Effects of Antimanic Mood-Stabilizing Drugs on Fetuses, Neonates, and Nursing Infants

Mohammad Masud Iqbal, MD, MPH, MSPH, DTM; Sai Prakash Gundlapalli, MD, William G. Ryan, MD, Thad Ryals, MD, Birmingham, Ala; Terry E. Passman, MD, Department of Psychiatry and Behavioral Neurobiology, the Regional Neonatal Intensive Care Unit, and the Department of Epidemiology and International Health, University of Alabama at Birmingham School of Medicine; and the Harbor Unit, Thomas Hospital, Fairhope, Ala

South Med J. 2001;94(3) 

In This Article

Lithium

Risk to Fetus

In Animals. Ample evidence indicates that lithium crosses the placenta freely.[34,35,36,37,38] Reproductive studies in rats and mice given doses higher than those recommended for humans have shown teratogenic effects such as cleft palate and anomalies of heart, external ear, eye, and skeletal system.[35] Fetotoxic effects such as increased perinatal mortality, decreased number and weight of the litters,[36] decrease in the number of living offspring,[37] and embryotoxic effects[38] are also noted. Differing results have been found in the offspring of rats, mice, rabbits, and monkeys exposed in utero to lithium.[37]

In Humans. Numerous studies have noted an association between first trimester administration of lithium carbonate and incidence of cardiovascular malformations such as Ebstein's anomaly in the neonates.[39,40,41] The International Register of Lithium Babies was started in 1968 to assess this potential teratogenicity of lithium in humans.[42] As of 1980, 225 infants who had been exposed to lithium during the first 3 months of prenatal life or longer were included in the register. Among these, 18 infants had the rare Ebstein's anomaly (6 cases) and other anomalies of the cardiovascular system (12 cases); 7 were stillborn; 2 had Down syndrome; and 1 had intracerebral toxoplasmosis. The data from the register suggest an incidence rate of 0.1% for Ebstein's anomaly, which is approximately 20 times the risk in the general population. Another report of data from 1970 to 1985 details nine cases of Ebstein's anomaly in the United States out of an estimated 9,000 exposures.[39] Therefore, it appears that risk of fetal malformation, especially pertaining to the cardiovascular system, is increased by first trimester lithium administration.[43]

A number of other abnormalities have also been reported. Kallen and Tandberg[44] conducted a cohort study of 350 women with manic-depressive disease. They found a non-significant trend toward higher risks of perinatal mortality and congenital malformations among pregnancies in which lithium had been used in the first trimester, and an increase in cardiac defects in particular, but none with Ebstein's anomaly. In a nested, case-control study observing congenital heart defects in children, Kallen[45] reported that 3 (27%) of the cases and 4 (20%) of the controls (N = 20) were exposed to lithium in utero. Among these cases, a single child, who was not exposed to lithium, had Ebstein's anomaly. This study showed a statistically insignificant association between prenatal exposure to lithium and congenital heart defects. Similarly, several other studies have found that lithium has been safely used during pregnancy by many patients, suggesting a lack of association between cardiovascular anomalies and prenatal lithium.[46,47,48]

Lithium is also known to impair the synthesis and release of thyroid hormones and subsequently increase the pituitary secretion of thyroid-stimulating hormone by its inhibitory action on adenosine triphosphatase activity and cyclic adenosine monophosphate.[49] Many studies have reported nontoxic goiters in both mothers treated with lithium during pregnancy and their infants.[50,51,52] This may result in a difficult vaginal delivery for the mother, may necessitate a cesarean section, or may impair respiration in the neonate after delivery.

Many authors have reported lithium toxicity, characterized by shallow respiration, muscle flaccidity, hypotonia, absent Moro's reflex, lethargy, cyanosis, and poor suck and grasp reflexes in neonates born to women who received toxic or therapeutic doses of lithium salts near term or during labor. These toxicities may take up to 10 days to resolve.[53,54,55] Other adverse effects reported in the neonate include atrial flutter,[56] functional tricuspid regurgitation, congestive heart failure,[51] and nephrogenic diabetes insipidus, which may persist for 2 months postnatally.[57]

A study of 241 infants from the Lithium Registry observed an association between maternal treatment with lithium carbonate during gestation and the occurrence of premature delivery (39%), macrosomia (36%), and perinatal mortality (8.3%) in newborns.[58] A statistically significant association was noted between higher dosages of lithium during the first trimester and premature deliveries, with a significantly higher rate of macrosomia in these premature infants.

In contrast to those findings, Rosa[59] described a study of 229,101 completed pregnancies (1985 to 1992); of the 62 newborns exposed to lithium during the first trimester of pregnancy, only 2 had birth defects. The data gathered from this study do not support an association between the drug and congenital malformations. Isolated cases of other congenital anomalies in newborns exposed to lithium in utero appear in the literature have included malformed right external auditory canal and meatus,[60] bilateral clubfoot, lumbar meningomyelocele,[61] polyhydramnios,  deep-seated ears, bilateral agenesis of kidneys, and a septal defect with transposition of the great vessels.[62]

In summary, because of the risk of teratogenicity, especially with regard to the cardiovascular system, lithium should be avoided during the period of organogenesis and if possible throughout pregnancy. A dosage that had been increased during pregnancy must be immediately reduced at delivery, or the mother will have a toxic condition, since lithium clearance increases by 50% to 100% early in pregnancy and returns to normal at delivery. Alternative drugs that have less teratogenic effects on the fetus should be used. When the use of lithium is unavoidable, the risk of teratogenicity can be minimized by monotherapy with the lowest effective dose for the shortest duration, use of a sustained-release preparation of lithium,[63] careful monitoring of lithium levels, close collaboration with the obstetrician, and screening for anomalies using ultrasonography and fetal echocardiography between 16 and 18 weeks of gestation.

Risk to Infant During Breast-Feeding

Lithium has been found consistently in both breast milk and infants' serum. Lithium concentrations in breast milk have been reported to be approximately 40% (range, 24% to 72%) of the mothers' serum concentrations.[34,64,65]

We found three case reports of nursing infants who had adverse events that were attributed to lithium.[55,65,66] The first case, reported by Tunnessen and Hertz,[66] described cyanosis, hypotonia, heart murmur, T-wave changes on electrocardiography, lethargy, and hypothermia in a nursing infant whose mother received lithium (600 to 1,200 mg/day) while nursing. No lithium levels were reported until day 5, when the baby had a cyanotic episode. At that time, the infant's serum level and the breast milk level of lithium (0.6 mEq/L) were within the therapeutic range, and the mother had a serum lithium level of 1.5 mEq/L. The baby's condition was completely normal by day 8. This type of toxicity is more likely to occur during episodes of dehydration and infection and may be due to a combination of high maternal serum levels while nursing and the residual lithium concentration from birth.[65,66] Similar findings were also reported in two other studies.[67] On the basis of these reports, nursing by mothers taking lithium should be either partially or totally discontinued because of the immature excretory systems in the infants, particularly during an infant's illness or infection, or when maternal serum lithium levels are high. However, if lithium is to be used, collaboration with a pediatrician is essential, and the risk-benefit ratio must be discussed with mother and her partner.

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