Study of Effectiveness and Safety of Azithromycin-based Extended-spectrum Prophylaxis to Prevent Post Cesarean Infection: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Effectiveness and Safety of Azithromycin-based Extended-spectrum Prophylaxis to Prevent Post Cesarean Infection (NCT01235546), a randomized na study. The primary outcome is Participants With Endometritis and/or Wound Infection and/or Other Post-cesarean Infections (Occurring Within 6 Weeks of Delivery).

2. Clinical Question

The posted primary result is a count of participants meeting a combined infection endpoint, rather than separate comparative results for each infection type. In the placebo group, 119 of 992 participants had the endpoint; in the azithromycin group, 62 of 1018 did. The registry reports a risk difference of -0.059, with an interval from -0.084 to -0.034, and p < 0.001. These are descriptions of the posted trial results, not treatment advice.

The question concerns the added azithromycin regimen against placebo when both groups received standard care. It is therefore not a comparison of azithromycin alone with no antibiotic prophylaxis. The registry's brief summary frames the trial around extended-spectrum prophylaxis added to standard narrow-spectrum prophylaxis. The degree to which actual care followed every stated preference or timing is not detailed beyond the reported similarity of selected delivery-related characteristics between groups.

3. Trial Design

The registry identifies this as a randomized, parallel-group trial with quadruple masking. The record labels the phase as NA. It lists an enrollment of 2013 and a completed status. The start is recorded as 2011-05 and primary completion as 2015-12. The trial is titled the Cesarean Section Optimal Antibiotic Prophylaxis Trial, also described in the registry summary as a large pragmatic multi-center randomized clinical trial.

Participants were assigned to azithromycin and standard care or placebo and standard care. The intervention description identifies 500 mg azithromycin in 250 cc normal saline; the placebo description identifies 250 cc normal saline. The summary describes standard prophylaxis as a narrow-spectrum cephalosporin, preferably before the surgical incision, with clindamycin noted for cephalosporin allergy. The registry does not describe the allocation sequence or the specific roles masked under the quadruple-masking label, so those details are not reported in the registry record.

The primary endpoint was assessed up to 6 weeks after delivery and combined endometritis, wound infection, and other post-cesarean infections. The registry reports 992 participants in the placebo arm and 1018 in the azithromycin arm for this outcome. It also states that selected cesarean-delivery characteristics, receipt of standard prophylaxis, timing of study medication, and skin preparation were similar across groups. These statements describe the posted trial record; details of the full eligibility criteria, participant flow, and analysis population are not reported in the registry record.

Random assignment supports a comparative interpretation of the groups, while masking can limit some influences on care and outcome assessment. Those design features do not by themselves establish how missing outcomes, protocol deviations, or analysis decisions were handled. Such details are not reported in the registry record.

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.

Before assignment: The addition of azithromycin and the standard of care (cephazolin or clindamycin) for antibiotic prophylaxis before cesarean delivery may further reduce the rate of postoperative infection. We evaluated the benefits and safety of azithromycin prophylaxis and the standard of care in women undergoing nonelective cesarean section.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The specific characteristics related to the cesarean delivery, including indications for cesarean delivery, receipt of standard prophylaxis, timing of receipt of study medication, and type of surgical skin preparation, were similar in the two groups.

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 Participants With Endometritis and/or Wound Infection and/or Other Post-cesarean Infections (Occurring Within 6 Weeks of Delivery), measured over Up to 6 weeks after delivery.

The primary endpoint counts participants with endometritis, wound infection, or another post-cesarean infection occurring within 6 weeks of delivery. It is a composite outcome: meeting any qualifying infection definition contributes to the combined endpoint. The posted result does not give separate counts or comparative estimates for each component, so it cannot show which component accounts for the group-level result.

The registry defines endometritis as at least two specified signs with no other recognized cause: fever, abdominal pain, uterine tenderness, or purulent drainage from the uterus. Wound infection includes superficial or deep incisional surgical-site infection with described signs around or at the incision, and includes necrotizing fasciitis. Wound hematoma, seroma, or breakdown alone does not qualify without the preceding infection signs. The temperature threshold is stated as at least 38°C [100.4°F].

Combining clinically related events can capture more of the overall infection burden than a single component alone, which is a general reason trials may use a composite endpoint. The trade-off is that the combined result does not reveal whether components occurred with similar frequency or have similar importance. For this outcome, the registry provides an overall participant count and group comparison, but component-level results are not reported in the registry record. The endpoint is also bounded by the stated follow-up period; infections outside that period are not represented in the reported primary outcome.

7. Results Posted in the Registry

• Azithromycin: 6.1% (62/1018) versus 12.0% (119/992) on control; risk difference -5.9 percentage points (95% CI -8.4 to -3.4), risk ratio 0.51 (0.38–0.68); unadjusted two-proportion z-test p = <0.001.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary at the participant level: each participant either met the composite infection definition within the stated follow-up or did not. For a binary outcome, the event count and the number of participants at risk describe the observed group result. Here, the placebo arm has 119 events among 992 participants, and the azithromycin arm has 62 among 1018. The registry also reports group proportions of 0.12 and 0.061.

What does the risk difference express?

The risk difference is the event probability in one group minus the event probability in the comparison group, with the comparison direction stated for the result. The posted estimate is -0.059 for azithromycin relative to placebo. Its sign indicates that the observed event proportion was lower in the azithromycin group. The estimate is an absolute contrast, rather than a relative measure. The interval from -0.084 to -0.034 conveys uncertainty around that contrast under the method used for the reported interval.

Risk differences are often useful for describing the size of a group contrast on the probability scale. In general, the same relative effect can correspond to different absolute differences when baseline event probabilities differ. The registry's posted group proportions help place the reported absolute contrast in context, but no additional contrast should be inferred beyond the reported estimates.

How do the risk ratio and odds ratio differ?

The registry reports a risk ratio of 0.508, with an interval from 0.378 to 0.681. A risk ratio compares the probability of the event between groups. A value below one indicates a lower observed event probability in the group named in the comparison, relative to its comparator. The odds ratio, reported as 0.476 with an interval from 0.345 to 0.655, compares odds rather than probabilities. Odds and probabilities are related but are not the same quantity, so the odds ratio should not be described as a risk ratio.

Relative measures can make proportional contrasts easier to recognize, while the risk difference describes the absolute contrast. These are general statistical interpretations. For a clinical decision, the meaning of any estimate also depends on outcome importance, population, setting, and uncertainty; the statistical measures alone do not provide medical advice.

What does the p-value contribute?

The registry reports an unadjusted p-value of p < 0.001. A p-value is calculated relative to a null hypothesis and the assumptions of the test. In general, it describes the compatibility of the observed data with that null model; it is not the probability that the null hypothesis is true, nor the probability that the result occurred by chance in an everyday sense. The label unadjusted matters because the record does not say that this value accounts for multiple outcomes or repeated analyses. No inferential adjustment plan is reported in the registry record.

The planning illustration uses a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. That is a planning calculation based on the observed effect and stated fractions of that effect, not evidence of the trial's original design choices. The trial's original sample-size assumptions and statistical analysis plan are not reported in the registry record.

What can randomization and masking support?

Randomization is intended to make assigned groups comparable in expectation, so a group difference can be interpreted as a treatment contrast more credibly than a simple comparison of nonrandomized groups. It does not guarantee identical groups, and it does not resolve every concern about missing outcomes or analysis choices. The registry identifies quadruple masking but does not specify which participant, clinician, investigator, or outcome-assessment roles were masked. Those particulars are not reported in the registry record.

The reported outcome definitions help clarify what counted as an event. The registry's composite combines infection categories and specifies criteria for endometritis and wound infection. General methodological caution applies: composite outcomes can be informative about an overall outcome family, yet an overall estimate does not reveal the separate contribution of each component. Component-specific results and additional sensitivity analyses are not reported in the registry record.

The listed statistical measures are estimates from the posted group data. The registry does not provide analysis population details, handling of missing outcomes, covariate adjustment methods, or a full account of model diagnostics. Accordingly, the reported estimates can be described, but methodological details beyond those explicitly recorded cannot be attributed to the trial.

10. Confidence Intervals and Precision

The risk-difference estimate is -0.059, with an interval from -0.084 to -0.034. The risk-ratio estimate is 0.508, with an interval from 0.378 to 0.681. The odds-ratio estimate is 0.476, with an interval from 0.345 to 0.655. These intervals communicate statistical uncertainty around the respective estimates; they are not guarantees that the true value lies within the displayed limits.

In general, a confidence interval is a range generated by a statistical procedure that, under its assumptions and repeated use, has a specified coverage property. The confidence level and calculation method for these registry intervals are not reported in the registry record. The endpoints should therefore be read as the intervals posted, without assigning an unreported confidence level or method.

The risk-difference interval is entirely below zero, consistent with the reported direction of the estimate. The relative-measure intervals are below one, also consistent with the direction of the group comparison. These observations describe the interval locations; they do not establish that all potential sources of uncertainty have been captured. Sampling uncertainty is only one part of uncertainty, and registry-level summaries do not by themselves address uncertainty from outcome classification, missing data, generalizability, or unreported analytic choices.

The participant counts indicate the amount of outcome information recorded for each arm, but precision cannot be judged from counts alone. The interval width and the measure's scale matter. Risk differences, risk ratios, and odds ratios also use different scales, so their numerical interval widths should not be compared as if they represented the same quantity.

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 planning figures are participants per arm, not total events. They illustrate sample sizes for detecting specified fractions of the observed effect under the stated assumptions: a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The trial's own original design assumptions are not reported in the registry record, so these calculations should not be read as a reconstruction of its original planning.

For planning for 100% of the observed effect, the illustration lists 370 participants per arm for 80% power and 494 participants per arm for 90% power. For planning for 75% of the observed effect, it lists 705 participants per arm for 80% power and 944 participants per arm for 90% power. For planning for 50% of the observed effect, it lists 1,694 participants per arm for 80% power and 2,267 participants per arm for 90% power.

In plain language, the 80% power column gives the modeled number of participants per arm for a planning scenario with an 80% chance of detecting the specified effect if that effect and the assumptions are correct. The 90% column gives the corresponding planning number for a 90% chance. These are planning illustrations based on the observed effect, not observed power for the completed trial. Smaller effects require more participants under the same assumptions, as reflected by the increasing figures across the stated effect scenarios.

The registry does not report the original design justification, so the illustration should not be used to infer what effect the investigators expected before enrollment or whether the trial met an original target. The effect fractions are hypothetical planning scenarios relative to the observed estimate.

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

Worked calculation for this trial

1. Control proportion p₀ = 0.120; treatment proportion p₁ = 0.061; average p̄ = 0.090.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.4056 = 0.7950.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.4034 = 0.3395.
4. n = (0.7950 + 0.3395)² / (-0.0591)² = 369.0, rounded up to 370 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 <- 0.119959677419355                          # control proportion
p1 <- 0.0609037328094303                          # 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(1235546)
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 = 370 (80% power), 494 (90% power)
 75% of observed effect: n per arm = 705 (80% power), 944 (90% power)
 50% of observed effect: n per arm = 1,694 (80% power), 2,267 (90% power)
power.prop.test: 369 
Simulated power at n = 370 per arm: 0.815 (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.

13. Multiplicity, Missing Data and Analysis Populations

The registry lists no secondary outcomes posted and zero analyses. The primary result is accompanied by an unadjusted p-value. No multiplicity plan is reported in the registry record, including whether the investigators prespecified any adjustment for multiple outcomes, comparisons, or analyses. Consequently, the reported p-value should be understood as the posted unadjusted value rather than as a value documented to control a family-wise error rate.

In general, multiplicity arises when several statistical questions are tested; repeated testing can increase the chance of at least one apparently notable result under a set of null hypotheses. Adjustment strategies depend on which outcomes and analyses were prespecified and on the inferential goal. Because the registry does not report such a plan, no adjustment method or confirmatory status beyond the registered primary outcome can be attributed to this record.

Missing-data handling and analysis populations are also not reported in the registry record. The posted arm denominators are 992 for placebo and 1018 for azithromycin. The registry enrollment figure is 2013, but participant flow, exclusions, losses to follow-up, and the relation between enrollment and the outcome denominators are not detailed in the registry record for this account. The record therefore does not establish whether the primary analysis followed an intention-to-treat principle, a per-protocol principle, or another approach.

General statistical practice distinguishes missing outcomes from participants who were not eligible for an analysis, and the method used to address each can affect interpretation. Without a reported missingness account, imputation method, sensitivity analysis, or population definition, the risk of bias from incomplete outcome information cannot be assessed from the registry summary. These omissions do not show that data were missing or that an analysis was inappropriate; they indicate that the relevant details are not reported in the registry record.

14. 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.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: severe allergic reaction (2.9%).

The registry lists serious adverse events affecting 29 of 992 participants in the placebo and standard-of-care group and 15 of 1018 participants in the azithromycin and standard-of-care group. Other adverse events are listed for 14 of 992 participants in the placebo group and 9 of 1018 in the azithromycin group. Deaths are recorded as 0 in each group.

The serious adverse-event term listed among the top terms is severe allergic reaction, with a reported value of 2.9%. The registry summary does not provide the event count or a group-specific breakdown for that term in the registry record, nor does it explain how that percentage was calculated. The adverse-event definitions, collection period, severity criteria, and attribution to study medication are not reported in the registry record.

These figures are registry summaries and should not be treated as a complete assessment of comparative safety. General interpretation of safety data depends on how events were defined, collected, classified, and attributed, as well as on follow-up and participant exposure. The posted counts describe what the record lists; they do not establish that a particular event was caused by or unrelated to either study assignment.

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

The posted randomized comparison shows fewer participants with the combined primary infection endpoint in the azithromycin group than in the placebo group, using the registry's reported counts and denominators. The risk-difference estimate is -0.059, with an interval from -0.084 to -0.034, and the unadjusted p-value is p < 0.001. The relative measures also point in the same direction, with their reported intervals below one. These findings describe the registry's primary endpoint and its statistical uncertainty.

The result does not provide separate estimates for endometritis, wound infection, and other post-cesarean infections. It cannot identify which components contributed most to the composite difference. The follow-up window is up to 6 weeks after delivery, so the primary result does not describe later outcomes. No secondary outcome results are posted in the registry record.

The finding is a comparison of azithromycin plus standard care against placebo plus standard care. It is not a comparison of azithromycin without standard prophylaxis against no prophylaxis. The registry summary describes standard prophylaxis and its preferred timing, but does not detail every treatment received by each participant or provide full participant-flow information.

Statistical evidence is not the same as a complete clinical judgment. Whether a difference matters in practice depends on the outcome's importance, the trial population and setting, the balance of benefits and harms, and the quality and completeness of reporting. The registry summary does not supply enough detail to answer every such question. The safety entries are also limited summaries, with event definitions and attribution methods not reported. The findings should therefore be read as the posted comparative result, not as medical advice or a claim about every patient or circumstance.

16. Why This Trial Matters Statistically

This trial offers a randomized comparison of an extended-spectrum prophylaxis strategy added to standard care, with a primary endpoint that groups several post-cesarean infections. Statistically, that design makes the between-group contrast more informative than an uncontrolled event count, while the composite endpoint captures a broader infection outcome than any single component. The posted risk difference, risk ratio, odds ratio, and intervals show the result on both absolute and relative scales.

The case also illustrates why estimates and uncertainty should be read together. The point estimate summarizes the observed contrast, while the interval conveys a range of values compatible with the data under the interval procedure. The reported p-value addresses a null-hypothesis comparison but does not measure the size or clinical importance of the result. Different measures answer related but distinct questions, so clear labeling of their scales is important.

Several reporting limits matter statistically. The record does not post component-specific primary results, secondary outcome results, a missing-data approach, analysis populations, or the full analysis plan. These omissions restrict assessment of multiplicity, robustness, and the exact scope of inference. The sample-size illustration is useful for understanding how smaller target effects require larger planning samples, but it is based on the observed effect rather than the trial's original design assumptions.

Together, these features make the trial a useful example of interpreting a randomized binary endpoint without overstating what a registry summary can establish. The posted result is informative for the stated composite and follow-up window; it is not a substitute for component-level reporting or fuller documentation of analysis and safety methods.

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 registry summary has several trial-specific limitations for interpretation. The primary endpoint combines endometritis, wound infection, and other post-cesarean infections, but the posted result does not separate those categories. The definitions clarify some components, yet the record does not provide independent counts, estimates, or intervals for them. The primary outcome is limited to events occurring up to 6 weeks after delivery; the posted result does not address later infections.

The enrollment figure is 2013, while the primary outcome arms list denominators of 992 and 1018. Participant flow, outcome completeness, exclusions, and reasons for any difference between enrollment and outcome denominators are not reported in the registry record. The record also does not describe the analysis population or missing-data handling, which limits assessment of how the posted estimates relate to all randomized participants.

The registry identifies randomization and quadruple masking but does not give the sequence-generation method, allocation concealment details, or the roles masked. It describes similarity between groups for selected delivery-related characteristics, but comprehensive baseline information is not reported in the registry record for this account. The original sample-size rationale and detailed statistical analysis plan are likewise not reported.

Safety reporting is concise: the record lists serious and other adverse-event counts, deaths, and a serious-event term, but does not report event definitions, collection procedures, attribution, or a group breakdown for the listed term. These gaps do not establish that a problem occurred; they limit the level of detail that can be assessed from this registry record.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Study of Effectiveness and Safety of Azithromycin-based Extended-spectrum Prophylaxis to Prevent Post Cesarean Infection — NCT01235546.
• Registry record last updated 2017-07-28; status last verified 2017-06.
• Results first posted 2017-07-28.
• 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

The registry record describes a completed, randomized, parallel-group, quadruple-masked trial comparing azithromycin plus standard care with placebo plus standard care. Enrollment is listed as 2013. The primary endpoint is a composite of endometritis, wound infection, or other post-cesarean infection up to 6 weeks after delivery.

The primary outcome was recorded for 119 of 992 participants in the placebo group and 62 of 1018 in the azithromycin group. The reported risk difference is -0.059, with an interval from -0.084 to -0.034; the unadjusted p-value is p < 0.001. Risk-ratio and odds-ratio estimates are also posted.

The record lists serious adverse events, other adverse events, and deaths by group. It does not post secondary outcome results, and important details about missing data, analysis populations, component-specific outcomes, and the original statistical plan are not reported in the registry record.