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Pregnancy Outcome Following In Utero Exposure to Lithium: A Prospective, Comparative, Observational Study
Orna Diav-Citrin, M.D.; Svetlana Shechtman, Ph.D.; Esther Tahover, M.D.; Victoriya Finkel-Pekarsky, M.Sc.Pharm.; Judy Arnon, Ph.D.; Debra Kennedy, M.D.; Aida Erebara, M.D.; Adrienne Einarson, R.N.; Asher Ornoy, M.D.
Am J Psychiatry 2014;171:785-794. doi:10.1176/appi.ajp.2014.12111402
View Author and Article Information

Adrienne Einarson has received consulting fees from Eli Lilly for a duloxetine pregnancy registry. All other authors report no financial relationships with commercial interests.

The Motherisk Program has received an unrestricted educational grant from Eli Lilly to study the safety of duloxetine in pregnancy.

From the Israeli Teratology Information Service, Israel Ministry of Health, Jerusalem; the Hebrew University Hadassah Medical School, Jerusalem; MotherSafe, Royal Hospital for Women, Sydney, Australia; and the Motherisk Program, Hospital for Sick Children, Toronto.

Previously presented in part at the 19th International Conference of the Organization of Teratology Information Specialists, June 24–27, 2006, Tucson, Ariz., and the 25th International Conference of the Organization of Teratology Information Specialists, June 22–26, 2012, Baltimore.

Address correspondence to Dr. Diav-Citrin (orna.diav-citrin@moh.health.gov.il).

Copyright © 2014 by the American Psychiatric Association

Received November 08, 2012; Revised August 07, 2013; November 21, 2013; Accepted February 10, 2014.

Abstract

Objective  The authors conducted a prospective, comparative observational study to evaluate the risk of major anomalies following exposure to lithium during pregnancy.

Method  A total of 183 lithium-exposed pregnancies of women who contacted the Israeli Teratology Information Service were followed up (90.2% in the first trimester) and compared with 72 disease-matched and 748 nonteratogenic-exposed pregnancies.

Results  There were significantly more miscarriages (adjusted odds ratio=1.94, 95% CI=1.08–3.48) and elective terminations of pregnancy (17/183 [9.3%] compared with 15/748 [2.0%]) in the lithium-exposed group compared with the nonteratogenic exposure group. The rate of major congenital anomalies after exclusion of genetic or cytogenetic anomalies was not significantly different between the three groups (lithium-exposed in the first trimester: 8/123 [6.5%]; bipolar: 2/61 [3.3%]; nonteratogenic: 19/711 [2.7%]). Cardiovascular anomalies occurred more frequently in the lithium group exposed during the first trimester when compared with the nonteratogenic exposure group (5/123 [4.1%] compared with 4/711 [0.6%]) but not after excluding anomalies that spontaneously resolved (3/123 [2.4%] compared with 2/711 [0.3%]). Ebstein’s anomaly was diagnosed in one lithium-exposed fetus and in two retrospective lithium cases that were not included because contact with the information service was made after the prenatal diagnosis by ultrasound. The rate of noncardiovascular anomalies was not significantly different between the groups. The rate of preterm deliveries was higher in the lithium group compared with the nonteratogenic exposure group (18/131 [13.7%] compared with 41/683 [6.0%]).

Conclusions  Lithium treatment in pregnancy is associated with a higher rate of cardiovascular anomalies. Women who are treated with lithium during organogenesis should undergo fetal echocardiography and level-2 ultrasound.

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TABLE 1.Maternal Characteristics and Obstetrical History of Study Participants
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a Values in bold indicate statistical significance (p<0.05).

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b There were statistically significant differences in comparison with the nonteratogenic exposure group (p<0.017).

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c There were statistically significant differences in comparison with the bipolar group (p<0.017).

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d Data were compared using Kruskal-Wallis test.

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e Data were compared using analysis of variance.

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TABLE 2.Pregnancy Outcome in Lithium-Exposed Pregnancies and in Bipolar and Nonteratogenic Exposure Comparison Groups
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a Values in bold indicate statistical significance (p<0.05).

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b Differences that reached statistical significance (p<0.017) were found when compared with the nonteratogenic exposure group.

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c The cohort included four sets of twins.

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d The cohort included two sets of twins.

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e The cohort included 16 twin sets and two sets of triplets.

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f Data are not applicable because more than 20% of the cells had an expected count less than 5.

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g Data were compared using Kruskal-Wallis test.

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h Data were compared using analysis of variance.

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TABLE 3.Comparison of the Rate of Major Anomalies From the Israeli Teratology Information Service
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a Data do not include non-first-trimester lithium exposures.

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b Two cases of multiple anomalies in the lithium group and one case in the bipolar group counted twice, both as a cardiovascular and a noncardiovascular anomaly.

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c Differences that reached statistical significance (p<0.017) were found when compared with the nonteratogenic group.

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TABLE 4.Comparison of the Rate of Major Anomalies From Multicenter Data
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a Data represent first-trimester exposure.

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b Differences that reached statistical significance (p<0.05) are indicated in bold.

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TABLE 5.Major Congenital Anomalies in the Lithium-Exposed and Bipolar Groups
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a Counted as both a cardiovascular and a noncardiovascular anomaly.

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b Potentially explained by other teratogens.

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c Cytogenetic condition.

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TABLE 6.Logistic Regression Analysis of Miscarriagesa
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a The dependent variable in this analysis is miscarriage, i.e., 0=no miscarriage and 1=miscarriage (model: χ2=90.180, df=7, p<0.001; pseudo R2=0.225; total number of cases included in the analysis, N=911).

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b Differences that reached statistical significance (p<0.05) are indicated in bold.

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TABLE 7.Logistic Regression Analysis of Cardiovascular Anomaliesa
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a The dependent variable in this analysis is cardiovascular anomalies, i.e., 0=no cardiovascular anomaly and 1=cardiovascular anomaly (model: χ2=10.676, df=4, p=0.03; pseudo R2=0.105; total number of cases included in the analysis, N=822).

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b Differences that reached statistical significance (p<0.05) are indicated in bold.

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1.
Which of the following malformations has been associated with first-trimester lithium exposure?
2.
Which of the following statements is true about the risk of cardiovascular anomalies after first-trimester lithium exposure in the present study?
3.
What would be an argument for continuing lithium treatment during pregnancy for women with bipolar disorder?
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