Lithium in the first trimester: the heart-defect risk is real, dose-driven, and smaller than psychiatry taught

This stop is about a number changing, and about why the first one was wrong in a way its design made predictable. It is not a claim that lithium in pregnancy is safe, or that it is dangerous. It is a claim about evidence.

Significant findings

Ebstein anomaly is a rare malformation of the tricuspid valve. In a population-based case-control study of nearly 4,400 cardiovascular malformations, 47 cases gave a prevalence of about 5.2 per 100,000 live births - roughly 1 in 19,000 (Teratology 1994, doi:10.1002/tera.1420500208). The starting risk is very small, and that matters for everything that follows.

The original signal came from the Register of Lithium Babies, to which physicians voluntarily submitted cases. As the 2017 cohort study that anchors this stop puts it in its own introduction, the early register work "suggested a risk of Ebstein's anomaly ... increased by a factor of 400 (on the basis of two cases associated with lithium exposure)"; the final report covered 225 exposed infants, of whom 18 had congenital cardiac defects (8%) and six had Ebstein anomaly (3%). The register's own first report said the data "were collected retrospectively and therefore overestimate rather than underestimate the risk of teratogenicity" (BMJ 1973, doi:10.1136/bmj.2.5859.135). A voluntary register of remembered cases with no control group counts the babies people thought to report; it cannot count the ones nobody did.

The reevaluation came in 1994, and its most useful finding is an absence: across four case-control studies of Ebstein anomaly involving 25, 34, 59 and 89 affected children, no mother had taken lithium in pregnancy (JAMA 1994, doi:10.1001/jama.1994.03510260078033). That paper gave no single replacement figure, and this row does not invent one for it.

The best current measurement is a cohort of 1,325,563 pregnancies in US Medicaid data, 663 of them lithium-exposed. Cardiac malformations occurred in 2.41 per 100 lithium-exposed live births, 1.15 per 100 unexposed and 1.39 per 100 exposed to lamotrigine - an excess of about 1.26 per 100 before adjustment. The adjusted risk ratio against unexposed pregnancies was 1.65 (95% CI 1.02-2.68), and it rose with dose: 1.11 (0.46-2.64) at 600 mg a day or less, 1.60 (0.67-3.80) at 601-900 mg, 3.22 (1.47-7.02) above 900 mg. For right ventricular outflow tract obstruction defects, the group Ebstein anomaly usually falls into, the rates were 0.60 against 0.18 per 100, adjusted risk ratio 2.66 - whose lower bound is exactly 1.00, which is another way of saying the estimate only just clears chance. A pooled analysis of six cohorts, 727 lithium-exposed pregnancies, put first-trimester major malformations at 7.4% (4.0-10.7) against 4.3% (3.7-4.8), adjusted odds ratio 1.71 (1.07-2.72) (Lancet Psychiatry 2018, doi:10.1016/S2215-0366(18)30180-9).

One finding cuts across the whole story. A European study of 264 Ebstein cases across 15 registries and 5.6 million births found the association ran with maternal mental health conditions and their treatment considered together - adjusted odds ratio 2.64 (1.33-5.21) against cardiac controls - and concluded that Ebstein anomaly "is associated with maternal mental health problems generally rather than lithium or benzodiazepines specifically; therefore, changing or stopping medications may not be preventative" (Cardiol Young 2017, doi:10.1017/S1047951116001025). Confounding by indication again, on the drug side this time.

Worth asking

Lithium is not a medication anyone should start or stop on their own account, in pregnancy or out of it, and the questions here are for a prescriber and an obstetrician together: what dose you are on and what these dose bands mean for you, what fetal cardiac screening is offered and when, how monitoring changes across pregnancy and delivery, and what the alternatives would cost you in relapse risk - the subject of a later stop in this trail.