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American Journal of Obstetrics and Gynecology (2004) 190, 218e21

Frequency of infant adverse events that are associatedwith citalopram use during breast-feeding

Amy Lee, MSc, Juliana Woo, BSc, Shinya Ito, MD*

Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, and the Departments of Pharmacologyand Pediatrics, University of Toronto, Toronto, Ontario, Canada

Received December 4, 2002; revised May 5, 2003; accepted June 21, 2003

––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––Objective: The purpose of this study was to determine the frequency of infantile adverse eventsfrom exposure through breast-feeding to maternal citalopram therapy.Study design: This was a prospective, observational cohort study. Women who were breast-feed-

ing were placed in three groups on the basis of citalopram use: group 1 consisted of 31 womenwho were depressed and were undergoing citalopram therapy, group 2 consisted of 12 womenwho were depressed but were not undergoing citalopram therapy, and group 3 consisted of

31 healthy women who were matched to group 1 by maternal age and parity. Data collection in-cluded infant feeding method, medication use, and adverse events.Results: There was no statistically significant difference in the rate of adverse events in the three

groups (3/31 events, 0/12 events, and 1/31 events in groups 1, 2, and 3, respectively). The averagedose of citalopram that was used in group 1 was 25.3G11.4 mg per day (range, 10-60 mg/d).Conclusion: To our knowledge, this is the first prospective, controlled study to examine the safety of

citalopram during breast-feeding, which should be continued during maternal citalopram therapy.� 2004 Elsevier Inc. All rights reserved.

KEY WORDSBreast-feedingAntidepressant

Citalopram

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Studies have demonstrated that citalopram is moreselective and specific than other antidepressants in itsclass.1 Because 10% to 15% of women have depressionin the postpartum period and may require antidepres-sants while breast-feeding, the safety of maternal citalo-pram use to the nursed infant becomes an issue.

Supported by a Restracomp Studentship, Hospital for Sick

Children, and a Connaught Scholarship, University of Toronto

(A. L.) and a Canadian Institutes of Health Research grant (S. I.).

* Reprint requests: Shinya Ito, MD, Division of Clinical

Pharmacology and Toxicology, Hospital for Sick Children, 555

University Ave, Toronto, ON M5G 18X.

E-mail: shinya.ito@sickkids.ca

0002-9378/$ - see front matter � 2004 Elsevier Inc. All rights reserved.

doi:10.1016/S0002-9378(03)00868-8

To date, four case reports and series have been pub-lished in the literature, with a total of 11 infants whowere exposed to maternal citalopram through breast-feeding.2-5 Reported milk-to-plasma ratios ranged from1.2 to 3.3, which indicates higher concentrations of thedrug in milk than in maternal plasma. Despite this,the amount of citalopram the infant would ingestthrough milk is small (approximately 5% of the mater-nal dose per body weight, although one investigatorfound levels of 9% in a woman who was receiving 60mg/d).6 One case of ‘‘uneasy sleep’’ was reported,5

whereas a recent study by Heikkinen et al7 on 11 infantswho were nursed by women who were receiving citalo-pram therapy and 10 infants who were not exposed tothe medication failed to note a difference in the rate ofadverse events in the two groups.

Lee, Woo, and Ito 219

Table Group demographics

Demographic Group 1 Group 2 Group 3 P value

n 31 12 31 dMaternal age (y)* 33.7G5.1 33.2G4.9 33.6G4.9 .95Parity (%) .991 11 (35.5) 5 (41.7) 11 (35.5)2 14 (45.2) 5 (41.7) 14 (45.2)R3 6 (19.4) 2 (17.7) 6 (19.4)

Education level above secondary (%) 25 (80.7) 11 (91.7) 29 (93.6) .27Marital status (%)Single 1 (3.2) 0 (0) 1 (3.2)Married 28 (90.3) 12 (100.0) 29 (93.6) .84Common law 2 (6.5) 0 (0) 1 (3.2)

Family income (%)!$40,000 4 (12.9) 0 (0) 1 (3.2) .11$40,000-59,999 12 (38.7) 4 (33.3) 5 (16.1)$60,000-79,999 11 (35.5) 4 (33.3) 13 (41.9)R$80,000 4 (12.9) 4 (33.3) 12 (38.7)

Gestational age (wk)* 39.1G1.9 39.3G1.6 39.5G1.5 .84Birth weight (kg)* 3.6G0.7 3.5G0.4 3.4G0.6 .34Age at follow-up (mo)* 16.3G10.8 13.2G6.7 11.2G9.2 .06Breast-feeding duration (mo)y 7.0 [4.0, 13.3] 8.0 [6.8, 11.0] 8.0 [4.0, 10.3] .88Age formula introduced (mo)* 5.2G3.2 4.7G2.6 5.4G4.0 .90

* Data are given as meanGSD.y Data given as median, interquartile range.

In the current study, we sought to determine the fre-quency of adverse events of infants nursed by womenwho are undergoing citalopram therapy.

Methods

The study was approved by the Institutional Ethics Re-view Board and conducted in the Motherisk Program atthe Hospital for Sick Children, Canada, which is a te-ratogen information service.8 The cases of women whocontacted the Motherisk program between January1999 and May 2001 regarding the safety of citalopramduring breast-feeding were followed up. Those womenwho were undergoing citalopram therapy while breast-feeding were placed in group 1. Those women whoopted not to use the drug (regardless of whether they de-cided on a different form of pharmacologic treatmentfor their depression) were placed in group 2 (disease-matched control subjects). A healthy control group ofwomen, who contacted the program regarding nontera-togenic exposures and short-term exposures that wereknown to be compatible with breast-feeding, were en-rolled in group 3. These were matched to their group 1counterparts by maternal age and parity.

Information concerning the following characteristicswas obtained during the telephone interviews: initialchoice of feeding method, source and nature of adviceon the feeding methods, duration of breast-feeding,

and demographic data such as annual family income,maternal and paternal education, and marital status.The women were also asked specifically about maternaladverse drug reactions (group 1 only) and any clinicalevents in the infants for which they may or may not havesought medical attention (all groups). All data were col-lected with the use of standardized questionnaires.9,10

Maternal reports of infant adverse events that requiredmedical attention were confirmed by direct contact withthe physicians’ offices.

Continuous data were analyzed with the use of one-way analysis of variance or Kruskal Wallis, where ap-propriate. Categoric data were analyzed with the useof c2 statistics.

Results

Of 43 women who inquired about citalopram safety dur-ing breast-feeding, 31 women breast-fed while undergo-ing the therapy (group 1) and 12 women breast-fed butdid not use citalopram, although 7 of 12 women were re-ceiving a different selective serotonin reuptake inhibitor(SSRI) (paroxetine, 3 women; sertraline, 2 women, andfluvoxamine and fluoxetine, 1 woman each; group 2).Thirty-one healthy breast-feeding women served as con-trol subjects (group 3). There were no statistically signif-icant differences among the three groups when maternaland infant demographics were compared (Table). The

220 Lee, Woo, and Ito

average dose of citalopram that was given to the womenin group 1 was 25.3G11.4 mg per day (range, 10-60 mg/d). The mean duration of infant exposure to citalopramthrough the breast milk at time of study was 4.8G3.9months. Twenty of the 31 women in group 1 were stillbreast-feeding while undergoing citalopram therapy atthe time of follow-up.

Three of 31 (9.7%) infants in group 1 were reportedby the mothers to have adverse events during breast-feeding (one case each of colic, decreased feeding, andirritability/restlessness). In the cases of colic and de-creased feeding, physician attention was sought, butthe symptoms were considered nonspecific and insignif-icant by the physicians and medical intervention was notrequired. In the other case of irritability and restlessness,the symptoms were noted after the mother commencedcitalopram therapy at 2 months after delivery. Althoughthe physical examination was unremarkable and nomedical intervention was needed, breast-feeding was dis-continued 2 weeks after the start of therapy, and thesymptoms in the infant subsided. No clinical event wasreported for the infants in group 2. One mother in group3 reported that the infant had ‘‘gassiness.’’ There was nostatistically significant difference in the frequency of in-fant clinical events among the groups. There was also nomaternal adverse event that was related to the therapy.

Comment

The current study failed to detect a statistically significantincrease in the risk of adverse events in infants who werenursed by women who were undergoing citalopram ther-apy. Although there is apparently a temporal relation be-tween the symptoms of one of the infants in group 1 andthe maternal use of the drug, the cause is unclear. In a re-cent cohort study, no difference was found in develop-ment at 1 year of age between 10 control infants and 11infants who were exposed to the drug in utero and post-natally through milk.7 In one case report, ‘‘uneasy sleep’’in the infant was attributed to the maternal drug.5

Infant exposure levels to citalopram in milk are usu-ally small because the maximal dose the infant would in-gest (estimated from the drug concentrations in milk) isapproximately 5% to 6% of the maternal dose ona weight-adjusted basis.3,4 This is comparable to theother SSRIs, with paroxetine being excreted at 0.7%to 3.4%,11-13 fluvoxamine at 0.8% to 1.4%,14 sertralineat 0.2% to 2.0%,15-17 and fluoxetine at 3.0% to10.8%.18-21 All these levels are !10% of the cutoffvalue that is viewed as the standard threshold of safety,with the exception of the one study that found levels offluoxetine to be 10.8%.21 Similar to other SSRIs, lowor undetectable levels of citalopram were measured inthe serum of infants who were nursed by women whowere undergoing citalopram therapy. Unless infant drug

eliminating capacity is extremely low, it is unlikely thatthe infant serum concentrations reach a therapeuticlevel.5 It is unknown, however, whether the pharmaco-dynamic effects of the drug in the infants are similarto those in adults.

On the basis of the existing data that include ourstudy and the known benefits of human milk, we suggestthat it is not necessary to discontinue breast-feedingwhile a mother is undergoing citalopram therapybecause serious side effects were not noted. Infants areexposed to minimal amounts of the drug through thebreast milk, and these levels do not appear to be ofclinical consequence. However, because the number ofexposed infants is still relatively small, infants shouldstill be monitored for possible side effects.

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