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Centre for Evidence-
Based Medicine

Completed Harm Worksheet for Evidence-Based Mental Health


Kulin, NA. Pastuszak, A; Sage, AR et al Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors: a prospective controlled multicenter study. JAMA 279 (8):609-610, 1998.

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?
    Clearly defined, but heterogeneous. Women taking SSRIs different from control women (fewer primips, more previous therapeutic abortions, more tobacco consumption).
  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. Interviews regarding exposures, confounders and outcomes before and after childbirth in both cases controls. No mention of blinding and primary outcome (major malformations) not objective
  3. Was the follow-up of study patients complete and long enough?
    Women followed up 6-9 months following pregnancy - probably long enough for the primary outcomes, though not long enough for more subtle impairment of neurodevlopment
  4. Do the results satisfy some "diagnostic tests for causation"?
    No strong association
  5. Is it clear that the exposure preceded the onset of the outcome?
  6. Is there a dose-response gradient?
  7. Is there positive evidence from a "dechallenge-rechallenge" study?
  8. Is the association consistent from study to study?
  9. Does the association make biological sense?

Are the valid results from this harm study important?

Major malformations Totals
Present (Case) Absent (Control)
Exposed to SSRI Yes (Cohort)






a + b

No (Cohort)






c + d


a + c


b + d


a + b + c + d

In this study:

Odds ratio (OR) = ad/bc
= 1.06 (95% Confidence interval 0.41 to 2.72)

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

  1. Can the study results be extrapolated to your patient?
    Depends on the patient's view. Although it is most likely that there is no additional risk, the likelihood of major malformation could be as high as almost 3x normal.
  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))
    If we assume our patient is like the average individual in this study, then her Absolute Risk Increase in serious malformation is 4.05% - 3.83% = 0.22% = and 1/0.22% gives an NNH of 455. If the OR really was as high as 2.72, then using the formula on the left, the NNH would be:
    NNH = (0.0383(2.72-1)+1)/(0.0383(2.72-1)x(1-0.0383))
    = 17
  3. What are your patient's preferences, concerns and expectations from this treatment?
    Need to be determined.
  4. What alternative treatments are available?
    It may be possible to withdraw the antidepressant before conception and start later in pregnancy or following childbirth. These strategies will probably increase the risk of relapse. Alternatively, use a different drug if there is good evidence of it not causing a significant increase in risk

Additional Notes

This demonstrates the difficulty of excluding a possible increase in the risk of an adverse effect. While it is most likely that there SSRIs will not cause damage, the range of possible values includes quite a significant increase risk that may be unacceptable to the patient. The finding of this study is therefore indeterminate - they cannot rule out the possibility of a potentially unacceptable degree of risk.

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