Calkins, M

Gur, R.E.

Guri, Y

McDonald-McGinn, D.M.

Van Den Bree, Marianne

Weisman, O

Online Research @ Cardiff

Correspondencen engl j med 377;9 nejm.org August 31, 2017 893Lithium Use in Pregnancy and the Risk of Cardiac MalformationsTo the Editor: Patorno et al. (June 8 issue)1 pro-vided information on the risk of cardiac malfor-mation in infants exposed to lithium during the first trimester of pregnancy. The risk is higher than in nonexposed infants or in infants exposed to lamotrigine, but the association is of a smaller magnitude than previously reported.We emphasize that these findings do not imply or support the idea that lithium treatment should be discontinued in women who are preg-nant or planning a pregnancy or that lithium treatment should be avoided in women of child-bearing age. If properly managed, lithium is the most effective prophylactic treatment option for bipolar disorder, both in and outside the perina-tal period, and it has a side-effect profile that is more favorable than usually assumed.2,3 The in-creased risk of cardiac malformation presented in this research needs to be weighed against the high risk of a postpartum recurrence of bipolar disorder in women who do not receive treatment (in a recent meta-analysis, the risk was found to be 66% [95% confidence interval, 57 to 75]4), as well as against the risks associated with alter-native perinatal treatment options, such as lamo-trigine3 or the combined use of antipsychotics and antidepressants.5Arianna Di Florio, M.D., Ph.D.Cardiff University Cardiff, United Kingdom diflorioa@ cf . ac . ukTrine Munk-Olsen, Ph.D.Aarhus University Aarhus, DenmarkVeerle Bergink, M.D., Ph.D.Erasmus MC Rotterdam, the NetherlandsNo potential conflict of interest relevant to this letter was re-ported.1. Patorno E, Huybrechts KF, Bateman BT, et al. Lithium use in pregnancy and the risk of cardiac malformations. N Engl J Med 2017; 376: 2245-54.2. Geddes JR, Miklowitz DJ. Treatment of bipolar disorder. Lancet 2013; 381: 1672-82.3. Wesseloo R, Liu X, Clark CT, Kushner SA, Munk-Olsen T, Bergink V. Risk of postpartum episodes in women with bipolar disorder after lamotrigine or lithium use during pregnancy: a population-based cohort study. J Affect Disord 2017; 218: 394-7.4. Wesseloo R, Kamperman AM, Munk-Olsen T, Pop VJ, Kush-ner SA, Bergink V. Risk of postpartum relapse in bipolar disor-der and postpartum psychosis: a systematic review and meta-analysis. Am J Psychiatry 2016; 173: 117-27.5. Tosato S, Albert U, Tomassi S, et al. A systematized review of atypical antipsychotics in pregnant women: balancing be-tween risks of untreated illness and risks of drug-related adverse effects. J Clin Psychiatry 2017; 78(5): e477-e489.DOI: 10.1056/NEJMc1708919To the Editor: The article by Patorno et al. on the relationship between maternal lithium use and the risk of congenital cardiac malformations is difficult to interpret because of the incorrect identification of Ebstein’s anomaly, which has previously been linked to lithium use during pregnancy. Ebstein’s anomaly is distinctly not a form of right ventricular outflow obstruction. It involves the inflow portion of the right ventricle, not the outflow tract, and results in valvular in-sufficiency, not obstruction. No clinician would classify right ventricular outflow obstruction as Ebstein’s anomaly because of maternal lithium use. Although Ebstein’s anomaly is occasionally associated with pulmonary stenosis or atresia, these are exceptions.Thus, it is not possible to determine whether lithium exposure is associated with Ebstein’s anomaly. The authors state that none of the right ventricular outflow tract lesions were specifical-ly coded as Ebstein’s anomaly. I hope not, because these are entirely different malformations.The article does provide reassurance that the risk associated with maternal lithium use is prob-ably lower than previously thought and seems to be present only when large doses of the medica-tion are used.Howard Gutgesell, M.D.University of Virginia Medical School Charlottesville, VA hpg@ virginia . eduNo potential conflict of interest relevant to this letter was re-ported.DOI: 10.1056/NEJMc1708919The authors reply: Di Florio et al. emphasize the important point that patients and clinicians need to balance the increased risk of cardiac malformations we found in our study and the benefits of lithium for treating bipolar disorder in women who are pregnant or who may poten-tially become pregnant.1,2The New England Journal of Medicine Downloaded from nejm.org on September 12, 2017. For personal use only. No other uses without permission.  Copyright © 2017 Massachusetts Medical Society. All rights reserved. T h e  n e w  e ngl a nd  j o u r na l  o f  m e dic i n en engl j med 377;9 nejm.org August 31, 2017894Gutgesell clarifies the anatomical characteris-tics of Ebstein’s anomaly and gives us the oppor-tunity to justify the classification scheme we used in our analyses. We examined the effect of lithium exposure on three different end points related to cardiac malformations: cardiac mal-formations overall (primary outcome), right ven-tricular outflow (and inflow) tract defects, and Ebstein’s anomaly. We combined right heart de-fects, as had been done in other epidemiologic studies, because these defects might be pathoge-netically related.3 The wide net that was cast in the first two levels of analysis aimed to capture any potential less specific effects of lithium on cardiac malformations. However, it is important to note that we also evaluated Ebstein’s anomaly specifically and found none in the 663 pregnan-cies with lithium exposure. As Gutgesell con-cludes, this finding provides reassurance, since the initially proposed relative risk of 400 from the uncontrolled International Register of Lithium Babies2,4 would have predicted approximately 15 cases of Ebstein’s anomaly, given a baseline prevalence of 5 cases per 100,000 births.5 Our findings further suggest a much more modest association of lithium exposure, particularly at lower doses, with cardiac defects overall and with right heart defects considered as a composite group.Elisabetta Patorno, M.D., Dr.P.H. Krista F. Huybrechts, Ph.D.Harvard Medical School Boston, MA epatorno@ bwh . harvard . eduSonia Hernandez-Diaz, M.D., Dr.P.H.Harvard T.H. Chan School of Public Health Boston, MASince publication of their article, the authors report no fur-ther potential conflict of interest.1. Viguera AC, Whitfield T, Baldessarini RJ, et al. Risk of recur-rence in women with bipolar disorder during pregnancy: pro-spective study of mood stabilizer discontinuation. Am J Psychia-try 2007; 164: 1817-24.2. Cohen LS, Friedman JM, Jefferson JW, Johnson EM, Weiner ML. A reevaluation of risk of in utero exposure to lithium. JAMA 1994; 271: 146-50.3. Rasmussen SA, Olney RS, Holmes LB, Lin AE, Keppler-Noreuil KM, Moore CA. Guidelines for case classification for the National Birth Defects Prevention Study. Birth Defects Res A Clin Mol Teratol 2003; 67: 193-201.4. Nora JJ, Nora AH, Toews WH. Letter: Lithium, Ebstein’s anomaly, and other congenital heart defects. Lancet 1974; 2: 594-5.5. Correa-Villaseñor A, Ferencz C, Neill CA, Wilson PD, Bough-man JA. Ebstein’s malformation of the tricuspid valve: genetic and environmental factors. Teratology 1994; 50: 137-47.DOI: 10.1056/NEJMc1708919Myeloproliferative NeoplasmsTo the Editor: In his article on myeloprolifera-tive neoplasms, Spivak (June 1 issue)1 briefly ad-dresses the diagnostic effect of morphologic fea-tures and states that “bone marrow histologic features cannot provide specificity, except that myelodysplasia can be ruled out on the basis of histologic features.” The author completely dis-regards the World Health Organization (WHO) classification of myeloproliferative neoplasms, particularly the advancements introduced in the 2016 revision.2 Specifically, Spivak did not men-tion the bone marrow biopsy characteristics and the associated clinical effects of early-stage poly-cythemia vera3 or the clinical relevance of prefi-brotic myelofibrosis and its differentiation from essential thrombocythemia.4 Until now, none of the various molecular mutations have proven to be specific and therefore cannot be applied to the molecular classification of myeloproliferative neo-plasms or used to distinguish essential throm-bocythemia from prefibrotic myelofibrosis. The so-called transformation of myeloproliferative neoplasms, erroneously assumed by the author to make diagnosis a moving target — with essen-tial thrombocythemia (i.e., early polycythemia vera) progressing to overt polycythemia vera or es-sential thrombocythemia (i.e., prefibrotic myelofi-brosis progressing to myelofibrosis) — is actually related to the accuracy of the initial diagnosis.5Tiziano Barbui, M.D.FROM Research Foundation Hospital Bergamo, Italy tbarbui@ asst-pg23 . itJürgen Thiele, M.D.University of Cologne Cologne, GermanyAyalew Tefferi, M.D.Mayo Clinic Rochester, MNNo potential conflict of interest relevant to this letter was re-ported.1. Spivak JL. Myeloproliferative neoplasms. N Engl J Med 2017; 376: 2168-81.The New England Journal of Medicine Downloaded from nejm.org on September 12, 2017. For personal use only. No other uses without permission.  Copyright © 2017 Massachusetts Medical Society. All rights reserved. 

Lithium use in pregnancy and the risk of cardiac malformations

https://orca.cardiff.ac.uk/id/eprint/104414/2/Lithium%20Use%20in%20Pregnancy.pdf

Lithium use in pregnancy and the risk of cardiac malformations

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