Harm Scenario

You are a midwife. During your antenatal classes, a woman asks whether it is safe to take Vitamin A supplements as she has heard that there may be a risk of birth defects from supplements containing Vitamin A. She wants your advice on what to do regarding vitamin supplementation.

You tell her you will investigate and you form the question, do pregnant women receiving vitamin a supplements have a higher risk of children having birth defects? You go to the library and search Medline.

What is your advice to her regarding Vitamin A supplements?

Search strategy for Vitamin A and Pregnancy
Type in: Vitamin A. You will see ‘exp retinoids’
Type in:
1. exp retinoids
2. exp abnormalities
3. #1 and #2
4. exp pregnancy
5. #3 and #4
6. limit #5 to human
7. vitamin a.tw.
8. #6 and #7

You find the article: Rothman KJ, Moore LL, Singer MR et al. Teratogenicity of high vitamin A intake. NEJM 1995;333(21):1369-1373.

Read the article and decide:

  • Are the results of this harm study valid?
  • Are the results of this harm study important?
  • Should these valid, important results of this study about a potentially harmful treatment change the treatment of your patient?

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?

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
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.
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”?

Is it clear that the exposure preceded the onset of the outcome?
Yes. Vit A before conception and in the early weeks of pregnancy
Is there a dose-response gradient?
Yes. See Fig 1
Is there positive evidence from a “dechallenge-rechallenge” study?
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.
Does the association make biological sense?

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 > 10,000 iu/day 7
a + b
No < 5000 iu/day 51
c + d
a + c
b + d
a + b + c + d

text{Relative Risk} &=(7/317)/(51/11083)\
&= 4.8

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

Can the study results be extrapolated to your patient?
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):

$$mathit{NNH} = [mathit{PEER} (mathit{OR} – 1) + 1 ] / [ mathit{PEER} (mathit{OR} – 1) times (1 – mathit{PEER}) ]$$

text{Assume your $PEER$ as same as in the study}.\
text{Risk with supp}&> 10000\

text{$Risk$ with supp} &< 5000\
&= 0.005

text{$ARI$ with supp} &> 10000\
&= 0.017

mathit{NNH} &= 1/mathit{ARI}\
&= 1/0.017\
&= 59

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.
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.

Neural Tube Defects - Vitamin A in pregnancy increases the risk

Clinical Bottom Line

Pregnant women taking supplements of vitamin A > 10,000 UI/d increase their risk of having a child with cranial-neural-crest (CNC) defect by nearly 5 times (NNH=57 with a baseline risk of 0.5%).


Rothman KJ, Moore LL, Singer MR et al. Teratogenicity of high vitamin A intake. NEJM 1995;333(21):1369-1373.

Clinical Question

Do pregnant women receiving vitamin A supplementation have a higher risk of having children with birth defects?

Search Terms

'retinoids' and 'abnormalities' and 'pregnancy'

The Study

  1. Cohort study of pregnant women being screened by AFP or amniocentesis (23,491 out of 24,559 gave consent to participate), outcomes known for 22,748 (96.8%).
  2. Exposure assessed between week 15 and week 20 (since last menstruation) by telephone interview performed by nurse (blind to outcome) with detailed questions on diet, medications and illnesses during first trimester, allowing calculation of estimated daily Vit A intake.
  3. Outcome was obtained around expected time of delivery from obstetricians (76.5%) and mothers (23.5%) by questionnaire and then classified by blinded coders. Disagreements were submitted to a third coder.

The Evidence

Outcome EER 1 CER 2 RR 3 (95% CI) ARI NNH (95% CI)
All birth defects 0.031 0.013 2.3 (2.36 to 2.45) 1.8% 55 (30 to 1250)
CNR defects 0.022 0.005 4.8 (2.2 to 10.5) 1.7% 59 (NNT 2044 to infinity; NNH 26 to infinity)


  • The risk is only associated with preformed vitamin A supplement not beta carotene.
  • There was a dose-response gradient.
  • There was no statistically significant association between cranial neural crest defects and high Vit A intake from food only.


  1. Vit A >15,000 IU/d. 
  2. Vit A ≤ 5,000 IU/d. 
  3. called Prevalence ratio in paper.