Harm Scenario

You see a child at age 3 with congenital disabling spastic cerebral palsy (CP). The cause of the CP remains a mystery, and the anxious parents are seeking your expert opinion. The little girl was born full-term with normal birth weight and cord blood pH. Her 5-minute Apgar Score was 5. Her mother had fever during labour, but there was no evidence of infection in the newborn infant. You recently attended a conference at which intrauterine infection was reported as a major risk factor for CP in premature infants. You wonder whether this is also true for term newborns.

You formulate the question, “In children who were born full-term with normal birth weight, is maternal infection a possible cause of congenital cerebral palsy?”

You perform a PubMed search using the MeSH terms “cerebral palsy” and “maternal infection”. Of the 6 articles identified, only one deals with infants of normal birth weight. You review the abstract in PubMed and decide to copy the entire article JAMA 1997; 278:207-11.

Read the article and decide:

  • Is the evidence from this randomised trial valid?
  • If valid, is this evidence important?
  • If valid and important, can you apply this evidence in caring for your patient?

Completed Harm Worksheet for Evidence-Based Neonatal Medicine

Citation

Grether JK., Nelson KB. Maternal infection and cerebral palsy in infants of normal birth weight. JAMA 1997; 278:207-11.

Are the results of this harm study valid?
Were there clearly defined groups of patients, similar in all important ways other than exposure to the treatment or other cause?
Yes. Cases were all singleton children born in 1983 through 1985 to residents of 4 San Francisco Bay-area counties and included all children who met the following criteria: weighed 2500 grams or more at birth, survived to age 3 years, were residents of California to that age, and had moderate or severe congenital CP. Control children were randomly selected from singleton children who met all the case criteria except for having CP.
Were treatment exposures and clinical outcomes measured the same ways in both groups (e.g., was the assessment of outcomes either objective (e.g., death) or blinded to exposure)?
Yes. Nurses masked to outcome of interest and to case or control status abstracted clinical data from maternal labor and delivery and newborn records.
Was the follow-up of study patients complete and long enough?
This is a case-control study. Case children were old enough to make an accurate diagnosis of CP.
Do the results satisfy some “diagnostic tests for causation”?
Is it clear that the exposure preceded the onset of the outcome?
Yes, but there are problems with the ascertainment of the exposure: Histologic diagnosis of inflammation of placental membranes was not consistently available, and therefore, some misclassification of exposure status may have occurred.
Is there a dose-response gradient?
No
Is there positive evidence from a “dechallenge-rechallenge” study?
N/A; the harm in question is permanent.
Is the association consistent from study to study?
Hard to say. You only found this one study in infants of normal birth weight. However, the findings are consistent with recent studies in infants of very low birth weight.
Does the association make biological sense?
It is uncertain why maternal infection is associated with CP. However, it is plausible that cytokines and other mediators may cross the placenta and the blood-brain barrier of the fetus, and disturb neuronal and glial development.

Are the valid results from this harm study important?

Adverse Outcome Totals
Present (case) Absent (control)
Exposed to the potential harm Yes (Cohort) 10
a
11
b
21
a + b
No (Cohort) 36
c
367
d
403
c + d
Totals a + c
46
b + d
378
a + b + c + d
424

In a randomised trial or cohort study:

$$ qquad qquad text{Relative Risk ($RR$)} = [a/(a+b)]/[c/(c+d)] $$

In a case-control study:

$$ qquad qquad text{Odds Ratio (or Relative Odds) ($OR$)} = ad/bc $$

In this study, maternal infection was considered to be present, if at least one of the following had been documented: Fever>38 ยบC in labour; Chorioamnionitis, clinical diagnosis; Histologic evidence of placental infection; Amniotic fluid foul; Maternal sepsis; Bladder or kidney infection.

begin{align}qquad qquad
mathit{OR} &= ad/bc \
&= (10times367)/(11times36)\
&= 9.3end{align}

Should these valid, potentially important results of a critical appraisal about a harmful exposure change the treatment of your patient?

The permanently disabling outcome of your patient cannot be reversed; however, the strong association between maternal infection and congenital CP provides an impetus for future research aimed at preventing and treating intrauterine inflammation.

Additional Notes

Cerebral Palsy: Associated with maternal infection

Clinical Bottom Line

There is a strong association between maternal infection and congenital CP. This provides an impetus for future research aimed at preventing and treating intrauterine inflammation.

Citation

Grether JK., Nelson KB. Maternal infection and cerebral palsy in infants of normal birth weight. JAMA 1997; 278:207-11.

Clinical Question

In children who were born full-term with normal birth weight, is maternal infection a possible cause of congenital cerebral palsy?

Search Terms

You perform a PubMed search using the MeSH terms “cerebral palsy” and “maternal infection”. Of the 6 articles identified, only one deals with infants of normal birth weight. You review the abstract in PubMed and decide to copy the entire article JAMA 1997; 278:207-11.

The Study

  • Case-control Study.
  • The Study Patients: Cases were all singleton children born in 1983 through 1985 to residents of 4 San Francisco Bay-area counties and included all children who met the following criteria: weighed 2500 grams or more at birth, survived to age 3 years, were residents of California to that age, and had moderate or severe congenital CP. Control children were randomly selected from singleton children who met all the case criteria except for having CP.
  • Exposure of Interest: Maternal infection.
  • The Outcome: Congenital cerebral palsy.
  • Subjects defined and similar in other important ways, exposures and outcomes objective or measured blind.

The Evidence

Adverse Outcome Totals
Present (case) Absent (control)
Exposed to the potential harm Yes (Cohort) 10
a
11
b
21
a + b
No (Cohort) 36
c
367
d
403
c + d
Totals a + c
46
b + d
378
a + b + c + d
424

$$qquad qquad text{Odds ratio: 9.27, 95% $CI$ 8.43 to 10.10}\
qquad qquad X^2 :27.01 $$

Particular to my patient:

$$ qquad qquad mathit{PEER}: 0.08933 \
qquad qquad mathit{NNH}: 3 $$

Comments

It is uncertain why maternal infection is associated with CP. However, it is plausible that cytokines and other mediators may cross the placenta and the blood-brain barrier of the fetus, and disturb neuronal and glial development.

Appraised By

Barbara Schmidt, MD, MSc, FRCP(C), and Bo Zhang, MPH