Perinatal Outcome Following Third Trimester Exposure To Paroxetine

ARTICLE

Perinatal Outcome Following Third Trimester
Exposure to Paroxetine
Adriana Moldovan Costei, MD; Eran Kozer, MD; Tommy Ho, MD, FRCPC;
Shinya Ito, MD; Gideon Koren, MD, FRCPC

Background: Paroxetine hydrochloride is commonly women using paroxetine during the first or second tri-
used for maternal depression, panic disorder, and obses- mester and 27 women using nonteratogenic drugs were
sive-compulsive disorder. The drug readily crosses the matched for maternal age, gravity, parity, social drug use,
human placenta. Although it does not appear to in- and nonteratogenic drug use.
crease teratogenic risk, there have been case reports of
neonatal withdrawal. Symptoms were described soon af- Results: Of the 55 neonates exposed to paroxetine in
ter birth and lasted up to 1 month. late gestation, 12 had complications necessitating inten-
sive treatment and prolonged hospitalization. The most
Objective: To investigate whether there is a clinically prevalent clinical picture was respiratory distress (n=9),
important discontinuation syndrome in neonates ex- followed by hypoglycemia (n=2), and jaundice (n=1).
posed to paroxetine in utero. The symptoms disappeared within 1 to 2 weeks. In the
comparison group, only 3 infants experienced compli-
Methods: Prospective, controlled cohort study. cations (P = .03). In logistic regression, only third-
trimester exposure to paroxetine was associated with neo-
Patients: Fifty-five pregnant women counseled pro- natal distress (odds ratio, 9.53; 95% confidence interval,
spectively by the Motherisk program in Toronto, On- 1.14-79.3).
tario, regarding third-trimester exposure to paroxetine
and their infants were included in the study group. Preg- Conclusion: When used near term, paroxetine is asso-
nant women who discontinued paroxetine before the third ciated with a high rate of neonatal complications, pos-
trimester or those receiving other drugs known to cause sibly caused by its common discontinuation syndrome.
withdrawal-type symptoms, such as opioids or benzodi-
azepines, were excluded. A comparison group of 27 Arch Pediatr Adolesc Med. 2002;156:1129-1132

P
AROXETINE HYDROCHLORIDE plasma ratio ranging from 0.056 to 1.3, and
(Paxil; GlaxoSmithKline, the maximal daily dosage taken up by the
Research Triangle Park, NC) infant is estimated at 0.34% of the mater-
is commonly used for maternal dosage per kilogram of body weight.5-8
nal depression, panic disor- The objective of the present study was
der, and obsessive-compulsive disorder in to compare the perinatal outcome of in-
pregnant women. Although the drug does fants exposed in utero to paroxetine with
not appear to cause major congenital mal- that of healthy controls and infants ex-
formations,1 its perinatal safety when used posed to the drug only during the first and
in late gestation has not been estab- second trimesters of pregnancy.
lished. The drug readily crosses the hu-
man placenta and has a mean elimina- METHODS
tion half-life of 21 hours.
There have been recently several neo- The Motherisk program provides counseling
natal case reports of symptoms associ- for women and their health care providers on
ated with maternal use of paroxetine,2-4 in- the risk or safety of drugs and chemicals dur-
ing pregnancy and lactation. Presently, we are
cluding irritability, jitteriness, constant
From the Motherisk program, counseling as many as 200 patients a day. Be-
Division of Clinical
crying, shivering, eating or sleeping diffi- tween September 1996 and September 1999,
Pharmacology/Toxicology, culties, gastrointestinal symptoms, and sei- we followed all pregnant women who called
the Hospital for Sick Children, zures. These symptoms were described the Motherisk program about paroxetine ex-
and the University of Toronto, soon after birth and lasted up to 1 month posure during the third trimester of preg-
Toronto, Ontario. after birth. Paroxetine has a reported milk- nancy. These women were prospectively fol-

(REPRINTED) ARCH PEDIATR ADOLESC MED/ VOL 156, NOV 2002 WWW.ARCHPEDIATRICS.COM
1129
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between the study and control groups (P .10) or those that
Table 1. Maternal Characteristics* might confound the relationship between other variables and
respiratory distress were included in a multivariate analysis. Vari-
Paroxetine Hydrochloride ables were retained in the multivariate analysis if they met the
Exposure in the significance level of P .05 or if they changed the point of es-
Third Trimester timate of another variable by more than 10%.
Comparison
Cases Group† P RESULTS
Characteristic (n = 55) (n = 54) Value
Of 291 pregnant women who were counseled by the
Maternal age, mean, y 32.9 32.4 .82
Gravidity
Motherisk program about paroxetine use, 55 met the in-
1 19 (35) 18 (33) clusion criterion, being exposed to the drug during the
.95
1 36 (65) 36 (67) third trimester. They used paroxetine for depression (31
Parity‡ women [56%]), anxiety (17 women [31%]), anxiety and
0 24 (44) 23 (43) depression (7 women [13%]), and panic attacks (5 women
1 22 (40) 19 (35) .94 [9%]) (some patients had more than 1 indication). The
2 7 (13) 9 (17)
Social drug use
daily dosage ranged from 10 mg to 60 mg (mean, 23 mg;
Alcohol 4 (7) 9 (17) .12 median, 20 mg).
Smoking 14 (26) 5 (9) .05 The maternal characteristics of the 2 groups are sum-
marized in Table 1. The infants in the 2 comparison sub-
*Data are presented as the number (percentage) of subjects unless groups did not differ in any characteristic and therefore
otherwise indicated. were combined for the sake of comparison with the study
†Comparison group included 27 women who used paroxetine only during
the first and/or second trimesters and 27 women who used nonteratogenic group.
drugs. Of the 55 infants exposed to paroxetine during the
‡Some women had parity higher than 2. third trimester of pregnancy, 12 experienced neonatal
complications that necessitated prolonged hospitaliza-
lowed up by telephone calls after delivery. The interview
tions (Table 2). The most prevalent clinical picture was
addressed the course of pregnancy, delivery, and the neonatal respiratory distress (n = 9), followed by hypoglycemia
period, including malformations, developmental milestones, nu- (n=2) and jaundice (n=1). None of the infants had pneu-
trition, etc. Interviewers did not make any suggestions about monia, cardiac malformation, respiratory distress syn-
potential adverse outcomes. The protocol of the interview has drome, sepsis, or other causes of respiratory distress. In
been previously outlined in detail.9 contrast, only 3 infants in the comparison group had neo-
The inclusion criterion was exposure to paroxetine natal complications (2 infants with paroxetine expo-
throughout the third trimester. Pregnant women who discon- sure in trimesters 1 and 2 had respiratory distress and
tinued paroxetine before the third trimester or those receiving meconium aspiration, respectively; 1 of the nonterato-
other drugs known to cause withdrawal-type symptoms, such genic controls had jaundice). The rate of neonatal com-
as opioids, benzodiazepines, barbiturates, or heavy use of etha-
nol, were excluded from the study. At the time of counseling,
plications among neonates exposed to paroxetine in the
we collected data on reproductive and medical history, de- third trimester (22%) was significantly higher than among
tailed exposure data, and information on all other drugs used controls (6%) (P=.03). In the study group, there was a
concomitantly. Details about cigarette, alcohol, and recre- significantly higher rate of prematurity (20% vs 3.7%;
ational drug use were also collected. After delivery, partici- P =.02) (Table 3).
pants were contacted again to record the pregnancy outcome In the third-trimester paroxetine exposure group,
and neonatal complications, including withdrawal symptoms 36 women breastfed and continued taking paroxetine af-
and breastfeeding. ter delivery. During breastfeeding, 8 women reported
For each case, we chose a control mother-child pair from symptoms in their infants, including alertness (n=6), con-
the same prospective cohort and matched them for maternal stipation (n=3), sleepiness (n=1), and irritability (n=1).
age, gravity, parity, social drug use (alcohol and smoking), and
nonteratogenic drug use (eg, acetaminophen, vitamins, and cal-
In the comparison group, 44 babies were breastfed, and
cium supplements). Two comparison groups were chosen. The none of the mothers reported adverse neonatal effects,
first group included women counseled by Motherisk about ges- (P=.001).
tational use of paroxetine only during the first and second tri- The following variables were initially included in a
mesters (1-week to 6-months gestational age; median age, backward logistic stepwise regression model: prematu-
6 weeks). Daily dosage of paroxetine hydrochloride ranged from rity, maternal smoking, cesarean delivery, and exposure
10 mg to 40 mg, with a median of 20 mg. The second group to paroxetine in the third trimester (Table 4). The only
included women counseled by Motherisk about first- factor retained in the model and found to be associated
trimester exposure to nonteratogenic agents (eg, acetamino- with respiratory distress in the newborn was exposure
phen or dental x-rays). to paroxetine in the third trimester (odds ratio, 9.53; 95%
Data were analyzed with Statistical Product and Service
Solutions software for Windows, version 10 (SPSS Inc, Chi-
confidence interval, 1.14-79.30).
cago, Ill). Descriptive statistics were used to summarize demo-
graphic data. The 2 test was used to compare categorical vari- COMMENT
ables, and the t test or Mann-Whitney test, as appropriate, was
used for continuous variables. Backward stepwise logistic re- Paroxetine discontinuation symptoms have been re-
gression was used to identify factors that could affect the rates ported at a rate of 0.3 per 1000 perscriptions.10 This may
of respiratory distress. Variables found to differ significantly be partly due to the relatively high potency of parox-

1130

Table 2. Complications Among Neonates Exposed to Paroxetine in the Third Trimester and the Comparison Groups*

Patient No. Complication Relevant Details
Paroxetine Hydrochloride Third Trimester Group (n = 55)
4 Bradycardia Term, septic workup was negative, echocardiogram, computed tomographic
scan, 4-d hospitalization, no diagnosis
5 Respiratory distress Term, no sepsis, 1-wk hospitalization
9 Hypoglycemia Term, no sepsis
15 Respiratory distress, jaundice Preterm, intubation, phototherapy, 10-d hospitalization
20 Respiratory distress Term, placenta previa, bleeding, cesarean delivery, 2-wk hospitalization
21 Suckling problems Term, 2-wk hospitalization, no diagnosis
25 Respiratory distress Term, intubation
33 Respiratory distress, hypoglycemia Preterm, problems resolved in first few hours
35 Respiratory distress, tachycardia Preterm, 1 day in intensive care unit for respiratory distress
36 Respiratory distress Term
Paroxetine First and Second Trimesters Group (n = 27)
18 Respiratory distress first few hours ...
29 Meconium aspiration, intubation ...
Nonteratogenic Drugs Group (n = 27)
56 Jaundice ...

*Ellipses indicate not applicable.

Table 3. Pregnancy Outcome* Table 4. Univariate Analysis of the Association
Between Risk Determinants for Respiratory Distress
Paroxetine Hydrochloride in the Study Group
Exposure in the
Third Trimester Odds Ratio
Variable (95% Confidence Interval)
Comparison
Cases Group† P Maternal smoking
Variable (n = 55) (n = 54) Value No smoking 1.00 (Reference)
Smoking 2.22 (0.52-9.52)
Gestational age
Maternal use of paroxetine hydrochloride
Term 42 (76) 35 (65) .33
in the third trimester
Preterm 11 (20) 2 (4) .02
Did not use paroxetine 1.00 (Reference)
Postterm 2 (4) 17 (32) .001
Used paroxetine 10.35 (1.27-84.67)
Birth weight, mean ±SD, g 3394 ± 650 3578 ± 464 .09
Gestational age, wk
Sex
37 1.00 (Reference)
Female 24 (44) 28 (52)
.45 37 3.81 (0.85-17.13)
Male 31 (56) 26 (48)
Mode of delivery
Major malformation 0 0
Vaginal 1.00 (Reference)
Breastfed 36 (65) 44 (81) .85
Cesarean 0.92 (0.18-4.65)

*Data are presented as the number (percentage) of subjects unless otherwise
indicated.
†Comparison group included 27 women who used paroxetine only during the and their conditions improved without further interven-
first and/or second trimesters and 27 women who used nonteratogenic drugs. tion or emergence of other underlying diagnoses.
It may be argued that the high rate of adverse neo-
natal events, especially during breastfeeding, among in-
etine at the serotonin uptake site. In adults, discontinu- fants exposed to paroxetine during the third trimester may,
ation of selective serotonin reuptake inhibitors (SSRIs) at least in part, be associated with maternal psychiatric
leads to nonspecific symptoms such as dizziness, pares- morbidity or disorders associated with it. However, half
thesia, tremor, anxiety, nausea, and emesis, which typi- of our comparison group was composed of mothers who
cally occur 2 days after the last dose and continue for an had similar conditions and who received the drug only
average of 10 days.10 In a large British study, withdrawal during the first and second trimesters. Infants exposed
reactions with paroxetine were 10-fold more common to the drug only during the first and second trimesters
than with fluvoxamine maleate, which has a similarly short did not exhibit neonatal complications or higher rates
half-life (fluvoxamine, 15 h; paroxetine, 17 h), and 15- of prematurity, as did those exposed in the third trimes-
fold more common than with fluoxetine hydrochloride. ter. This strongly suggests that paroxetine exposure near
In the present study, we detected a high rate of new- term may compromise fetal and neonatal health. The fact
borns who developed neonatal complications at birth af- that the adverse events were brief and without other un-
ter exposure to paroxetine in the third trimester. They derlying abnormalities further supports drug exposure
all required intensive treatment for a short period of time, as the mechanism for the adverse effects. Logistic regres-

1131

What This Study Adds Accepted for publication June 27, 2002.
This study was supported in part by a grant from the Ca-
nadian Institutes of Health, Ottawa, Ontario. Dr Kozer has a
Paroxetine, an SSRI, is commonly used for depression, fellowship from the Research Training Center and Dr Koren
panic disorder, and obsessive-compulsive disorder. Dis- holds the Research Leadership for Better Pharmacology Dur-
continuation symptoms have been frequently de-
ing Pregnancy and Lactation, Hospital for Sick Children,
scribed in adults. Several case reports suggest that in-
fants exposed in utero to paroxetine during the third Toronto, Ontario. Dr Ito is a scholar and Dr Koren is a senior
trimester may have poor neonatal adaptation. The pres- scientist of the Canadian Institutes for Health Research.
ent study is the first to compare the perinatal outcome Corresponding author: Gideon Koren, MD, FRCPC, Di-
of women exposed to paroxetine during the third tri- vision of Clinical Pharmacology, Hospital for Sick Chil-
mester of pregnancy with women who took paroxetine dren, 555 University Ave, Toronto, Ontario M5G 1X8,
in early pregnancy and women who took nonterato- Canada (e-mail: gkoren@sickkids.ca).
genic drugs. The incidence of complications (mainly res-
piratory distress) was significantly higher in neonates
exposed to paroxetine in late pregnancy. REFERENCES

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Perinatal Outcome Following Third Trimester Exposure To Paroxetine

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