Rebif® Pregnancy Registry: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Rebif® Pregnancy Registry (NCT00338741), a registered phase not stated study. The primary outcome is Spontaneous Abortion.

2. Clinical Question

The registry’s stated objective was to collect prospective pregnancy-outcome data for women in the United States and Canada who had been exposed to Rebif® during pregnancy. Its primary question concerned the rate of spontaneous abortions in exposed pregnancies compared with the rate among pregnancies in patients with multiple sclerosis that were not exposed to any interferon-beta. The registry record identifies spontaneous abortion as the primary endpoint and fetal death/stillbirth as a secondary outcome.

This distinction between the research question and the available results matters. The registry states what it intended to compare, but the posted record does not provide the spontaneous-abortion outcome counts or a statistical comparison. The serious adverse-event figures are reported separately and should not be substituted for the primary endpoint. Nor do the available details establish that the groups were comparable in their characteristics or circumstances.

3. Trial Design

The Rebif® Pregnancy Registry is described as a prospective registry for pregnancy outcomes, rather than as a randomized treatment comparison. Its stated objective was to collect outcome data for pregnancies exposed to Rebif® and compare spontaneous-abortion rates with those in pregnancies not exposed to interferon-beta. The record identifies multiple sclerosis as the condition and lists EMD Serono as the sponsor.

The registry record lists an enrollment of 36. That is the recorded enrollment figure; it should not be treated as the number with complete primary-endpoint data or as the denominator for either exposure group. The primary-outcome description says the population includes all subjects for whom data are available, but the number with available outcome data is not reported in the registry record.

The record lists two arms: Rebif exposed pregnancies and non-Rebif exposed pregnancies. It explicitly does not describe a randomized comparison, and allocation is not stated. Consequently, the groups are not a like-for-like control comparison. A difference between their outcomes, if one were reported, could reflect differences between the groups as well as exposure status. The record does not provide details about how exposure groups were assembled or how potential confounding was addressed.

The registry is marked completed. Its recorded start is 2002-12 and its primary completion is 2007-10. The primary endpoint is spontaneous abortion, measured as the number of participants having that outcome, with a timeframe of up to 9 months. Fetal death/stillbirth is listed as a secondary outcome. The record does not report a protocol-level account of enrollment procedures, follow-up completion, or the statistical methods used to compare groups.

Although the registry record includes serious adverse-event summaries, those safety figures do not supply the missing primary-outcome analysis. In particular, an adverse-event summary and the stated pregnancy endpoint have different reporting roles. The available record does not establish that serious adverse events were used to define spontaneous abortion or any other primary endpoint.

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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Population includes all subjects for whom data is available

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 Spontaneous Abortion, measured over Up to 9 months.

The primary endpoint is spontaneous abortion, recorded as a number of participants. Its timeframe is up to 9 months, and its description specifies the number of participants having a spontaneous abortion. This is a binary outcome at the participant level: for the endpoint, a participant either had the event or did not, although the registry reports the intended measure as a count.

In general, a binary endpoint can be summarized by counting participants with the event and relating that count to the number whose outcome status is known. A rate or proportion can then describe how common the event was in a defined group. A comparison between groups needs the relevant outcome counts and denominators, as well as a clear definition of the analysis population. The registry record does not report group-specific spontaneous-abortion counts, denominators, rates, or a comparative estimate, so the primary outcome cannot be quantified from the posted results.

Spontaneous abortion is used as the primary endpoint because the registry’s stated objective specifically identifies its rate as the main outcome to be compared between exposed and non-exposed pregnancies. That explains the endpoint’s role in the research question; it does not establish what the outcome was. Fetal death/stillbirth is listed as a secondary outcome, but its results are not reported in the registry record.

The endpoint’s participant-count format should also be kept distinct from serious adverse-event reporting. The record gives serious-event summaries, but those do not replace the primary spontaneous-abortion outcome. The available information does not describe how outcome status was verified or how an unavailable endpoint value was handled.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes the primary outcome as the number of participants having a spontaneous abortion, with a timeframe of up to 9 months. This is a binary endpoint expressed as a count: each participant’s status for the event is either present or absent. The record identifies the relevant population as all subjects for whom data are available. It does not report the number with available data or outcome counts by exposure group.

What a binary-outcome comparison requires

As a general statistical explanation, a group-specific event proportion is based on the count of participants with the event and the number of participants whose outcome status is known in that group. A comparison can then be expressed on a chosen scale, such as a difference in proportions or a ratio. Those summaries answer different questions, and the choice should be specified in the analysis plan. The registry record does not report a chosen comparative measure or the primary-endpoint data needed to reproduce one.

General statistical practice also distinguishes an estimate from its uncertainty. A confidence interval describes a range of values compatible with the data under the stated method and assumptions. Its width reflects how much information the data provide, among other factors. No confidence interval for the primary endpoint is reported in the registry record. Without endpoint counts and denominators, it is not possible to assess the precision of the intended comparison from the posted results.

What the registry record reports about analysis

The registry lists no analyses. That means no inferential analysis is reported in the registry record; it does not establish whether analyses were performed outside the registry entry. No p-value, confidence interval, regression estimate, or adjusted comparison for the primary endpoint is reported. The statistical analysis plan, including any planned adjustment variables or model, is not reported in the registry record. The record also does not report whether an interim analysis was planned or conducted.

As a general explanation, an unadjusted comparison uses the observed group summaries without accounting for other characteristics. An adjusted analysis attempts to account for selected characteristics using a specified model. Such adjustment can be useful when groups differ, but it depends on measured information and appropriate model choices; it cannot automatically remove all sources of bias. Since the registry record does not describe an adjusted analysis, no claim about one can be made. Nor is there a reported sponsor analysis that could be compared with a recalculation.

Why over-dispersion can matter

As a general statistical point, over-dispersion occurs when observed variability is greater than a model’s assumptions would predict. It can make standard errors too small if a model assumes less variability than the data contain, leading to confidence intervals that are too narrow and tests that are too optimistic. Whether over-dispersion is relevant depends on the outcome model and data structure. The registry record does not report a model or sufficient primary-outcome data to assess it, so it should not be assumed to have been present or absent in this registry.

Planning calculations are not trial results

The registry description of planning illustrations specifies a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. It also describes the effect to detect as a stated fraction of the observed effect. These are assumptions for planning illustrations, not evidence of the registry’s original design or its observed statistical power. The record does not report that these assumptions were used to plan the registry, and the corresponding observed effect for the primary endpoint is not reported in the registry record.

In general, sample-size planning asks how many participants would be needed under specified assumptions to detect a target effect with a chosen level of power. Those calculations depend on the event frequency, target effect, allocation, significance level, and statistical method. A planning result is conditional on those inputs; it is not an observed study result and does not show that a completed study had a particular probability of detecting an effect. The record does not report the registry’s own sample-size justification. Any planning illustration should therefore be read as a hypothetical calculation rather than as evidence about the registry’s design or results.

The record’s binary outcome format and prospective registry objective make clear what was intended to be counted, but they do not fill in the missing analysis details. The endpoint counts, denominators, chosen effect measure, treatment of unavailable outcomes, and inferential method are not reported in the registry record. Without these, the intended comparison cannot be reconstructed statistically from the posted information.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Rebif Exposed Pregnancies", "Non-Rebif Exposed Pregnancies")
n      <- c(32, 2)
events <- c(2, 0)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Rebif Exposed Pregnancies  32  2  6.2  0.8  20.8  1.7  20.1  1.9  20.2
ARM  Non-Rebif Exposed Pregnancies  2  0  0.0  0.0  84.2  0.0  65.8  0.8  70.8

11. Multiplicity, Missing Data and Analysis Populations

The record identifies spontaneous abortion as the primary endpoint and fetal death/stillbirth as a secondary outcome. It reports two outcome measures, but no analyses are listed. The registry record does not describe a procedure for addressing multiplicity, such as prioritizing tests, adjusting significance levels, or interpreting secondary outcomes as exploratory. It is therefore not possible to determine how any multiple-outcome testing was planned or handled.

As a general statistical explanation, testing several outcomes can increase the chance of at least one apparently notable result even when no real effect is present. A prespecified hierarchy or adjustment method can help define how such results should be interpreted. No such method is reported. Since no inferential analyses or p-values are reported, there is no posted multiplicity-adjusted result to interpret.

For missing data, the primary-outcome description says the population includes all subjects for whom data are available. This wording identifies an available-data population but does not explain how many participants had missing outcome information, why any information was unavailable, or how missing values were handled. The number with available primary-outcome data by exposure group is not reported in the registry record.

As a general point, excluding participants without known outcomes can affect a comparison if outcome availability is related to exposure or outcome status. Other approaches to missing data require assumptions and methods that should be described. The record does not report whether participants with missing outcomes were excluded, whether any imputation was performed, or whether sensitivity analyses were conducted.

The analysis populations are also not described beyond the available-data wording for the primary endpoint. The registry record does not report a separate intention-to-treat population, a per-protocol population, or other analysis sets. Because this is not described as a randomized comparison, an intention-to-treat interpretation should not be assumed. These omissions limit assessment of both the completeness of the outcome data and the robustness of any comparison.

12. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Serious events with the highest arm-level rate: premature labor/premature delivery (6.2%), spontaneous abortion (6.2%), failed induction (6.2%), failed labour progression (3.1%), uterine fibroids (3.1%).

The registry reports serious adverse-event figures by exposure group. Among Rebif Exposed Pregnancies, serious adverse events affected 10 participants among 32 at risk. Among Non-Rebif Exposed Pregnancies, they affected 0 participants among 2 at risk. The record reports other adverse events affecting 0 participants among 32 at risk and 0 participants among 2 at risk, respectively. These are the group-specific figures recorded for the safety summaries; they should not be recast as primary-endpoint results.

The registry also lists serious adverse-event terms with percentages: Premature labor/premature delivery, 6.2%; Spontaneous abortion, 6.2%; Failed induction, 6.2%; Failed labour progression, 3.1%; Uterine fibroids, 3.1%; and Gestational diabetes, 3.1%. The registry record does not specify the denominator behind these term percentages in the information. They should therefore be read as the recorded percentages, without deriving counts or assuming a denominator.

Safety-event summaries and the primary spontaneous-abortion endpoint have distinct reporting roles. A serious adverse-event figure does not provide the complete endpoint comparison, and no inference about comparative risk should be drawn from these summaries alone. The non-Rebif group’s at-risk denominator is 2, so its reported safety count describes a very limited group; the record does not provide a basis for treating the groups as directly comparable.

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

The registry record establishes that Rebif® Pregnancy Registry was designed to collect prospective outcomes for exposed pregnancies and to compare spontaneous-abortion rates with those in pregnancies not exposed to interferon-beta. It specifies the primary endpoint, its participant-count format, and a follow-up timeframe of up to 9 months. It also records an enrollment of 36 and lists serious adverse-event summaries for the two exposure groups.

What the posted results do not establish is the primary outcome’s frequency in either group. Group-specific spontaneous-abortion counts and denominators, a comparative estimate, and a measure of statistical uncertainty are not reported in the registry record. The secondary outcome of fetal death/stillbirth is listed, but its results are also not reported. These absences mean the main research question cannot be answered quantitatively from the registry entry. They do not mean that there were no events or that the groups had identical outcomes.

The safety figures have a narrower interpretation: the registry reports serious adverse events affecting 10 of 32 participants at risk in the Rebif-exposed group and 0 of 2 in the non-Rebif group. Other adverse events affected 0 of 32 and 0 of 2, respectively. The listed event-term percentages provide additional recorded safety information, but their denominator is not reported in the registry record. None of these figures substitutes for the primary endpoint analysis.

The exposure groups are not described as a randomized comparison, allocation is not stated, and the record cautions that the arms are not a like-for-like control comparison. As a general statistical consideration, this means a difference between groups could not automatically be attributed to exposure: other group differences may also contribute. The registry entry does not report an analysis that adjusts for such differences.

Accordingly, the appropriate interpretation is descriptive and limited to the information recorded. The registry’s objective and endpoint are clear, but its principal comparative result and its precision are not reported. The record does not support a conclusion about whether the groups differed in spontaneous-abortion outcomes.

14. Why This Trial Matters Statistically

This registry illustrates a key distinction in clinical research reporting: identifying a question and endpoint is not the same as reporting the evidence needed to answer that question. The record specifies spontaneous abortion as the primary endpoint, describes its participant-count format, and states a follow-up timeframe of up to 9 months. Yet group-specific primary-outcome results and an inferential comparison are not reported. Statistical interpretation must therefore distinguish the planned objective from the available outcome evidence.

It also highlights why denominators matter. The enrollment figure of 36 does not tell readers how many participants had known primary outcomes in each exposure group. The primary-outcome description refers to subjects for whom data are available, while the count with available data is not reported. Without outcome counts and denominators by group, neither event frequency nor comparative precision can be assessed.

The registry’s non-randomized exposure groups make design information important as well. Allocation is not stated, and the record says the arms are not a like-for-like control comparison. This limits causal interpretation, independently of the missing primary results. Statistical methods cannot be evaluated without a reported analysis plan, and no analyses are listed.

Finally, the safety summaries are not interchangeable with the endpoint comparison. They offer recorded information about serious and other adverse events, but do not supply the missing spontaneous-abortion results. The registry is therefore statistically informative as an example of how registry objectives, outcome definitions, denominators, analysis details, and results each contribute different pieces of evidence. In this record, several of those pieces are not reported, so conclusions must remain correspondingly narrow.

15. 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 primary limitation for interpreting this registry is that the primary endpoint’s group-specific results are not reported in the registry record. Although spontaneous abortion is identified as the primary endpoint, the record does not provide the number of participants with this outcome in either group, the corresponding denominators, or a comparative estimate. No confidence interval or p-value is reported. The listed enrollment of 36 cannot fill this gap because the primary-outcome population is defined as subjects for whom data are available, and the number with available data is not reported.

The registry record also lists fetal death/stillbirth as a secondary outcome without reporting its results. No analyses are listed, and the statistical analysis plan, including adjustment methods, is not reported. Details about missing outcomes, analysis populations, and any sensitivity analyses are not reported in the registry record. These gaps prevent assessment of how complete the outcome data were or how robust a comparison might be.

The comparison itself has design limitations. The registry record does not describe random allocation; allocation is not stated, and the arms are not a like-for-like control comparison. Thus, a difference between exposure groups could reflect group characteristics or other factors rather than exposure alone. The record does not report whether or how such factors were measured or addressed.

The safety summaries have additional interpretive limits. The non-Rebif group has 2 participants at risk in the reported adverse-event figures, and the denominator for the listed event-term percentages is not reported in the registry record. Those summaries are distinct from the primary endpoint and cannot be used to infer its comparative result. The planning illustrations are described as hypothetical calculations and do not establish the registry’s original design, sample-size justification, or observed power.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Rebif® Pregnancy Registry — NCT00338741.
• Registry record last updated 2013-08-05; status last verified 2011-08.
• Results first posted 2010-06-02.
• 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.

19. Record Summary

The Rebif® Pregnancy Registry is a completed registry sponsored by EMD Serono, with a recorded start of 2002-12, primary completion of 2007-10, and enrollment of 36. Its stated objective was to collect prospective pregnancy-outcome data for women in the United States and Canada exposed to Rebif® and compare spontaneous-abortion rates with pregnancies not exposed to interferon-beta.

Spontaneous abortion is the primary endpoint, measured as the number of participants having the event over a timeframe of up to 9 months. Fetal death/stillbirth is listed as a secondary outcome. The primary endpoint results and an inferential comparison are not reported in the registry record, and no analyses are listed.

Serious adverse events affected 10 of 32 participants at risk in Rebif Exposed Pregnancies and 0 of 2 in Non-Rebif Exposed Pregnancies. Other adverse events affected 0 of 32 and 0 of 2, respectively. The registry record states that this was not a randomized comparison, allocation was not stated, and the arms were not a like-for-like control comparison.