Lithium and pregnancy have always been a major concern for psychiatrists, obstetricians, and of course women who need to take the medication for mood stabilization. In the Lithium Encyclopedia (published in 1983) - there is a chapter on the physiological effects of pregnancy and how that potentially affects lithium balance and a separate chapter on teratogenesis. That chapter describes the Lithium Baby Registry that was established in 1970 to collect information on the effects of lithium in pregnancy. In the first 10 years, 225 infants exposed to lithium were described and 25 had congenital malformations. Of these births 18/25 had cardiovascular abnormalities including Ebstein's anomaly, 7 were stillborn, 2 had Down's syndrome and 1 had intracerebral toxoplasmosis. The results suggested that lithium was a cardiovascular teratogen, but there was a question of reporting bias. That is, results consistent with the study concern about lithium being a teratogen were more likely to be reported than normal births.
Those references set the knowledge about lithium and pregnancy for all residents trained in my era in the late 1980s. The standard question by attendings and on examinations was: "What is the cardiac anomaly associated with intrauterine exposure to lithium?". The answer was Ebstein's anomaly. The follow up question was expected: "And what is Ebstein's anomaly?" In those days the short answer was downward displacement of the tricuspid valve into the right ventricle. Today Ebstein anomaly (no longer a possessive) is described in greater detail. A modern reference describes the extension of the tricupsid valve into the right atrium to the extent that most of the functional chamber chamber is collapse to a very small volume. In some cases it is collapsed to the right ventricular outflow tract. The downward valve displacement is due to a number of morphological abnormalities in the tricuspid valve. The myocardium is also abnormal because the valve tissue has failed to completely separate from the myocardium during fetal development - a process called delamination. That is associated with a thin and poorly contractile myocardium and poor right ventricle performance. There are several associated cardiac abnormalities including ventricular septal defect, patent foramen ovale, patent ductus arterious, and accessory conduction pathways that can lead to arrhythmias. The associated clinical syndromes of cyanosis, congestive heart failure and arrhythmia can occur in infancy to adulthood depending on the degree of anatomical disruption. The complications can be fatal at any age (2).
Ebstein abnormality is a preventable complication and one that must be avoided. In real life that is easier to say than do. In a controlled hospital or clinic environment it is a very straightforward process to take a history and determine the obstetric history and last menstrual period. Urine and serum pregnancy tests can be done for confirmation. The best advice to physicians in this situation is to treat very woman of childbearing age as if they were pregnant until proven otherwise. In my experience life is less regimented. There are lapses in contraception and planning that lead to pregnancies in women taking lithium who know that exposure to the infant is an avoidable risk. Many of these women are on lithium maintenance. Since lithium remains a mainstay of treatment for bipolar disorder and may be a superior agent in postpartum psychosis - the question of teratogenicity remains an important one.
There have been a number of estimates of congenital malformations due to psychiatric medications and I recently reviewed a few of them and cited extensive database references. In one of the reviews very large databases were examined looking for major congenital malformations to lithium exposed women especially Ebstein anomaly.
The New England Journal of Medicine published another large retrospective database study of the question of lithium exposure in pregnancy and risk of cardiac malformations. Their database involve a Medicaid cohort of 1,325,563 pregnancies over the ten year period between 2000 and 2010. In this cohort there were cardiac malformations noted in 16 of 663 (2.4%) lithium exposed infants. Lower rates of cardiac malformations were noted in nonexposed infants (1.15%) and lamotrigine exposed infants (1.39%). In addition there appeared to be a dose related effect with increasing risk ratio noted with increasing doses of lithium. For example at the dose of 600 mg or less/day the risk ratio was 1.11 but the risk ratio increased to 1.11 and 3.22 for doses of 601-900 mg/day and greater than 900 mg respectively.
The authors have a detailed report on how the cardiac malformations were determined. They make an interesting point that a misclassification bias can occur with Ebstein anomaly. Some clinicians may make the diagnosis of right ventricular outflow tract obstruction defects or Ebstein anomaly based on whether or not there has been a history of exposure to lithium. That may make it more likely to misclassify Ebstein anomaly. They provide data for the total prevalence of all cardiac malformations and cardiac malformations classified as right ventricular outflow obstruction. They were focused on "major cardiac defects that were likely to be consequential for the infant." The diagnostic codes had to be listed several times or associated with surgery.
The calculated prevalence of Ebstein abnormality in unexposed pregnancies was 7 cases per 100,000 live births. They did not provide the prevalence of Ebstein anomaly in the lithium exposed due to the low number. After a detailed analysis and analysis of possible sources of error like terminate pregnancies where lithium exposure occurred the authors conclude that lithium had a modest effect in terms of increased risk of cardiac malformations. Their final estimate was an increased risk of 1 additional case per 100 live births if the exposure occurred early in the pregnancy. They describe this as a modest increase in risk of cardiac malformations due to lithium. The difference in the ratio of cardiac malformations in this study (16/663) compared with the Lithium Baby Registry (18/225) is probably due to a more rigorous methodology.
The authors looked at five sources of error in their final discussion of the results. For clinical psychiatrists the most relevant point was that other factors affecting treatment decisions in pregnancy were not investigated. They are considerable given that it is highly likely that the women being treated with lithium have severe mood disorders and suicide in the postpartum period in the number one cause of death. This study can best be viewed as a study that supports current clinical practice to avoid first trimester exposure to lithium by careful screening and then planning if additional adjustments need to be made for planned pregnancies based on the trimester. In those cases of accidental exposure, consultation with high risk obstetrics and a decision based on a detailed discussion with the patient is usually the preferred option.
George Dawson, MD, DFAPA
References:
1. Jefferson JW, Greist JH, Ackerman DL. Lithium Encyclopedia for Clinical Practice. Washington, DC; American Psychiatric Press, Inc., 1983: 264-265.
2. Connolly HM, Qureshi, MY. Clinical manifestations and diagnosis of Ebstein anomaly. In UpToDate, Greutmann M, Fulton DR, Yeon SB (Accessed on June 9, 2017).
3. Patorno E, Huybrechts KF, Bateman BT, Cohen JM, Desai RJ, Mogun H, Cohen LS, Hernandez-Diaz S. Lithium Use in Pregnancy and the Risk of Cardiac Malformations. N Engl J Med. 2017 Jun 8;376(23):2245-2254. doi: 10.1056/NEJMoa1612222.
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