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Centre for Evidence-
Based Medicine

Completed Harm/Etiology Worksheet for Child Health

Clinical Question

In pregnancy, does taking Vit A supplements increase the risk of birth defects?

Are the results of this harm study valid?

  1. Were there clearly defined groups of patients, similar in all important ways other than exposure to the treatment or other cause?
    Yes. Cohort of 22,748 pregnant women
  2. 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. all were interviewed regarding diet etc. early in pregnancy. Everyone was blind to outcome (birth defects) and birth defects were clearly defined
  3. Was the follow-up of study patients complete and long enough?
    Yes. 96.8% follow up

Do the results satisfy some "diagnostic tests for causation"?

  1. Is it clear that the exposure preceded the onset of the outcome?
    Yes. Vit A before conception and in the early weeks of pregnancy
  2. Is there a dose-response gradient?
    Yes. See Fig 1
  3. Is there positive evidence from a "dechallenge-rechallenge" study?
    No
  4. Is the association consistent from study to study?
    Yes. See last paragraph of Pg. 1369. Results similar to those from animal studies and synthetic retinoids
  5. Does the association make biological sense?
    Yes.

Are the valid results of this harm study important?

From table 3 for Vit A supplements:

Adverse Outcome CNC Defects Totals
Present (Case) Absent (Control)
Exposed to the Treatment Yes > 10,000iu/day

7

a

310

b

317

a + b

No < 5000iu/day

51

c

11032

d

11083

c + d

a + c

58

b + d

11342

a + b + c + d

11400

Relative Risk = (7/317)/(51/11083)
= 0.022/0.0046
= 4.8

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

  1. Can the study results be extrapolated to your patient?
    Yes
  2. What are your patient's risks of the adverse outcome?

    To calculate the NNH (the Number of Patients you Need to treat to Harm one of them) for any Odds Ratio (OR) and your Patient's Expected Event Rate for this adverse event if they were NOT exposed to this treatment (PEER):

    NNH = [ PEER (OR - 1) + 1 ] / [ PEER (OR - 1) x (1 - PEER) ]

    Assume your PEER as same as in the study. Risk with supp > 10000
    =7/317
    =0.022

    Risk with supp < 5000
    =51/11083 = 0.005

    ARI with supp > 10000
    =0.022-0.005
    = 0.017

    NNH
    = 1/ARI
    = 1/0.017
    = 59
  3. What are your patient's preferences, concerns and expectations from this treatment?
    Mother must balance potential benefits for her own health with risks of high doses to her baby's health.
  4. What alternative treatments are available?
    She can take low dose supplements (i.e. < 5000 iu Vit A/day)

Additional Notes

  1. If you look at cranial-neural crest defects (CNC) and Vit A supplements, RR is 4.8 (ie. nearly fivefold increase in the risk of CNC defects) in women taking supplements >10,000 iu Vit A/day compared to <5000 iu Vit A/day.
  2. You can work out the 95% CI around the RR for Vit A supplements and CNC defects of 2.2 to 10.5 does not include 1 so is statistically significant and clinically important.

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