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Criteria abstracted from The Users' Guides to the Medical Literature series in JAMA

Treatment of neonatal sepsis with intravenous immune globulin.

The INIS Collaborative Group.

N Engl J Med 2011 365(13):1201-11.[abstract]

Reviewed By: Karen Sethi MD, University of Rochester Medical Center, Rochester, NY

Review posted March 12, 2012

  1. What is being studied?

    The study objective:

    To examine the use of intravenous immunoglobulin for neonatal sepsis in patients with “proven or suspected serious infection”

    The study design:

    Double blinded randomized control trial of adjunctive therapy with intravenous IgG immune globulin compared with placebo

    The patients included:

    Newborn infants who had suspected or proven sepsis and who were receiving antibiotic therapy with one of the following characteristics: “a birth weight less than 1500 g; evidence of infection in blood culture, CSF or usually sterile body fluid; or need for respiratory support through an endotracheal tube.”

    The patients excluded:

    “Previous administration of intravenous immunoglobulin and a decision by clinical staff that intravenous immune globulin was either definitely needed or contraindicated.”

    The interventions compared:

    Two infusions of either polyvalent IgG immune globulin or matching placebo 48 hours apart

    The outcomes evaluated:

    To measure the primary (composite) outcome of death or major disability at 2 years of age and secondary short-term outcomes with adjustment for gestational age. Major disability was assessed by questionnaires to the parents and health care professionals and defined by pre-specified criteria.

  2. Are the results in the study valid?

    Primary questions:

    1. Was the assignment of patients to treatments randomized?

      The infants were randomly assigned in a double blind fashion to receive either the intravenous immune globulin or placebo and depending on the country the patient was located, the randomization technique was different. 

    2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

      Was followup complete?

      It was unclear how many infants were screened for the study and how many infants were excluded.  The CONSORT flowsheet (1) usually includes numbers screened with prospective randomized control trials; this was not included for this study. 

      All of the patients who were actually enrolled in the trial were accounted for. In the treatment group 43 of 1759 were lost to follow-up and 15 had missing data and were excluded. In the placebo group, 43 were lost to follow-up and 14 excluded with missing data.

      Despite having the inclusion criteria, it is unclear what made the children who were not included in the study different? The exclusion criteria should have been defined.  Selection bias cannot be determined; the patients who were screened and not enrolled should be described.

      Were patients analyzed in the groups to which they were randomized?

      Yes, the groups analyzed were either patients who received intravenous immune globulin versus the patients who received placebo. There was no cross over and analysis was by intention-to-treat.

      Secondary questions:

    3. Were patients, health workers, and study personnel "blind" to treatment?

      Yes, the assignments for randomization of the patients only provided a numbered pack in which the medication was contained.  The infusion volumes, frequency of administration, physical characteristics of color and consistency were identical.  The only thing that was not mentioned was whether the syringes of the immune globulin were different based on the manufacturer who produced them (though they took care to mention that the syringes and tubing were masked with yellow tape).

    4. Were the groups similar at the start of the trial?

      The baseline characteristics included birth weight, age at randomization, gestational age, evidence of infection, cause of infection were very similar in terms of percentages between the test and placebo group.  One of the things that was not discussed was the comorbidities that afflicted the patients enrolled which could confound the outcome. For example, how many patients were requiring mechanical ventilation.

    5. Aside from the experimental intervention, were the groups treated equally?

      Due to the fact we are not informed about other aspects of management of these patients, we are not sure. Concomitant medications (i.e. vasopressors), ventilator support or length of hospitalization prior to treatment can affect outcomes and were not discussed. However, given the size of this trial and the complete blinded nature, it is unlikely that there were systematic differences in the other management of these patients between groups that would be likely to bias the results.

  3. What are the results?

    1. How large was the treatment effect?

      For the primary outcome:


      Death/Disability at 2 years

      No Death/Disability at 2 years










      • Control Event Rate (CER) = 677/1759= 39% of the patients would have death/disability by 2 yo
      • Experimental Event Rate (EER) = 686/1759= 39% of the patients would have death/disability by 2 yo
      • Relative Risk = EER/CER=1; the risk in the experimental group is the same if they had not received IVIG
      • Relative Risk reduction: 1 – RR = 0; there is no decreased risk of the event in the IVIG compared to the placebo
      • Absolute Risk Reduction = EER – CER = 0; there is no difference in the rates of bad outcomes between the experimental and control group
      • Number needed to treat = 1/ARR = 1/0 = an infinite number patients need to be treated to prevent a bad outcome

      For the secondary outcome of death at 2 years,


      Death at 2 yo

      No Death at 2 years










      • Control Event Rate = 322/1759 = 18.3% of the patients would have death by 2 yo
      • Experimental Event Rate = 306/1734 = 17.6% of the patients would have death by 2 yo
      • Relative Risk = 17.6/18.3 = 0.96; patients treated with IVIG were 0.96 times as likely to die as those treated with placebo
      • RRR = 1-0.96 = 0.4 or 4%; there is a 4 % relative decrease risk of death in the IVIG group compared to the control
      • ARR =18.3-17.6 = 0.7; there is a 0.7% absolute reduction in mortality rate in those treated with IVIG
      • NNT = 1/ARR = 1/0.007; 143 patients need to be treated to prevent 1 death


      All of the primary and secondary outcomes listed  show virtually no difference between the groups and have confidence intervals which crossed 1. This leads to the conclusion that there was no difference in most of the outcomes Because there was no difference in outcomes, the treatment has no effect on the outcomes studied.

    2. How precise was the estimate of the treatment effect?

      • Confidence intervals for RR of death or disability at 2 years of age: 0.92-1.08
      • Confidence intervals for the secondary outcome of RR of death: 0.92-1.20
      • Confidence intervals for the secondary outcome of the RR of death in hospital: 0.86-1.16

      The intervals were relatively narrow indicating the results were precise.

  4. Will the results help me in caring for my patients?

    1. Can the results be applied to my patient care?

      It does not seem there is any benefit to using IVIG in the treatment of neonatal sepsis according to this study. We do not know, however, whether the treatment is beneficial in certain subgroups of neonates with proven or suspected sepsis, such as those with extreme prematurity, a particular type of infection, or those requiring mechanical ventilation or inotropic support.

    2. Were all clinically important outcomes considered?

      The primary and some of the secondary outcomes are clinically significant for these patients.
      The secondary outcomes of death in hospital, use of supplemental oxygen by day 28, major cerebral abnormality, and confirmed sepsis after trial entry were also appropriate and important shorter-term outcomes.

    3. Are the likely treatment benefits worth the potential harms and costs?

      There does not seem to be a treatment benefit for these patients. founded 1995

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