Antidepressant
PREGNANCY RECOMMENDATION: Human Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity
PREGNANCY SUMMARY
Although occasional reports have associated the therapeutic use of amitriptyline with congenital malformations, the bulk of the evidence indicates that these widely used drugs are relatively safe during pregnancy. The single case of gross overdose is suggestive of an association between amitriptyline, perphenazine, or both, and malformations, but without confirming evidence no conclusions can be determined. Because of the experience with tricyclic antidepressants, one review recommended that they were preferred during gestation over other antidepressants (1).
FETAL RISK SUMMARY
Two reviews found reports of amitriptyline-induced teratogenicity in animals: encephaloceles and bent tails in hamsters (2) and skeletal malformations in rats (1). However, reproduction studies conducted by the manufacturer in mice, rats, or rabbits with oral doses up to 13 times the maximum recommended human dose revealed no evidence of teratogenicity (3). The manufacturer does cite the teratogenicity of amitriptyline in mice, hamsters, rats, and rabbits when higher doses were used (3).
The manufacturer states that amitriptyline crosses the placenta (3). The relatively low molecular weight (approximately 314) is consistent with this finding.
In humans, limb reduction anomalies have been reported with amitriptyline (4,5). However, analysis of 522,630 births, 86 with 1st trimester exposure to amitriptyline, did not confirm an association with this defect (6–13). Reported malformations other than limb reduction defects after therapeutic dosing included: micrognathia, anomalous right mandible, left pes equinovarus (1 case); swelling of hands and feet (1 case); hypospadias (1 case); and bilateral anophthalmia (1 case) (8,12–14).
A case of maternal suicide attempt with a combination of amitriptyline (725 mg) and perphenazine (58 mg) at 8 days’ gestation was described in a 1980 abstract (15). An infant was eventually delivered with multiple congenital defects. The abnormalities included microcephaly, “cotton-like” hair with pronounced shedding, cleft palate, micrognathia, ambiguous genitalia, foot deformities, and undetectable dermal ridges (15).
Thanatophoric dwarfism was found in a stillborn infant exposed throughout gestation to amitriptyline (>150 mg/day), phenytoin (200 mg/day), and phenobarbital (300 mg/day) (16). The cause of the malformation could not be determined, but both drug and genetic etiologies were considered.
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 467 newborns had been exposed to amitriptyline during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 25 (5.4%) major birth defects were observed (20 expected). Specific data were available for six defect categories, including (observed/expected) 6/5 cardiovascular defects, 0/1 oral clefts, 0/0 spina bifida, 2/1 polydactyly, 2/1 limb reduction defects, and 1/1 hypospadias. These data do not support an association between the drug and the defects.
In a 1996 descriptive case series, the European Network of the Teratology Information Services (ENTIS) prospectively examined the outcomes of 689 pregnancies exposed to antidepressants (17). Multiple drug therapy occurred in about two-thirds of the mothers. Amitriptyline (118 exposures; one set of twins) was the second most commonly used tricyclic antidepressant. The outcomes of these pregnancies were 18 elective abortions, 10 spontaneous abortions, 2 stillbirths, 79 normal newborns (including 7 premature infants), 5 normal infants with neonatal disorders, 4 infants with congenital defects, and 1 premature infant with other complications. The defects (all exposed in the 1st trimester or longer) were small ventricular septal defect; single palmar crease and small palpebral fissure; facial microangioma and right hydrocele (exposed also to clobazam, as well as diphtheria, tetanus, and typhoid vaccines); and facial muscle asymmetry and glucose-6-phosphate dehydrogenase (G6PD) deficiency (exposed also to clonazepam and oxazepam) (17).
Neonatal withdrawal after in utero exposure to other antidepressants (see Imipramine), but not with amitriptyline, has been reported. However, the potential for this complication exists because of the close similarity among these compounds. Urinary retention in the neonate has been associated with maternal use of nortriptyline, an amitriptyline metabolite (see Nortriptyline) (18).
A 2002 prospective study compared two groups of mother–child pairs exposed to antidepressants throughout gestation (46 exposed to tricyclics—18 to amitriptyline; 40 to fluoxetine) to 36 nonexposed, not depressed controls (19). Offspring were studied between the ages 15 and 71 months for effects of antidepressant exposure in terms of IQ, language, behavior, and temperament. Exposure to antidepressants did not adversely affect the measured parameters, but IQ was significantly and negatively associated with the duration of depression, and language was negatively associated with the number of depression episodes after delivery (19).
BREASTFEEDING SUMMARY
Amitriptyline and its active metabolites are excreted into breast milk (20–24). A recent study has measured the amount of a second active metabolite, E-10-hydroxynortriptyline, in milk (23).
Serum and milk concentrations of amitriptyline in one patient were 0.14 and 0.15 mcg/mL, respectively, a milk:plasma ratio of 1.0 (20). No drug was detected in the infant’s serum. In another patient, it was estimated that the baby received about 1% of the mother’s dose (22). No clinical signs of drug activity were observed in the infant.
In another study, the mother was treated with 175 mg/day of amitriptyline (23). Milk and maternal serum samples were analyzed for active drug and active metabolites on postpartum days 1–26. Amitriptyline serum levels ranged from 24 (day 1) to 71 ng/mL (days 3–26), whereas those in the milk ranged from 24 ng/mL (day 1) to only 54% of the serum levels on days 2–26. Nortriptyline serum levels ranged from 17 (day 1) to 87 ng/mL (day 26) with milk levels 74% of those in the serum. Mean concentration of the second metabolite, E-10-hydroxynortriptyline, was 127 ng/mL (days 1–26) in the serum and 70% of that in the milk. The total dose (parent drug plus metabolites) consumed by the male infant on day 26 was estimated to be 35 mcg/kg (80 times lower than the mother’s dose). The compounds were not detected in the nursing infant’s serum on day 26 and no adverse effects, including sedation, were observed in him (23).
Ten nursing infants of mothers taking antidepressants (two with amitriptyline 100–175 mg/day) were compared with 15 bottle-fed infants of mothers with depression who did not breastfeed (24). Concentrations of clomipramine in fore- and hind-milk were 30 ng/mL (one patient) and 113 and 197 ng/mL (two patients), respectively. The milk:maternal plasma ratios were 0.2 and 0.9, respectively. One infant had a plasma level of 7.5 ng/mL when the mother was taking 100 mg/day. No toxic effects or delays in development were observed in the infants. The estimated daily dose consumed by the infants was about 1% of the mother’s weight-adjusted dose (24).
A 1996 review of antidepressant treatment during breastfeeding found no information that amitriptyline exposure of the infant during nursing caused adverse effects (25).
Although amitriptyline and its metabolite have not been detected in infant serum, the effects of exposure to small amounts in the milk are unknown (26). The American Academy of Pediatrics classifies amitriptyline as a drug whose effect on the nursing infant is unknown but may be of concern (27).
References
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18.Shearer WT, Schreiner RL, Marshall RE. Urinary retention in a neonate secondary to maternal ingestion of nortriptyline. J Pediatr 1972;81:570–2.
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27.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.