TOPICAL
PAPERS:
Cardiovascular BY
MORTON
Drug
Side
Malformations R. WEINSTEIN,
M.D.,
Effects
with AND
MICHAEL
Lithium D. GOLDFIELD,
The 143 cases oflithium use during pregnancy collected by the Register ofLithium Babies show that infants exposed to lithium appear to have a higher than expected ratio ofcardiovascular anomalies to all anomalies and may have an increased risk ofcongenital heart disease. The authors believe that thesefindingsjustify a conservative policy on the use oflithium with fertile and pregnant women.
IN COLLABORATION WITH colleagues in Denmark and Canada, we have for several years been soliciting information about infants exposed to lithium carbonate in utero. A total of I 50 such reports have now been received; of these, 143 met the following criteria and have been incorporated into the Register of Lithium Babies: 1) lithium ingestion by the mother at least some time during the first trimester of pregnancy, and 2) the availability of the infant or fetus or sufficient fetal tissue to permit identification ofsignificant anomalies. Through a series of reports ( 1 -6), the register has been brought
to
the
attention
of
those
likely
to encounter
The authors are with the Department of Psychiatry, University of California, San Francisco, Calif. 94143, where Dr. Weinstein is Associate Professor in Residence and Dr. Goldfield is Assistant Clinical Professor. Dr. Weinstein is also Senior Psychiatrist, Langley Porter Neuropsychiatric Institute, San Francisco, Calif. This work was supported by Langley Porter General Research Support grant FR 72-6 and by grants from Smith Kline & French Laboratories and the J.B. Roerig Division of Pfizer Pharmaceuticals.
The papers
in this section this material
are grouped to constitute
around
a specific
a comprehensive
During
Pregnancy
M.D.
Several articles have described the work of the register since its inception (3, 6, 7). These earlier reports acknowledgcd that data gathered by a register of this kind could not generate reliable information about the incidence of anomalies in infants exposed to lithium. However, they noted that a register could give early warning if the alarming frequency (30 to 60 percent) of fetal anomalies and maternal and fetal deaths reported in rodents cxposed in utero to lithium also occurred in human fetuses exposed to the drug (8, 9). It became reassuringly clear early in the work of the register that this was not the case, but on the basis of earlier analyses of material in the register we recommended a conservative approach to the use of lithium in fertile women, discontinuation of lithium in the first trimester if possible, and avoidance of breastfeeding by lithium-treated mothers (5, 7). However, we did not believe the evidence then at hand warranted tcrmination of pregnancy because of lithium exposure alone, and we did not feel that lithium treatment should always be interrupted when a pregnancy occurred.
INCIDENCE
“lithium babies.” Also, all hospitals with AMA-approved obstetrical and pediatric internships and residencies were contacted twice in the last two years with information about the register and forms for reporting lithium babies to it. Each hospital department was also asked to designate a staff member to serve as liaison with the register.
tors consider
Use
OF
CARDIOVASCULAR
ABNORMALITIES
However, recent additions to the register have supported the view that there is an unexpectedly high proportion of major cardiovascular abnormalities among the malformed infants reported. The characteristics of the malformed lithium babies arc presented in table 1, which shows that there are 13 malformed infants among the 143 in the register (9.1 percent). Two of these babies (subjects 3 and 4) had anomalies of the central nervous system and of the external ears, respectively. The 11 other infants were born with significant malformations of the cardiovascular system (7.7 percent of all register entries and 85 percent of all of the malformed infants). Of the 11 with cardiovascular anomalies, 10 had major abnormalities of the heart and great
topic. analysis
Publication
here
does
not,
however,
imply
that
the Edi-
of the topic.
Am
J Psychiatry
132.5.
May
1975
529
MALFORMATIONS
WITH
TABLE I Data on Malformed
Infants
Birth Date
Subject
LITHIUM
From
Other During
USE
the Register
ofLithium
Drugs Used Pregnancy
Babies
Sex
Weight
Type
I
3/9/69
-
Female
2
5/22/69
-
Male
6 lbs.
2 oz.
3
8/23/69
Chlorpromazine, diuretics
Female
6 lbs.
13 oz.
4
9/28/69
None
Male
7 lbs.
I I oz.
5
1/30/71
Nortriptyline, diazepam
Female
5 lbs.
6 oz.
6
2/
7 8
2/23/71 9/28/71
Haloperidol. barbiturates, None
9 10 II 12
2/22/72 5/23/72 I I /8/72 1/18/73
13
6/30/74
*The **The
mother mother
--/71
was was
nortriptyline, and others
Coarctation
-
-
-
Female Male
6 lbs. 4 lbs.
I I oz. 13 oz.
Amitriptyline None None* Nortriptyline**
Female Female Female Female
7 4 7 7
8 13 0 8
Trifluoperazine
Female
8 lbs.
-
lbs. lbs. lbs. lbs.
14 oz.
Am
ofthe
aorta
High intraventricular septal defect Stenosis ofaqueduct with hydrocephalus, spina bifida with sacral meningomyelocele, bilateral talipes equinovarus with paralysis Unilateral microtia
Mitral atresia, rudimentary left ventricle without inlet or outlet, aorta and pulmonary artery arising from right ventricle, patent ductus arteriosus, left superior vena cava Mitral atresia Ebstein’s anomaly Single umbilical artery, bilateral hypoplasia of maxilla Ebstein’s anomaly Atresia oftricuspid valve Ebstein’s anomaly Patent ductus arteriosus, ventricular septal defect Ebstein’s anomaly
Child’s Malformation with surgery Died on day
Source of Report
Fate corrected
U.S.A.
4
U.S.A.
-
Canada
Developing normally age 3, apart from the malformed ear Died on day 5
at
Died soon after corrective surgery Died a few days after birth Died 5 hours after birth
Died I day Stillborn Survived report
after
birth
3 months -
as of
Denmark
U.S.A.
U.S.A. U.S.A. Canada
Denmark Denmark U.S.A. England U.S.A.
a ‘gestational diabetic.” 39 at time of pregnancy.
vessels, and the other (subject 8) had a single umbilical artery. Information about the use of other drugs during pregnancy was available for 10 of the 13 malformed infants; 6 of these had been exposed to medications other than lithium, and in another instance (subject 1 1) the mother had “gestational diabetes.” It is especially noteworthy that 4 cases of Ebstein’s anomaly (subjects 7, 9, 1 1, and 13) have been reported to the register (10, 1 1). This rare malformation (10, 12) consists of a distorted and displaced tricuspid valve, with secondary abnormalitics of the right ventricle and atrium. Atrial septal defect or patent foramcn ovale may also be present. Reports to a register such as this will tend to cxaggerate pathology, and data gathered in this way do not permit inferences or conclusions about the true incidence of any pathological state in the reporting population. However, the ratios among kinds or classes of pathology in the register should be similar to the corresponding ratios in the reporting population, and studies of general as well as selected populations of neonates consistently show that major anomalies of the cardiovascular system reprcsent a minority of all nontrivial congenital anomalies (13-16).
530
oz. oz. oz. oz.
of Malformation
J Psychiatry
132:5.
May
1975
Synthesized data from several studies in which infants were examined carefully at birth and during the first week of life (I 3- 17) indicate that the incidence of all nontrivial anomalies in such infants is about 30 per 1,000 births; the incidence of congenital heart disease is about 4 per 1,000 births; the incidence oftricuspid atresia is about .09 per 1,000 births; and the incidence of Ebstein’s anomaly is about .05 per 1,000 births. Overall, therefore, the ratio of Ebstein’s anomaly to all nontrivial anomalies is about 1:600, the ratio of Ebstein’s anomaly to all forms ofcongenital heart disease is about 1:80, and the ratio of congenital heart disease to all nontrivial malformations isabout
1:8.
In contrast, in the Register of Lithium Babies the ratio of Ebstein’s anomaly to all reported nontrivial anomalies is 1:3.3, the ratio of Ebstein’s anomaly to all forms of congenital heart disease is 1:2.5, and the ratio of congenital heart disease to all nontrivial malformations is 1: 1.3. In the register the ratio of malformations ofthc incuspid valve/tricuspid atresia (subjects 7, 9, 10, 1 1, and 13) to all cardiac anomalies is about 1:2, while the ratio of tricuspid atresia to all congenital heart defects in baseline studies (12, 14-16) is about 1:44 (see table 2).
MORTON
TABLE 2 Ratios Between
Various
R. WEINSTEIN
AND
ens our earlier recommendations posure of pregnant or potentially
Malformations
MICHAEL
D. GOLDFIELD
for caution pregnant
in the women
cxto
lithium. Expected (10-17)
Register of Lithium Babies
Malformations
REFERENCES Ebstein’s anomaly to all nontrivial anomalies Ebstein’s anomaly to all forms of congenital heart disease Malformations of the tricuspid valve/tricuspid atresia to all forms of congenital heart disease All forms of congenital heart disease to all nontrivial anomalies
1:3.3
1:600
1:2.5
1:80
1:2.0
1:44
1: 1 .3
1:8
DISCUSSION
We cannot say with certainty that congenital cardiovascular anomalies occur in infants exposed to lithium more often than in nonexposed infants, but it seems very likely that they do. The alternatives to this conclusion arc to assume 1 ) that abnormal babies arc more assiduously reported than are normal babies and that dramatic abnormalities (such as Ebstein’s anomaly) arc reported more completely than are less impressive defects, 2) that exposure to lithium protects the fetus against malformations other than those of a cardiovascular nature, or 3) that there is an association between manic-depressive illness and cardiovascular anomalies independent of lithium exposure. The first of these possibilities is very likely true and is discussed elsewhere (6, 7). The other two possibilities merit investigation. Meanwhile, we believe that the apparent overrepresentation
among
malformed
of
important
lithium
cardiovascular
babies
confirms
anomalies
and
strength-
1. Weinstein M, Goldfield M: Lithium carbonate treatment during pregnancy: report ofa case. J Nerv Ment Dis 30:828-832, 1969 2. Weinstein MR. Goldfield MD: Lithium ion toxicity and pregnancy (ltr to ed). JAMA 214:1325, 1970 3. Goldfield M, Weinstein M: Lithium in pregnancy: a review with recommendations. Am J Psychiatry 127:888-893, 1971 4. Weinstein MR, Goldfield MD: Wanted: reports of lithium babies. Pediatrics48:161-l62, 1971 5. Goldfield MD, Weinstein MR: Lithium carbonate in obstetrics: guidelines for clinical use. Am J Obstet Gynecol I 16: 15-22, 1973 6. Schou M, Goldfield MD, Weinstein MR. et al: Lithium and pregnancy-I, report from the Register of Lithium Babies. Br Med J 2: 135-136, 1973 7. Weinstein MR. Goldfield MD: Pharmacology-lithium teratology, in Lithium: Its Role in Psychiatric Research and Treatment. Edited by Gershon 5, Shopsin B. New York, Plenum Press, 1973, pp 147- 166 8. Szabo KT: Teratogenic effect of lithium carbonate in the foetal mouse. Nature 225:73-75, 1970 9. Szabo KT, Hawk AM, Henry M: The teratogenic effect of lithium carbonate upon the palate of random-bred mice. Toxicol AppI Pharmacol 17:274-275, 1970 10. Nora JJ, Nora AH, Toews WH: Lithium, Ebstein’s anomaly and other congenital heart defects. Lancet 2:594-595, 1974 I 1. Nora JJ: Personal communication, Oct 3, 1974 12. Van den berg B: Personal communication, Oct 23, 1974 13. Yerushalmy J, Milkovich L: Evaluation of the teratogenic effect of meclizine in man. Am J Obstet Gynecol 93:553-562, 1965 14. Leck I, Record RG, McKeown T, et al: The incidence of malformations in Birmingham, England, 1950-1959. Teratology 1:263-280, 1968 15. Hoffman JIE: Natural history of congenital heart disease: problems in its assessment with special reference to ventricular septal defects. Circulation 37:97-125, 1968 16. Mitchell SC, Korones SB, Berendes HW: Congenital heart disease in 56,109 births: incidence and natural history. Circulation 43:323332, 1971 17. Apgar V, Stickle G: Birth defects. JAMA 204:371-374, 1968
A mJ
Psychiatry
/32:5.
May
1975
531
PAPERS:
Cardiovascular BY
MORTON
Drug
Side
Malformations R. WEINSTEIN,
M.D.,
Effects
with AND
MICHAEL
Lithium D. GOLDFIELD,
The 143 cases oflithium use during pregnancy collected by the Register ofLithium Babies show that infants exposed to lithium appear to have a higher than expected ratio ofcardiovascular anomalies to all anomalies and may have an increased risk ofcongenital heart disease. The authors believe that thesefindingsjustify a conservative policy on the use oflithium with fertile and pregnant women.
IN COLLABORATION WITH colleagues in Denmark and Canada, we have for several years been soliciting information about infants exposed to lithium carbonate in utero. A total of I 50 such reports have now been received; of these, 143 met the following criteria and have been incorporated into the Register of Lithium Babies: 1) lithium ingestion by the mother at least some time during the first trimester of pregnancy, and 2) the availability of the infant or fetus or sufficient fetal tissue to permit identification ofsignificant anomalies. Through a series of reports ( 1 -6), the register has been brought
to
the
attention
of
those
likely
to encounter
The authors are with the Department of Psychiatry, University of California, San Francisco, Calif. 94143, where Dr. Weinstein is Associate Professor in Residence and Dr. Goldfield is Assistant Clinical Professor. Dr. Weinstein is also Senior Psychiatrist, Langley Porter Neuropsychiatric Institute, San Francisco, Calif. This work was supported by Langley Porter General Research Support grant FR 72-6 and by grants from Smith Kline & French Laboratories and the J.B. Roerig Division of Pfizer Pharmaceuticals.
The papers
in this section this material
are grouped to constitute
around
a specific
a comprehensive
During
Pregnancy
M.D.
Several articles have described the work of the register since its inception (3, 6, 7). These earlier reports acknowledgcd that data gathered by a register of this kind could not generate reliable information about the incidence of anomalies in infants exposed to lithium. However, they noted that a register could give early warning if the alarming frequency (30 to 60 percent) of fetal anomalies and maternal and fetal deaths reported in rodents cxposed in utero to lithium also occurred in human fetuses exposed to the drug (8, 9). It became reassuringly clear early in the work of the register that this was not the case, but on the basis of earlier analyses of material in the register we recommended a conservative approach to the use of lithium in fertile women, discontinuation of lithium in the first trimester if possible, and avoidance of breastfeeding by lithium-treated mothers (5, 7). However, we did not believe the evidence then at hand warranted tcrmination of pregnancy because of lithium exposure alone, and we did not feel that lithium treatment should always be interrupted when a pregnancy occurred.
INCIDENCE
“lithium babies.” Also, all hospitals with AMA-approved obstetrical and pediatric internships and residencies were contacted twice in the last two years with information about the register and forms for reporting lithium babies to it. Each hospital department was also asked to designate a staff member to serve as liaison with the register.
tors consider
Use
OF
CARDIOVASCULAR
ABNORMALITIES
However, recent additions to the register have supported the view that there is an unexpectedly high proportion of major cardiovascular abnormalities among the malformed infants reported. The characteristics of the malformed lithium babies arc presented in table 1, which shows that there are 13 malformed infants among the 143 in the register (9.1 percent). Two of these babies (subjects 3 and 4) had anomalies of the central nervous system and of the external ears, respectively. The 11 other infants were born with significant malformations of the cardiovascular system (7.7 percent of all register entries and 85 percent of all of the malformed infants). Of the 11 with cardiovascular anomalies, 10 had major abnormalities of the heart and great
topic. analysis
Publication
here
does
not,
however,
imply
that
the Edi-
of the topic.
Am
J Psychiatry
132.5.
May
1975
529
MALFORMATIONS
WITH
TABLE I Data on Malformed
Infants
Birth Date
Subject
LITHIUM
From
Other During
USE
the Register
ofLithium
Drugs Used Pregnancy
Babies
Sex
Weight
Type
I
3/9/69
-
Female
2
5/22/69
-
Male
6 lbs.
2 oz.
3
8/23/69
Chlorpromazine, diuretics
Female
6 lbs.
13 oz.
4
9/28/69
None
Male
7 lbs.
I I oz.
5
1/30/71
Nortriptyline, diazepam
Female
5 lbs.
6 oz.
6
2/
7 8
2/23/71 9/28/71
Haloperidol. barbiturates, None
9 10 II 12
2/22/72 5/23/72 I I /8/72 1/18/73
13
6/30/74
*The **The
mother mother
--/71
was was
nortriptyline, and others
Coarctation
-
-
-
Female Male
6 lbs. 4 lbs.
I I oz. 13 oz.
Amitriptyline None None* Nortriptyline**
Female Female Female Female
7 4 7 7
8 13 0 8
Trifluoperazine
Female
8 lbs.
-
lbs. lbs. lbs. lbs.
14 oz.
Am
ofthe
aorta
High intraventricular septal defect Stenosis ofaqueduct with hydrocephalus, spina bifida with sacral meningomyelocele, bilateral talipes equinovarus with paralysis Unilateral microtia
Mitral atresia, rudimentary left ventricle without inlet or outlet, aorta and pulmonary artery arising from right ventricle, patent ductus arteriosus, left superior vena cava Mitral atresia Ebstein’s anomaly Single umbilical artery, bilateral hypoplasia of maxilla Ebstein’s anomaly Atresia oftricuspid valve Ebstein’s anomaly Patent ductus arteriosus, ventricular septal defect Ebstein’s anomaly
Child’s Malformation with surgery Died on day
Source of Report
Fate corrected
U.S.A.
4
U.S.A.
-
Canada
Developing normally age 3, apart from the malformed ear Died on day 5
at
Died soon after corrective surgery Died a few days after birth Died 5 hours after birth
Died I day Stillborn Survived report
after
birth
3 months -
as of
Denmark
U.S.A.
U.S.A. U.S.A. Canada
Denmark Denmark U.S.A. England U.S.A.
a ‘gestational diabetic.” 39 at time of pregnancy.
vessels, and the other (subject 8) had a single umbilical artery. Information about the use of other drugs during pregnancy was available for 10 of the 13 malformed infants; 6 of these had been exposed to medications other than lithium, and in another instance (subject 1 1) the mother had “gestational diabetes.” It is especially noteworthy that 4 cases of Ebstein’s anomaly (subjects 7, 9, 1 1, and 13) have been reported to the register (10, 1 1). This rare malformation (10, 12) consists of a distorted and displaced tricuspid valve, with secondary abnormalitics of the right ventricle and atrium. Atrial septal defect or patent foramcn ovale may also be present. Reports to a register such as this will tend to cxaggerate pathology, and data gathered in this way do not permit inferences or conclusions about the true incidence of any pathological state in the reporting population. However, the ratios among kinds or classes of pathology in the register should be similar to the corresponding ratios in the reporting population, and studies of general as well as selected populations of neonates consistently show that major anomalies of the cardiovascular system reprcsent a minority of all nontrivial congenital anomalies (13-16).
530
oz. oz. oz. oz.
of Malformation
J Psychiatry
132:5.
May
1975
Synthesized data from several studies in which infants were examined carefully at birth and during the first week of life (I 3- 17) indicate that the incidence of all nontrivial anomalies in such infants is about 30 per 1,000 births; the incidence of congenital heart disease is about 4 per 1,000 births; the incidence oftricuspid atresia is about .09 per 1,000 births; and the incidence of Ebstein’s anomaly is about .05 per 1,000 births. Overall, therefore, the ratio of Ebstein’s anomaly to all nontrivial anomalies is about 1:600, the ratio of Ebstein’s anomaly to all forms ofcongenital heart disease is about 1:80, and the ratio of congenital heart disease to all nontrivial malformations isabout
1:8.
In contrast, in the Register of Lithium Babies the ratio of Ebstein’s anomaly to all reported nontrivial anomalies is 1:3.3, the ratio of Ebstein’s anomaly to all forms of congenital heart disease is 1:2.5, and the ratio of congenital heart disease to all nontrivial malformations is 1: 1.3. In the register the ratio of malformations ofthc incuspid valve/tricuspid atresia (subjects 7, 9, 10, 1 1, and 13) to all cardiac anomalies is about 1:2, while the ratio of tricuspid atresia to all congenital heart defects in baseline studies (12, 14-16) is about 1:44 (see table 2).
MORTON
TABLE 2 Ratios Between
Various
R. WEINSTEIN
AND
ens our earlier recommendations posure of pregnant or potentially
Malformations
MICHAEL
D. GOLDFIELD
for caution pregnant
in the women
cxto
lithium. Expected (10-17)
Register of Lithium Babies
Malformations
REFERENCES Ebstein’s anomaly to all nontrivial anomalies Ebstein’s anomaly to all forms of congenital heart disease Malformations of the tricuspid valve/tricuspid atresia to all forms of congenital heart disease All forms of congenital heart disease to all nontrivial anomalies
1:3.3
1:600
1:2.5
1:80
1:2.0
1:44
1: 1 .3
1:8
DISCUSSION
We cannot say with certainty that congenital cardiovascular anomalies occur in infants exposed to lithium more often than in nonexposed infants, but it seems very likely that they do. The alternatives to this conclusion arc to assume 1 ) that abnormal babies arc more assiduously reported than are normal babies and that dramatic abnormalities (such as Ebstein’s anomaly) arc reported more completely than are less impressive defects, 2) that exposure to lithium protects the fetus against malformations other than those of a cardiovascular nature, or 3) that there is an association between manic-depressive illness and cardiovascular anomalies independent of lithium exposure. The first of these possibilities is very likely true and is discussed elsewhere (6, 7). The other two possibilities merit investigation. Meanwhile, we believe that the apparent overrepresentation
among
malformed
of
important
lithium
cardiovascular
babies
confirms
anomalies
and
strength-
1. Weinstein M, Goldfield M: Lithium carbonate treatment during pregnancy: report ofa case. J Nerv Ment Dis 30:828-832, 1969 2. Weinstein MR. Goldfield MD: Lithium ion toxicity and pregnancy (ltr to ed). JAMA 214:1325, 1970 3. Goldfield M, Weinstein M: Lithium in pregnancy: a review with recommendations. Am J Psychiatry 127:888-893, 1971 4. Weinstein MR, Goldfield MD: Wanted: reports of lithium babies. Pediatrics48:161-l62, 1971 5. Goldfield MD, Weinstein MR: Lithium carbonate in obstetrics: guidelines for clinical use. Am J Obstet Gynecol I 16: 15-22, 1973 6. Schou M, Goldfield MD, Weinstein MR. et al: Lithium and pregnancy-I, report from the Register of Lithium Babies. Br Med J 2: 135-136, 1973 7. Weinstein MR. Goldfield MD: Pharmacology-lithium teratology, in Lithium: Its Role in Psychiatric Research and Treatment. Edited by Gershon 5, Shopsin B. New York, Plenum Press, 1973, pp 147- 166 8. Szabo KT: Teratogenic effect of lithium carbonate in the foetal mouse. Nature 225:73-75, 1970 9. Szabo KT, Hawk AM, Henry M: The teratogenic effect of lithium carbonate upon the palate of random-bred mice. Toxicol AppI Pharmacol 17:274-275, 1970 10. Nora JJ, Nora AH, Toews WH: Lithium, Ebstein’s anomaly and other congenital heart defects. Lancet 2:594-595, 1974 I 1. Nora JJ: Personal communication, Oct 3, 1974 12. Van den berg B: Personal communication, Oct 23, 1974 13. Yerushalmy J, Milkovich L: Evaluation of the teratogenic effect of meclizine in man. Am J Obstet Gynecol 93:553-562, 1965 14. Leck I, Record RG, McKeown T, et al: The incidence of malformations in Birmingham, England, 1950-1959. Teratology 1:263-280, 1968 15. Hoffman JIE: Natural history of congenital heart disease: problems in its assessment with special reference to ventricular septal defects. Circulation 37:97-125, 1968 16. Mitchell SC, Korones SB, Berendes HW: Congenital heart disease in 56,109 births: incidence and natural history. Circulation 43:323332, 1971 17. Apgar V, Stickle G: Birth defects. JAMA 204:371-374, 1968
A mJ
Psychiatry
/32:5.
May
1975
531
