Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 215-183-4
CAS number: 1310-65-2
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
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
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.
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.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
Welcome to the ECHA website. This site is not fully supported in Internet Explorer 7 (and earlier versions). Please upgrade your Internet Explorer to a newer version.
Do not show this message again