These guidelines recommend that you consider 1) the severity of her current depression, 2) her history of depression severity, and 3) her preference for treatment.12 For mild depression during pregnancy, when there is no history of severe depression, or for a history of depression that responded well to psychotherapy in the past, a trial of psychotherapy without medications is recommended.
But Megan’s history of depression falls into the “severe” category, and a prior episode of depression did not respond well to psychotherapy. Your recommendation to her, therefore, is that she should continue taking an antidepressant—unless she feels strongly that she should discontinue it.
Megan considers what you’ve discussed about her high risk of developing recurrent depression during pregnancy. She decides that she wants to continue taking her antidepressant during pregnancy, but she has concerns—based on what she has been reading on the Internet.
Megan hands you a detailed printout downloaded from a Web site unfamiliar to you and asks about risks to the baby of such medications as paroxetine.
What should you tell Megan about SRIs in pregnancy—paroxetine, specifically?
You preface your remarks to her by noting that the data physicians work with are imperfect—because randomized, controlled clinical trials pose an ethical dilemma as a method of study in pregnant women. You then discuss with her current scientific understanding of potential risks to her fetus.
The difference in the rates of structural malformation among SRI-exposed and SRI-unexposed groups has been studied; most studies have found no increased rate of major or specific cardiac malformations.12 However, first-trimester paroxetine appeared, in some studies, to be associated with an increased rate of cardiac malformations. That led to a category-“D” pregnancy classification in 2005 and an FDA “Public Health Advisory.”
Other large cohort studies have not uncovered such an association. It has been hypothesized that the methodology of data collection may have influenced this finding.13
Other malformations have been implicated in some studies but not others, and have included associations between specific SRIs and cardiac ventricular outflow defects, craniosynostosis, and omphalocele. The absolute risk of these defects remains extremely low, however, and close to the background rate seen in the general population.14
Megan asks: “With that risk-category ‘D’ for paroxetine, do you recommend I continue taking it or should I switch to another medication while I’m pregnant?”
You review again with Megan that, although some studies have linked first-trimester paroxetine to an increased risk of cardiac malformation, that finding has not been replicated in several large cohort studies. You explain that, if she had a history of recurrent depression that had failed to respond to many antidepressants and only paroxetine worked, an attempt at switching the SRI would not be recommended because of the potential for relapse.
Megan tells you that she would feel safer not taking a category-“D” drug. You agree and propose a judicious approach: Because she has come to see you before she became pregnant, with enough time to complete a slow crossover to an alternative SRI, and because she has not had any earlier trials of other SRIs, a slow taper of paroxetine, coupled with a crossover to an alternative SRI, is a reasonable option—with the caution that substitution always carries a risk of relapse.
Problems in newborns
Megan considers the risks you’ve discussed so far. She remembers a recent article in a magazine for pregnant women that described severe “respiratory” and “withdrawal” symptoms in infants who were born to mothers taking an SRI antidepressant. She wonders if she should consider discontinuing her SRI in the third trimester to try to mitigate those risks.
Megan is asking you about an SRI exposure risk that has been fairly consistent across studies, called neonatal abstinence syndrome (NAS) or poor neonatal adaptation.
NAS is a cluster of symptoms that occurs in 15% to 30% of newborns who have been exposed to an SRI during the third trimester of pregnancy.15 Signs include irritability, weak cry, tachypnea, temperature instability, and hypoglycemia—all of which are transient, peak during the first 48 hours after delivery, and resolve in less than 2 weeks.
Multiple hypotheses have been put forward to account for NAS, including the possibilities that it reflects a withdrawal syndrome, pharmacotoxicity, or an underlying gene–SRI interaction. The physiology behind NAS remains unknown, however.12
Megan next asks you about persistent pulmonary hypertension of the newborn (PPHN). You explain that PPHN is of recent concern in women who have been taking an SRI in the latter half of their pregnancy.
The rate of PPHN in the general population is 0.5 to 2 newborns for every 1,000. Associated mortality is approximately 10% to 20%.16-18 This rate is thought to rise to approximately 6 of every 1,000 newborns among those who have been exposed to an SRI in utero—with some evidence of increased risk conferred through SRI exposure during later pregnancy (studies define this as the second half of the pregnancy).15 Although the relative risk of PPHN is increased threefold to sixfold when an SRI is used in pregnancy, absolute risk remains extremely low.