Monday, January 29, 2007

Ask a Scientist: Antidepressants and Pregnancy (Intro, 1,2)

By request, and most especially for S and B, I am supplying a short and detailed, but not comprehensive, review of some common antidepressants and pregnancy.

Most doctors do not wish to prescribe any drugs for use in pregnancy; many doctors recommend that even Sudafed not be used- just in case!- even though there is an enormous amount of evidence that demonstrates no danger. For all my friends who wish to have adequate documentation with which to beat their doctors over the head, here you go.

This will be a series on Mondays and Thursdays.

For references relating to other drugs, more info, or PDFs, email me.

Series: Antidepressants, Pregnancy, Risks
  • Introduction
  1. Spontaneous abortion
  2. Premature birth
  3. Congenital or teratogenic defects; that is, malformations in utero
    • Cardiac defects
  4. Antenatal adaptation problems
    • Muscle stiffness
    • Breathing distress at birth
    • Neurological withdrawal symptoms
  5. Breastfeeding risks
    • Infant weight gain
    • Long-term neurologic development
  6. Maternal risks of going without treatment
    • Relapses
    • Infant failure to thrive
    • Parenting problems, attachment, child behavior

[Disclaimer: I am not a medical professional; this is an academic summary of the evidence available and not a medical opinion. I do not offer medical advice. If you require medical opinions or treatment, please consult your physician.]

This information is drawn from published articles in medical journals, some of which are compiled here, and from public databases. (See also: summaries on Motherisk, FDA registries for pregnant women, this excellent Medscape article, and the FDA's index by drug name.) Information is also available through PubMed by searching various terms; I suggest starting with 'antidepressants and pregnancy'.

A list of generic and trade names is here.


Despite the FDA's quite reasonable official stance that the risk/reward should be weighed individually, this attitude seems to be slow to catch on.

The FDA labels pregnancy drugs into five categories: A, B, C, D and X.

Category Description

Adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalities.


Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate and well-controlled studies in pregnant women.
or Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus.


Animal studies have shown an adverse effect and there are no adequate and well-controlled studies in pregnant women.
or No animal studies have been conducted and there are no adequate and well-controlled studies in pregnant women.
Studies, adequate well-controlled or observational, in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy may outweigh the potential risk.

Studies, adequate well-controlled or observational, in animals or pregnant women have demonstrated positive evidence of fetal abnormalities. The use of the product is contraindicated in women who are or may become pregnant.

The risks discussed arose through incident reporting, animal studies, cohort studies (comparing two more-or-less matched groups), long-term drug tracking by manufacturers (including pregnancy registries), and various medical studies. You will notice, if you read the individual papers, that there is a large amount of variability between studies; human populations are heterogeneous. The smaller or more biased (nonrandom) a sample, the more variation one will expect from study to study.

Relatively few drugs are Class A; even, say, sertraline, which is a relatively old and well-studied AD, is Class C. So is Sudafed. So is Benadryl. This is because it is difficult to demonstrate NO risk, and because many drugs have some small risk associated. A patient might think Class C is a terrible risk in pregnancy, or that there are no studies in humans, but actually there are a lot of studies in pregnant humans. Yet the FDA says there are "no adequate and well-controlled studies in pregnant women" in the drug labelling. In fact, the AAFP says that Benadryl and Sudafed are safe in pregnancy. Overall, the FDA system is confusing, inaccurate, and not very informative; the patient should look up each drug herself to get good information. (The FDA decided in 1997 to replace the A-X categorization with narrative. Aaaaand... not yet.)

After reading a lot of papers, I'd say that the data indicate that many antidepressants are NOT harmful during pregnancy, and patients with depression are better advised to continue treatment. I believe the small risk is worth the benefits. Many doctors will say 'But we don't know what all the risks could be, so it's better not to risk at all, and any risk is too much for your little embryo.' I could not disagree more. We do know what the risks could be: that's why we do studies. Each woman should be able to decide for herself what risk, including small risks, are acceptable to her.

It is always possible, of course, that there are risks these studies have not picked up. The studies could be:
  • Deliberately biased, by influence from drug companies. I find this unlikely because different studies mainly get similar results.
  • Looking for the wrong things. Many studies, however, look for all neurological symptoms or all congenital defects. Previous animal studies have given researchers some idea of what to look for; however, animal models are not perfect models for human disease.
  • Using a biased sample. This is possible, although many studies look at thousands of patients. But are they representative of the population? Are affluent white women more likely to take SSRIs? Are there genetic factors in other ethnic groups? (The African-American ethnic group, for example, is known to have a polymorphism that can reduce cardiac drug efficacy.)
  • Not picking up some rare conditions because the numbers are too low. This is possible as well; however, if it is the case, it may be either not above background (the naturally occurring level of X) in a reasonable number of patients, and/or it's so rare that it is probably not a major concern.
  • Anything else I haven't thought of.

I have a personal interest: depression runs in my family, and SSRIs are my new best friend. But aside from that, I believe in the informative power of research and reject the 'what if... you can't prove a negative' attitude.

1. Spontaneous abortion: Risk may increase a little.

For reference, the spontaneous abortion (SA), or miscarriage, rate is reported as around 10% of all confirmed pregnancies. SA rates in these studies vary widely.

A study on 136 women who took bupropion in the first trimester reports that SA incidence increased to 14.7% vs. 4.5%. Tricyclics are reported to have no effect on SA in one study of 689 women; a meta-analysis (an overview of many unrelated studies) finds an overall SA increase to 12.3% from 10% for tricyclics.

The same meta-analysis reports SSRIs raise SA from 8.4% to 12.8%. The authors note that they cannot rule out depression as a contributing factor to SA.

Another single-cohort study cites SAs at 12% for venlafaxine vs. 7% basal, and 10.7% in other SSRIs. These groups are not significantly different from each other.

CONCLUSION: SSRIs, tricyclics, bupropion, and other antidepressants (ADs) may somewhat increase the rate of spontaneous abortion in early pregnancy. Basal SA rate is generally 10% of confirmed pregnancies, though sometimes reported lower among small cohorts. Antidepressant SA risk is apparently raised to 10-15%. This increase may or may not be significant (i.e., real), and is small.

2. Premature Birth: ADs either do or don't increase preterm birth.

There are at least two good, large studies on preterm birth and AD use. The first uses a Swedish birth database which includes 997 mothers who took ADs, out of >500,000 women total. In the general population, 5% of babies are born before 37 weeks; in all AD-medicated mothers it is 10%, and 10% in SSRI users. The second study follows 1,782 mothers who took SSRIs, 360 throughout pregnancy and >1000 with 1st trimester purchases. They find no increase at all in preterm birth and no decrease in birth rate.

CONCLUSION: There is not a lot of data on preterm births. These studies are both large population-based studies, but are not random except in the sense of including all of a registry. It is not possible to say whether preterm births are truly increased by AD usage in pregnancy. It may be slightly increased; one study shows a small effect.