Monday, February 05, 2007

Ask a Scientist: Antidepressants and Pregnancy (4)

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/ postnatal 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.

4. Antenatal/ postnatal adaptation problems

Certain post-birth symptoms are associated with maternal antidepressant- usually SSRI, but also venlafaxine- use in the last trimester. They are all categorized as 'neonatal withdrawal [or abstinence] syndrome'. These syndromes rarely lead to anything other than an unpleasant week with a cranky baby, and maybe a couple days in the NICU.

Muscle stiffness and/or convulsions are treated with support and/or low doses of SSRIs. A certain amount of breathing and/or neonatal distress is associated with maternal SSRI usage; it is rarely fatal except in infants with other complications, and is treated supportively.

4a. Muscle stiffness

A recent study looked at reported incidences of seizure-like symptoms in mothers taking SSRIs. They found 93 reported cases of these symptoms in a large adverse-event database and tried to eliminate other factors and drugs that might have caused the symptoms. Then they compared the incidence to the overall incidence in the adverse-event database. 74 cases were 'certain'; of those, 51 involved paroxetine use, 10 fluoxetine, 7 sertraline, and 6 citalopram.
Most of the incidents were neurological (see below); there were 11 total instances of hypertonia and convulsions.

Two case studies on venlafaxine report increased hypertonia (stiffness) in neonates; one treats with a low dose for a week, and the other recommends breastfeeding to mitigate withdrawal.

One case study reports convulsions associated with paroxetine.

4b. Breathing distress at birth (and other distress, ICU)

Third-trimester SSRI use is associated with babies more often having to go the NICU with breathing problems, neonatal lowered heart rate, or other unspecified distress. Various studies estimate the risk at various levels.

A large Canadian cohort of 75,000 mothers taking any of 6 SSRIs showed that 13.9% vs. 7.8% of controls had some neonatal respiratory distress (that is, had to spend some time in the NICU). A Finnish population study likewise showed that, of infants whose mothers bought SSRIs in the 3rd trimester, 15.7% vs. 11.2% for infants whose mothers bought SSRIs in the 1st trimester. A Motherisk study specifically on citralopram found an increased chance of having to go to a special-care nursery.

Another study, the inspiration for a recent mildly hysterical FDA alert, looked for infants with PPHN (a condition where there is high blood pressure in the lungs and therefore oxygen deficit) and then tried to see how many mothers used SSRIs. They found an increased risk of about 6-fold; that is, in their study, from 7/1000 to 37/1000. The problem with this study is they looked for a condition and then tried to check drug usage. It would be better to look among a large cohort of SSRI users (like in the Canadian study) and check for PPHN. Also, they only find 14 cases of PPHN with SSRI use. I find this not terribly credible due to poor design and small sample size.

4c. Neurological withdrawal symptoms

Many newborns with SSRI exposure do manifest neurological signs of a 'neonatal abstinence syndrome.' In addition to the higher incidence of respiratory distress (as above), many infants cry a lot and have trouble sleeping. This number is reported as high as 30% in a small study (60 infants). Of these, 8 had 'severe' and 10 'mild' symptoms. The average duration was about three days.

Another small study examines 76 mothers who took ADs and 90 control. 63% of exposed infants had some neurological symptoms. 75% of these infants resolved within 3 days; premature infants were more strongly affected by SSRI side effects. And yet one more study of 46 infants found much the same: about 30% of infants have mild respiratory distress or twitchiness. (They also found that clonazepam, a benzodiazapene, exacerbated the effect, probably due to metabolic effects.)

Numerous case reports have been published on neonatal withdrawal symptoms in maternal use of citralopram, fluoxetine, paroxetine, and I'm sure other drugs.
The above case studies on venlafaxine also report irritability, etc.

One exceedingly crappy case report tries to correlate paroxetine levels in one newborn with- gasp!- pneumothorax. They do not measure maternal paroxetine levels, but cord-blood levels are four times above the normal therapeutic range. And then the infant is irritable in addition to intubated, but gets better within a week. Correlation is NOT causation here.

  • SSRIs cause some increase in post-natal problems.
  • These manifest as mild breathing distress, NICU time, and longer hospital stays.
  • Some infants will experience muscle stiffness and, occasionally, convulsions.
  • Some incidents of severe respiratory distress are reported.
  • Many 3rd-trimester-SSRI-exposed infants will be irritable for several days after birth, due to neurological withdrawal.
  • If symptoms are severe, some doctors recommend treating with tapered SSRI doses.
  • Breastfeeding may mitigate withdrawal.
  • These effects can be worse in premature infants, who are predisposed to breathing distress.
  • Motherrisk reminds us that "Among pregnant women, abrupt discontinuation of antidepressants has been associated with withdrawal symptoms, including nausea and vomiting, diarrhea, sweating, anxiety and panic attacks, mood swings, and suicidal thoughts."
  • They recommend exposed infants be monitored for a week or so after birth.
  • This sounds really alarming, but remember, this is an increase in nonfatal events.
  • A review on AD withdrawal in adults tells us that "Most reactions are mild and short-lived and require no treatment other than patient reassurance."