Lithium dodecyl sulphate

Health surveillance data

Administrative data

Endpoint:

health surveillance data

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study is deemed to be acceptable for assessment of lithium toxicity during pregnancy in humans.

Data source

Reference

Reference Type:

publication

Title:

Prospective multicentre study of pregnancy outcome after lithium exposure during first trimester.

Author:

Jacobson, S.J.

Year:

1992

Bibliographic source:

The Lancet 1992, 339, 530-33

Materials and methods

Study type:

medical monitoring

Endpoint addressed:

developmental toxicity / teratogenicity

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

148 women who called one of four teratogen information services to obtain information about the potential risks of therapeutic drugs and who reported lithium ingestion during part or all of their first trimester were prospectively enrolled. Outcome of pregnancy and reaching of developmental milestones of new borns were assessed after birth.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Lithium carbonate

EC Number:

209-062-5

EC Name:

Lithium carbonate

Cas Number:

554-13-2

IUPAC Name:

dilithium carbonate

Method

Type of population:

other: pregnant women

Ethical approval:

not specified

Details on study design:

148 women who called one of four teratogen information services to obtain information about the potential risks of therapeutic drugs and who reported lithium ingestion during part or all of their first trimester were prospectively enrolled. These centres were Motherisk Toronto, the California Teratogen Information Service (CTIS) San Diego, the Philadelphia Pregnancy Healthline, and Foetal Risk Assessment from Maternal Exposure (FRAME) London, Ontario. Lithium exposures as early as 3 weeks’ gestation were included. Information about drugs or other chemicals taken during or before pregnancy, including indication, dose, toxicity of the drug and its toxic effects, and monitoring were obtained. A medical and obstetric history was also elicited, as was occupational exposures and family history. After delivery a follow-up history of the pregnancy obtained pregnancy outcome, perinatal complications, birthweight, physical findings, and reaching developmental milestones. This was done either per telephone, by a physician in the clinic or by both. In addition, the physician caring for the baby was contacted to confirm this information and to provide a written report of the delivery and health status of the child.
Echocardiography at week 18 of gestation was offered to rule out cardiac anomalies. In cases prenatal echocardiography had not been done, infants were referred for postnatal echocardiographs. Pregnant women seeking advice about drugs that are not known or suspected to be teratogenic at the Motherisk clinic were matched with a woman of similar age (to within 2 years) and served as controls.

Results and discussion

Results:

10 of the 148 women were lost to follow-up postnatal; however, they were included in part of the analysis because all of the 10 women had prenatal echocardiography. A total of 68 patients had echocardiographs (46%). Maternal age ranged from 15 to 40 years (mean 30, SD 5 years). All patients were receiving lithium for major affective disorders. The mean daily lithium dose was 927 (SD 340) mg, range 50-2400 mg.
Pregnancy outcome:
Pregnancy outcome did not differ significantly between patients and controls with respect to the total number of live births, frequency of major anomalies, spontaneous or therapeutic abortions, ectopic pregnancy, and prematurity.
Malformations:
Three major congenital malformations occurred in each group corresponding to2.8 % of live births in the lithium group and 2.4 % in the control group. 2 children in the lithium group had neural-tube defects: 1 of these had hydrocephalus and meningomyelocele. The mother of this child was also exposed to carbamazepine during the first trimester. The other had spina bifida and tethered cord. A 3rd infant (one of a twin) had meromelia, and was born at week 23 weeks, dying shortly after birth. 1 fetus in the lithium group had a severe form of Ebstein's anomaly, which was diagnosed at week 16 week of gestation. This pregnancy was terminated. This fetus had also been exposed to fluoxetine, trazodone, and L-thyroxine in the first trimester. In the controls, 1 child had a ventricular septal defect, 1 had congential hip dislocation, and 1 had cerebral palsy and torticollis.
The risk ratio for all congenital defects was 1.2 (95 % confidence interval 0.2-5.7) when only live births were compared. When the case of Ebstein's anomaly was included (since this pregnancy would probably have gone to term if the anomaly had not been detected) the risk ratio became 1.5 (0.4-6.7). The risk ratio for cardiac anomalies was 1.1 (0.1-16.6) and for Ebstein's anomaly was 3.5 (0.1-84.9).
Mean body weight at birth:
The mean age at which postnatal follow-up was done in the lithium-exposed group was 61 (SD 87.5) weeks (range 1 week to 9 years ). Mean body weight at birth was 92 g higher in Lithium-exposed infants (p=0.01). Gestational age and frequency of prematurity did not differ between the groups. All controls were enrolled in Toronto. Therefore, it was examined whether the difference in birthweight was related to geographic factors in the various study groups. However, when the Motherisk data were analysed separately, the difference in birthweight persisted and remained significant (p=0.018). Although the mean birth weight was increased no correlation between maternal lithium dose and birthweight was observed. More women using lithium than controls were cigarette smokers (31.8 % vs 15.5 %; p = 0.002).
Developmental Milestones:
Data on attainment of major developmental milestones (smiling, lifting head, sitting, crawling, standing, talking, and walking) were available for 21 lithium-exposed patients enrolled by Motherisk and 1 patient enrolled by FRAME. Study and control groups did not differ in age of attainment of any of the milestones.

Any other information on results incl. tables

In medicine, lithium carbonate is used for prophylaxis and treatment of major affective disorders. In-utero exposure to lithium during the first trimester of pregnancy has been reported to be propably associated with an increased risk of cardiac malformations, especially the rare Ebstein's anomaly. 148 women with an mean age of 30 y ± 5 (range 15-40) using lithium carbonate during the first trimester of pregnancy were recruited prospectively and followed. Pregnancy outcome was compared with that of controls matched for maternal age. Mean daily dose of lithium was 927 mg ± 340. Rates of major congenital malformations did not differ between the lithium (2 .8%) and control (2 .4%) groups. 1 patient in the lithium group chose to terminate pregnancy after Ebstein's anomaly was detected by a prenatal echocardiogram. There was 1 ventricular septal defect in the controls. Birth weight was significantly higher in the lithium-exposed infants than in the controls.

One heart anomaly within the lithium group was observed. This was found to be the Ebstein's anomaly. Nevertheless also in the control group one heart anomaly was observed. Therefore, there is no clear indication that lithium carbonate causes developmental/teratogenic effects in humans. However, data do not allow excluding an association between lithium and Ebsteins anomalies, even though there was no difference in the number of anomalies between the lithium and control groups.