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Health surveillance data

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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
Study period:
1992
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Data not sufficient for evaluation. Epidemiological study with Li2CO3 used for read-across.
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Prospective multicentre study of pregnancy outcome after lithium exposure during first trimester
Author:
Jacobson, S.J. et al
Year:
1992

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:
Data from publication available.
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
Lithium carbonate
EC Number:
209-062-5
EC Name:
Lithium carbonate
Cas Number:
554-13-2
Molecular formula:
CH2O3.2Li
IUPAC Name:
dilithium carbonate
Details on test material:
The mean daily lithium dose was 927 (SD 340) mg, range 50-2400 mg.

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 during pregnancy were 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.

Results and discussion

Results:
Rates of major congenital malformations did not differ between Lithium and control groups. In this study no indication was seen that lithium carbonate may cause developmental/ teratogenic effects in humans.

Any other information on results incl. tables

10 of the 148 patients were lost to follow-up postnatally; however, they were included in part of the analysis because all had 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 did not differ between patients and controls with respect to the total number of livebirths, frequency of major anomalies, spontaneous or therapeutic abortions, ectopic pregnancy, and prematurity. Three major congenital malformations occurred in each group—2.8 % of livebirths in the lithium group and 2.4 % in controls. The 10 pregnancies for which final outcome was not known were not included in this part of the analysis. There were four sets of twins in the lithium group; one pair was born at 23 weeks' gestation and both infants died shortly after birth due to complications of prematurity. There was one set of twins in the control group.

2 children in the lithium group had neural-tube defects: 1 of these had hydrocephalus and meningomyelocele and had also been 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 23 weeks', dying shortly after birth. 1 fetus in the lithium group had a severe form of Ebstein's anomaly, which was diagnosed at 16 weeks' gestation, and this pregnancy was terminated. This fetus had also been exposed to fluoxetine, trazodone, and I.-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 livebirths 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).

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 I, Lithium-exposed infants weighed a mean of 92g more than controls (p=0.01) at birth. Gestational age and frequency of prematurity did not differ between the groups. Because all controls were enrolled in Toronto, we 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). There was no correlation between maternal lithium dose and birthweight. More women using lithium than controls were cigarette smokers (31.8 % vs 15.5 %; p = 0.002).

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.

Applicant's summary and conclusion

Conclusions:
Women with major affective disorders who wish to have children may continue lithium therapy, provided that adequate screening tests, including level 11 ultrasound and fetal echocardiography, are done.
Executive summary:

Lithium carbonate is an effective drug for prophylaxis and treatment of major affective disorders. In-utero exposure to lithium during the first trimester of pregnancy might be associated with an increased risk of cardiac malformations, especially the rare Ebstein's anomaly. 148 women (mean age 30 years, SD 5 range 15-40) using lithium during the first trimester of pregnancy were recruited and followed. The women consulted four teratogen information centres in the USA and Canada. Pregnancy outcome was compared with that of controls matched for maternal age. Complete follow-up of pregnancy outcome in 138 of 148 patients were recruited. In the other 10, fetal echocardiograms were available but postnatal follow-up was not done. Mean daily dose of lithium was 927 mg (SD 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. Birthweight was significantly higher in the lithium-exposed infants than in the controls despite identical gestational ages (3475 [660] g vs 3383 [566] g, p = 0.02). The true difference in birthweight might have been even larger, since significantly more women using lithium than controls were cigarette smokers {31.8% vs 15 .5%, p = 0.002).

Women with major affective disorders who wish to have children may continue lithium therapy, provided that adequate screening tests, including level 11 ultrasound and fetal echocardiography, are done.

In this study no indication was seen that Lithium carbonate may cause developmental/ teratogenic effects in humans.