoint is a continuous measurement, so the reported means and standard deviations give a direct description of the observed group values, while the mean difference and confidence interval communicate the estimated contrast and its uncertainty.

The record also illustrates why design labels and analysis details matter. The official title refers to a cluster crossover trial, but the listed model is parallel. The assignment unit and treatment of possible clustering or crossover are not explained. These distinctions can affect the independence assumptions underlying standard errors and confidence intervals. Without those details, a reader should focus on what is directly reported and avoid assuming a specific model or design implementation.

The primary result has an interval that excludes zero, whereas the secondary heart-rate interval includes zero. Reading both estimates with their uncertainty is more informative than treating a p-value as a stand-alone verdict. The differing precision also demonstrates that outcomes measured in the same participants can yield different levels of information.

The planning illustrations emphasize how sample requirements depend on the effect size one hopes to detect and the desired power. They also need to be distinguished from the original design rationale, which is not reported. This is particularly relevant when the enrollment and subset descriptions are not fully reconciled in the record.

Finally, the registry provides only a limited safety summary and no detailed missing-data or analysis-population information. Those limitations do not prevent a clear description of the posted results, but they set boundaries on the strength and scope of statistical interpretation.

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.

Several limitations are specific to the registry entry. First, the study’s official title describes a cluster crossover trial, while the model field lists a parallel design. The record does not explain the allocation unit, the crossover process, or whether and how site or cluster relationships were handled in analysis. This prevents a full assessment of whether the reported uncertainty accounts for the design.

Second, the brief summary describes three clinical sites collecting NIRS data in a subset of 200 infants enrolled in the primary MINVI trial, while the study enrollment is listed as 34. The record does not explain how these figures relate or provide a participant flow accounting for enrollment, measurement, and analysis. The characteristics of the infants contributing to the endpoint summaries are not reported in detail.

Third, the registry does not report the original sample-size rationale, detailed statistical plan, analysis population, missing-data handling, or any interim-analysis approach. It does not specify the inferential procedure underlying the posted comparisons. Without participant-level data, readers also cannot inspect distributions, identify outliers, or evaluate the timing and completeness of measurements within the 10-minute window.

The primary outcome is described as cerebral oxygenation derived from skeletal muscle oxygen saturation measured by NIRS. The record explains sensor placement and the measurement window, but not how multiple readings were reduced to an endpoint or how failed or delayed measurements were treated. No clinically important difference threshold is reported.

Finally, safety information is limited to group counts of events and deaths, without detailed definitions or follow-up description. Together, these limitations constrain causal, clinical, and generalizability interpretations, even though the posted mean comparisons can still be described.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Cardiac and Cerebral Hemodynamics With Umbilical Cord Milking Compared With Early Cord Clamping — NCT03621956.
• Registry record last updated 2024-07-08; status last verified 2024-07.
• Results first posted 2024-07-08.
• 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

The registry record for NCT03621956 describes a completed randomized study comparing umbilical cord milking with early cord clamping. It lists a parallel model and no masking, while the official title describes a cluster crossover trial. Enrollment is 34. The primary outcome is mean StO2 during the first 10 minutes of life, measured by NIRS; heart rate at 10 minutes is the listed secondary outcome.

The primary group means were 70.0 for cord milking and 74.5 for early clamping, with a reported mean difference of 4.5 percentage points and an unadjusted p-value of 0.019. The secondary heart-rate comparison had an unadjusted p-value of 0.072 and a confidence interval that includes zero. The registry reports no serious adverse events, other adverse events, or deaths in either group.

The record does not reconcile the subset and enrollment descriptions or report key details of the design implementation, analysis plan, missing data, or analysis population. Those gaps limit interpretation of the posted estimates and their precision.