Risk Factor: D
Class: Central nervous system drugs/ Tranquilizers
Fetal Risk Summary
Lithium is used for the treatment of manic episodes of manic-depressive illness. The drug is available as either lithium carbonate or lithium citrate.
The use of lithium during the 1st trimester may be related to an increased incidence of congenital defects, particularly of the cardiovascular system. A 1987 review of psychotherapeutic drugs in pregnancy evaluated several reproduction studies of lithium in animals, including mice, rats, rabbits, and monkeys, and observed no teratogenicity except in rats (1).
Lithium freely crosses the placenta, equilibrating between maternal and cord serum (1,2,3,4,5 and 6). Amniotic fluid concentrations exceed cord serum levels (3).
Frequent reports have described the fetal effects of lithium, the majority from data accumulated by the Lithium Baby Register (1,2,7,8,9,10,11,12,13,14 and 15). The Register, founded in Denmark in 1968 and later expanded internationally, collects data on known cases of 1st trimester exposure to lithium. By 1977, the Register included 183 infants, 20 (11%) with major congenital anomalies (13). Of the 20 malformed infants, 15 involved cardiovascular defects, including 5 with the rare Ebstein’s anomaly. Others have also noted the increased incidence of Ebstein’s anomaly in lithium-exposed babies (16). Two new case reports bring the total number of infants with cardiovascular defects to 17, or 77% (17 of 22) of the known malformed children (17,18). Ebstein’s anomaly has been diagnosed in the fetus during the 2nd trimester by echocardiography (19). Details on 16 of the malformed infants are given below.
Author Case No.
Defect Weinstein and Goldfield (12) 1 Coarctation of aorta 2 High intraventricular septal defect 3 Stenosis of aqueduct with hydrocephalus, spina bifida with sacral meningo-myelocele, bilateral talipes equinovarus with paralysis; atonic bladder, patulous rectal sphincter and rectal prolapse (see also Reference 7) 4 Unilateral microtia 5 Mitral atresia, rudimentary left ventricle without inlet or outlet, aorta and pulmonary artery arising from right ventricle, patent ductus arteriosus, left superior vena cava 6 Mitral atresia 7 Ebstein’s anomaly 8 Single umbilical artery, bilateral hypoplasia of maxilla Author Case No.
Defect 9 Ebstein’s anomaly
The fetal toxicity of lithium, particularly in regards to cardiac abnormalities and the Ebstein anomaly, was discussed in two 1988 References (21,22). As an indication of the rarity of Ebstein’s anomaly, only approximately 300 cases of the defect have been recorded in the literature since Ebstein first described it approximately 100 years ago (21). One author concluded that the majority of tricuspid valve malformations, such as Ebstein’s anomaly, are not related to drug therapy and, thus, the association between lithium and Ebstein’s anomaly is weak (22).
A 1996 case report described multiple anomalies in an aborted male fetus of a woman treated with lithium carbonate monotherapy for a schizodepressive disorder (23). Maternal plasma levels before pregnancy varied between 0.580.73 mmol/L, but were not determined during gestation. Following diagnosis of multiple defects, the pregnancy was terminated at 22 weeks. The findings in the fetus were deep-seated ears, clubfeet, bilateral agenesis of the kidneys (Potter’s syndrome), and a septal defect with transposition of the great vessels (23). In addition, the placenta had portions that were poorly vascularized and villi of different sizes. A causal association in this case between lithium and the defects cannot be determined. Moreover, Potter’s syndrome is thought to be a genetic defect (24).
A prospective study published in 1992 gathered data from four teratogen information centers in Canada and the United States on lithium exposure in pregnancy (25). A total of 148 pregnant women using lithium (mean daily dose 927 mg) during the 1st trimester were matched by age with 148 controls. Ten women using lithium were lost to postnatal follow-up, but information was available on the fetal echocardiograms performed. The number of live births in the two groups were 76% (105/138) and 83% (123/148), respectively. One stillbirth, in the exposed group, was observed. Other outcomes (figures based on 148 women in each group) included spontaneous abortion (9% vs. 8%), therapeutic abortion (10% vs. 6%), and ectopic pregnancy (1 case vs. 0 case). None of these differences were statistically significant. However, the birthweight of lithium-exposed infants was significantly higher than that of controls, 3475 g vs. 3383 g, p=0.02), even though significantly more of their mothers smoked cigarettes than did controls (31.8% vs. 15.5%, p=0.002). Three exposed infants and three controls had congenital malformations. The defects observed after lithium exposure were two infants with neural tube defects (hydrocephalus and meningomyelocelealso exposed to carbamazepine during the 1st trimester; spina bifida and tethered cord) and one with meromelia who was delivered at 23 weeks’ gestation and died shortly after birth. Defects in the offspring of control mothers were a ventricular septal defect (one), congenital hip dislocation (one), and cerebral palsy and torticollis (one). In addition to the above cases, one of the therapeutic abortions in the lithium group was a pregnancy terminated at 16 weeks’ gestation for a severe form of Ebstein’s anomaly. The mother had also taken fluoxetine, trazodone, and L-thyroxine in the 1st trimester. Ebstein’s anomaly has an incidence of 1 in 20,000 in the general population (25); thus, the appearance of this case is consistent with an increased risk for the heart defect among infants of women using lithium. However, a larger sample size is still needed to define the actual magnitude of the risk. The investigators concluded that lithium is not an important human teratogen and that, because it is beneficial in the therapy of major affective disorders, women may continue the drug during pregnancy. They cautioned, however, that adequate screening tests, including level II ultrasound and fetal echocardiography, were required when lithium is used during gestation (25).
A 1994 Reference evaluated the teratogenic risk of 1st trimester exposure to lithium and summarized the treatment recommendations for lithium use in women with bipolar disorder (26). Included in their assessment were four case-controlled studies in which no cases of Ebstein’s anomaly occurred among 207 lithium-exposed pregnancies as compared with 2 cases of the defects among 398 nonexposed controls. These data led them to the conclusion that the risk of teratogenicity after 1st trimester exposure to lithium was lower than previously reported (26). Reaching a similar conclusion, another review, published in 1995, concluded that the risk of teratogenicity with lithium was low in women with carefully controlled therapy, but that therapy should probably be avoided during the period of cardiac organogenesis (2nd4th month of pregnancy) (27).
Concerning nonteratogenic effects, lithium toxicity in the fetus and newborn has been reported frequently: Cyanosis (3,17,28,29,30,31 and 32,38) Hypotonia (3,11,28,29,30,31,32,33,34 and 35,38) Bradycardia (17,29,32,34,36,38) Thyroid depression with goiter (3,11,35) Atrial flutter (37) Hepatomegaly (32,38) Electrocardiogram abnormalities (T-wave inversion) (29,36) Cardiomegaly (30,32,37,38) Gastrointestinal bleeding (36) Diabetes insipidus (3,32,38,39) Polyhydramnios (38,39) Seizures (38) Shock (32) Most of these toxic effects are self-limiting, returning to normal in 12 weeks. This corresponds with the renal elimination of lithium from the infant. The serum half-life of lithium in newborns is prolonged, averaging 6896 hours, as compared with the adult value of 1020 hours (4,17). Two of the reported cases of nephrogenic diabetes insipidus persisted for 2 months or longer (3,32).
Premature labor, loss of fetal cardiac variability and acceleration, an unusual fetal heart rate pattern (double phase baseline), and depression at birth (Apgar scores of 4 and 7 at 1 and 5 minutes, respectively) were observed in a comatose mother and her infant after an acute overdose of an unknown amount of lithium and haloperidol at 31 weeks’ gestation (40). Because of progressive premature labor, the female, 1526-g infant was delivered about 3 days after the overdose. The lithium concentrations of the maternal plasma, amniotic fluid, and cord vein plasma were all greater than 4 mmol/L (severe toxic effect >2.5 mmol/L), while the maternal level of haloperidol at delivery was about 1.6 ng/mL (40). The effects observed in the fetus and newborn were attributed to cardiac and cerebral manifestations of lithium intoxication. No follow-up on the infant was reported.
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 62 newborns had been exposed to lithium during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Two (3.2%) major birth defects were observed (three expected), one of which was a polydactyly (0.2 expected). No anomalies were observed in five other categories of defects (cardiovascular defects, oral clefts, spina bifida, limb reduction defects, and hypospadias) for which specific data were available.
Fetal red blood cell choline levels are elevated during maternal therapy with lithium (41). The clinical significance of this effect on choline, the metabolic precursor to acetylcholine, is unknown but may be related to the teratogenicity of lithium because of its effect on cellular lithium transport (41). In an in vitro study, lithium had no effect on human sperm motility (42).
A review published in 1995 used a unique system to assess the reproductive toxicity of lithium in animals and humans (43). Following an extensive evaluation of the available literature, for both experimental animals and humans, up through the early 1990’s, a committee concluded that lithium, at concentrations within the human therapeutic range, could induce major malformations (particularly cardiac) and may be associated with neonatal toxicity. The evaluation included an assessment of human reproductive toxicity from lithium exposure in food, mineral supplements, swimming pools and spas, and drinking water, as well as from other environmental or occupational exposures. Because a linear relationship between lithium and toxicity was assumed, these exposures, which produce concentrations of lithium well below therapeutic levels, were not thought to produce human toxicity (43).
In the mother, renal lithium clearance rises during pregnancy, returning to pre-pregnancy levels shortly after delivery (44). In four patients, the mean clearance before delivery was 29 mL/minute, declining to 15 mL/minute 67 weeks after delivery, a statistically significant difference (p
In summary, lithium should be avoided during pregnancy if possible, especially during the period of organogenesis. In those cases in which 1st trimester use is unavoidable, adequate screening tests, including level II ultrasound and fetal echocardiography (e.g., at 1820 weeks’ gestation ), should be performed (25,26,45). Serum levels should also be monitored. Use of the drug near term may produce severe toxicity in the newborn, which is usually reversible. The long-term effects of in utero lithium exposure on postnatal development are unknown but warrant investigation.
Breast Feeding Summary
Lithium is excreted into breast milk (6,29,46,47 and 48). Milk levels are approximately 40%50% of the maternal serum concentration (29,47,48). Infant serum and milk levels are approximately equal. Although no toxic effects in the nursing infant have been reported, long-term effects from this exposure have not been studied. The American Academy of Pediatrics considers lithium to be contraindicated during breast feeding because of the potential for lithium-induced toxicity in the nursing infant (49).
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