Antidepressants in the first trimester: the cardiac-defect signal mostly vanishes once you adjust for the depression

The problem underneath every study in this stop has a name: confounding by indication. Women who take an antidepressant in pregnancy differ from women who do not - in the illness itself and everything that travels with it. A study that cannot separate illness from treatment is measuring both, and the honest thing is to say which studies could and which could not.

Significant findings

Cardiac malformations first, with the baseline. In 949,504 pregnancies in US Medicaid data, cardiac defects occurred in 72.3 per 10,000 infants with no antidepressant exposure and 90.2 per 10,000 after first-trimester SSRI exposure - 7.23 against 9.02 per 1,000. The unadjusted relative risk of 1.25 (95% CI 1.13-1.38) fell to 1.12 (1.00-1.26) when the comparison was restricted to women with depression, and to 1.06 (0.93-1.22) after full adjustment. Two specific alarms from earlier literature did not survive: paroxetine and right ventricular outflow tract obstruction, 1.07 (0.59-1.93), and sertraline and ventricular septal defect, 1.04 (0.76-1.41). The same analysis reproduced known positive controls - diabetes 3.7 (3.4-4.0), anticonvulsants 1.6 (1.3-1.8) - so the method could detect a real signal where one exists.

Persistent pulmonary hypertension of the newborn is serious and occurs in roughly 1.8 to 1.9 per 1,000 live births in the general population. In 3,789,330 pregnancies, it occurred in 20.8 per 10,000 infants unexposed to antidepressants late in pregnancy and 31.5 per 10,000 after SSRI exposure - 2.08 against 3.15 per 1,000, an excess of about 1 case per 1,000. The odds ratio of 1.51 (1.35-1.69) fell to 1.10 (0.94-1.29) after full adjustment (JAMA 2015, doi:10.1001/jama.2015.5605). One result should not be dropped: restricted to primary persistent pulmonary hypertension, the adjusted odds ratio for SSRIs was 1.28 (1.01-1.64), which still clears one. A small absolute risk that adjustment reduces but does not erase.

Neonatal adaptation after third-trimester exposure is common and usually self-limiting. A single-centre study of 120 term infants found signs in 18 of 60 exposed and none of 60 unexposed; a systematic review put the relative risk at 3.0 (2.0-4.4), described the signs as usually mild and resolving within about two weeks, found severe presentations rare in term infants, and reported no neonatal deaths attributable to exposure (JAMA 2005, doi:10.1001/jama.293.19.2372).

The autism literature is where sibling designs changed the picture. In an Ontario cohort of 35,906 births, the crude hazard ratio for autism spectrum disorder after prenatal serotonergic antidepressant exposure was 2.16 (1.64-2.86); adjusted, 1.59 (1.17-2.17); weighted by a high-dimensional propensity score, 1.61 with a lower bound of 0.997; and comparing siblings, 1.60 (0.69-3.74) (JAMA 2017, doi:10.1001/jama.2017.3415). The point estimate barely moves and the precision collapses, so the study can rule a causal relationship neither in nor out, and its authors said so. The larger Swedish analysis is more decisive: among 1,580,629 offspring, first-trimester exposure was associated with autism at a population hazard ratio of 2.02 (1.80-2.26) and ADHD at 2.21 (2.04-2.39); comparing siblings, 0.83 (0.62-1.13) and 0.99 (0.79-1.25) - while preterm birth survived the sibling comparison at 1.34 (1.18-1.52) (JAMA 2017, doi:10.1001/jama.2017.3413). Same data, same drugs: some associations were family background, one was not.

Worth asking

None of this settles what any individual should take, and none of it is a reason to change a medication on the strength of a paragraph. If you are pregnant or planning to be, the useful questions for a prescriber and an obstetrician are: what is known specifically about the drug I am on rather than its class; what the third trimester and the first days after birth would look like; what monitoring is offered; and what happens to my own illness on each option - the question the next stop is about.