Antidepressant
PREGNANCY RECOMMENDATION: Human Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity
PREGNANCY SUMMARY
Nortriptyline is a tricyclic antidepressant. The limited human pregnancy experience does not support a major association with congenital defects.
FETAL RISK SUMMARY
Limb reduction anomalies have been reported with nortriptyline (1,2). However, one of these children was not exposed until after the critical period for limb development (3). The second infant was also exposed to sulfamethizole and heavy cigarette smoking (1). Evaluation of data from 86 patients with 1st trimester exposure to amitriptyline, the active precursor of nortriptyline, does not support the drug as a major cause of congenital limb deformities (see Amitriptyline). Urinary retention in the neonate has been associated with maternal use of nortriptyline (4).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 61 newborns had been exposed to nortriptyline during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Two (3.3%) major birth defects were observed (two expected), both cardiovascular anomalies (0.5 expected).
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 (5). Multiple drug therapy occurred in about two-thirds of the mothers. There were four exposures to nortriptyline. The outcomes of these pregnancies were four normal newborns (one premature) without birth defects (5).
A 2002 prospective study compared two groups exposed to antidepressants throughout gestation, either to tricyclics (N = 46 including 3 to nortriptyline) or to fluoxetine (N = 40), with 36 nonexposed, not depressed controls (6). 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 (6).
BREASTFEEDING SUMMARY
Nortriptyline is excreted into breast milk in low concentrations (7–11). A milk level in one patient was 59 ng/mL, representing a milk:serum ratio of 0.7 (8). A second patient was treated with nortriptyline 100 mg daily during the 2nd and 3rd trimesters, and then stopped 2 weeks before an elective cesarean section (10). Treatment was restarted at 125 mg every night on the first postpartum day, then decreased to 75 mg nightly over the next 7 weeks. The mother was also receiving flupenthixol. Milk concentrations of nortriptyline, measured 11–13.5 hours after a dose on postpartum days 6 (four samples), 20 (two samples), and 48 (two samples), ranged from 90 to 404 ng/mL, mean 230 ng/mL. The milk:serum ratios for these samples ranged from 0.87 to 3.71 (mean 1.62). No effects of the drug exposure were observed in the nursing infant, who had normal motor development for the first 4 months. Infant serum concentrations were not determined (10).
Nortriptyline was not detected in the serum of other breastfed infants when their mothers were taking the drug (8,9,11); however, low levels (5–11 ng/mL) of the metabolite, 10-hydroxynortriptyline, were measured in the serum of two infants in one study (11). In this latter study, no evidence of accumulation in nursing infants after long-term (e.g., >50 days) maternal use of the antidepressant was observed (11). A 1996 review of antidepressant treatment during breastfeeding found no information that nortriptyline exposure during nursing resulted in quantifiable amounts of the parent compound in an infant or that the exposure caused adverse effects (12).
The significance of chronic exposure of the nursing infant to the antidepressant is unknown, but concern has been expressed about the effects of long-term exposure on the infant’s neurobehavioral mechanisms (10). The American Academy of Pediatrics classifies nortriptyline as a drug for which the effect on nursing infants is unknown but may be of concern (13).
References
1.Bourke GM. Antidepressant teratogenicity? Lancet 1974;1:98.
2.McBride WG. Limb deformities associated with iminobenzyl hydrochloride. Med J Aust 1972;1:492.
3.Australian Drug Evaluation Committee. Tricyclic antidepressants and limb reduction deformities. Med J Aust 1973;1:768–9.
4.Shearer WT, Schreiner RL, Marshall RE. Urinary retention in a neonate secondary to maternal ingestion of nortriptyline. J Pediatr 1972;81:570–2.
5.McElhatton PR, Garbis HM, Elefant E, Vial T, Bellemin B, Mastroiacovo P, Arnon J, Rodriguez-Pinilla E, Schaefer C, Pexieder T, Merlob P, Dal Verme S. The outcome of pregnancy in 689 women exposed to therapeutic doses of antidepressants. A collaborative study of the European Network of Teratology Information Services (ENTIS). Reprod Toxicol 1996;10:285–94.
6.Nulman I, Rovet J, Stewart DE, Wolpin J, Pace-Asciak P, Shuhaiber S, Koren G. Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: a prospective, controlled study. Am J Psychiatry 2002;159:1889–95.
7.Bader TF, Newman K. Amitriptyline in human breast milk and the nursing infant’s serum. Am J Psychiatry 1980;137:855–6.
8.Erickson SH, Smith GH, Heidrich F. Tricyclics and breast feeding. Am J Psychiatry 1979;136:1483.
9.Brixen-Rasmussen L, Halgrener J, Jorgensen A. Amitriptyline and nortriptyline excretion in human breast milk. Psychopharmacology (Berlin) 1982;76:94–5.
10.Matheson I, Skjaeraasen J. Milk concentrations of flupenthixol, nortriptyline and zuclopenthixol and between-breast differences in two patients. Eur J Clin Pharmacol 1988;35:217–20.
11.Wisner KL, Perel JM. Serum nortriptyline levels in nursing mothers and their infants. Am J Psychiatry 1991;148:1234–6.
12.Wisner KL, Perel JM, Findling RL. Antidepressant treatment during breast-feeding. Am J Psychiatry 1996;153:1132–7.
13.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.