Registration Dossier

Administrative data

Description of key information

Additional information

The developmental effects of lithium treatment during pregnancy were controversially discussed in the literature (Catalog of teratogenic agents, 13th edition, Shepard; 2010; Chemically induced birth defects, 3rd edition, Schardein, 2000) since the early 1970s. Publications of that time were mostly conducted in a retrospective design leading to biased results overestimating the risk of anomalies during pregnancy. A clear positive result with regard to major heart defects could never been shown or proven. Newer publications even qualify the fact of major heart defects by pointing out that the number of cases is small and the association of lithium treatment and major heart defects could be disproven in the future. It is therefore concluded that lithium compounds should not be regarded as reproductive toxicants also considering the evidence from animal test data (please refer to IUCLID section 7.8).

In 1968 an international register of lithium babies had been established merging Scandinavian, US American and Canadian registries which included cases of women who had been treated with lithium during the first trimester of pregnancy (Schou et al., 1973). The register was terminated in 1979 and by then contained information on 225 lithium babies. A follow up on 67 lithium babies revealed no increased frequency on mental or physical anomalies (Schou, M. 1976). Evaluation of the register data was performed by Schou in 1990. 11 % (25) of the lithium babies had visible malformations and 8 % (18) had cardiac anomalies including 6 cases of Ebstein anomaly (2.7%). Schou pointed out that from a scientific point of view “the numbers involved in the register are too small to provided definite proof of a teratogenic action of lithium in humans. If an association does in fact exist between Ebstein's anomaly and lithium, it is a weak one, and the risk of cardiovascular malformations is at most 5% to 10%.” Furthermore the information was collected retrospectively, and one must therefore expect an over-representation of abnormalities among the reports. A lithium baby is more likely to be recognized as such and reported to the Register if it is stillborn or malformed or dies soon after birth than if it is alive and normal in every respect. Little attention has been paid to drugs taken during the pregnancy by mothers of normal and healthy children, whereas the birth of an abnormal child almost certainly led to inquiries on this point. No appropriate control data further contribute to this estimate.

This was also observed by Cohen et al. (1994) who concluded that initial information in lithium teratogenicity has been derived from biased retrospective studies leading to an exaggeration on the risk of anomalies. In a prospective study 72 women were identified who were under lithium treatment and early in pregnancy (Cunniff et al., 1989). 50 women delivered live born infants. None of the children showed cardiovascular malformations suggesting that lithium is a not as teratogenic as believed from earlier studies and publications.

The effect of the source substance lithium carbonate was investigated in a prospective multicentre study of pregnancy outcome after lithium exposure during first trimester in pregnant women using lithium. The study showed that women with major affective disorders who wished to have children may continue lithium therapy, provided that adequate screening tests, including level 11 ultrasound and foetal echocardiography, are done (Jacobsen et al 1992).

Further studies on effects of lithium during pregnancy with ambiguous results (potential teratogenic target of lithium in humans: cardiovascular system) do not allow any conclusion with regard to the potential effects of lithium carbonate as all patients in this study were ill (manic depressive) and effects of confounding factors cannot be excluded. In addition, the cohort size was too small and bias effects are likely (Kallen and Tandberg (1983).

Possibly, cardiovascular malformations are specific to humans or to humans with coexisting psychiatric disorder (Giles and Bannigan 2006) but based on case-control studies, analysing cases of Ebstein's anomaly, also no clear conclusion could be drawn that lithium exposition during pregnancy is linked to an increased rate for Ebstein's anomaly (Zalzstein, E. et al, 1990, Correa-Villasenor, A. et al., 1994).

Warkany, J. (1988) referred to an unpublished analysis of 16 Ebstein anomaly cases and only one mother was identified by the investigating scientists (Shepard and van Allen) taking lithium. Kallen, B. (1988) expanded the published data of Warkany with information taken from the International Clearinghouse for Birth Defects Monitoring Systems. This was a joint case control study on infants with Ebstein anomaly or tricuspid atresia. Maternal drug use was identified in interviews or from prospectively collected information on drug use in early pregnancy. For the 25 cases of Ebstein anomaly no lithium exposure was detected. Additional information on 15 Ebstein cases in France did also not reveal any lithium exposure.

Shepard et al. (2002) further stated that the teratogenic findings have been observed by alert clinicians “who report rare defect syndromes in association with rare maternal treatments during pregnancy. The effective work of epidemiologists often using multiple centers has helped to make the associations more convincing. Despite existing evidence, however, the numbers are small and it is possible that future data could disprove the association."

Also in a study to quantify lithium exposure in nursing infants in 10 mother-infant pairs no serious adverse events were observed, and elevations of thyroid-stimulating hormone, blood urea nitrogen, and creatinine were few, minor, and transient and not considered of biological relevance (Viguera, A.C. et al., 2007).

Thus, an identification of the substance as reproductive toxicant (category 1A being equivalent to GHS statement H360: May damage fertility or the unborn child) as under GHS Japan system cannot be confirmed.
The data sources that are cited by the GHS Japan are

I. ACGIH (2001), identified by the lead registrant as publication of Schou, M (1990) and addressed in IUCLID section 7.10.1.

II. Book: Chemically Induced Birth Defects" (Birth Defects 3rd (2000)), identified by the lead registrant as Schardein 2000 (According to the article lithium carbonate is identified as developmental toxic under California Proposition 65 (1998) whereas the author states that the rationale for addition of chemical is not clearly "understood" (sufficient or limited evidence, animal or human).  The discussed data are of 1970 (Chapter 1, part VII).

III. Book: "Catalog of Teratogenic Agents" (Teratogenic 12th (2007)). The lead registrant refers to Catalog of teratogenic agents, 13th edition, Shepard, 2010 (compilation of studies with contradictory outcomes).

The lead registrant added some more literature sources (see above) in the course of this update in May 2018 to substantiate the statement that the developmental effects of lithium treatment during pregnancy are controversially discussed in the literature. In particular old studies and reports are considered exaggerated today as applied statistics, reporting, etc. were deficient and lead to over presentation of adverse effects.

Conclusion

Taking all available information together classification with respect to teratogenicity / developmental toxicity is not justified. Lithium is not a potent animal teratogen (please refer to IUCLID section 7.8) and available publications on lithium treatment during early pregnancy of humans do not give relevant statistical results with respect to adverse developmental effects.