Am J Psychiatry 158:10, October 2001
Pregnancy Outcome Following Gestational Exposure to
Venlafaxine: A Multicenter Prospective Controlled Study
Adrienne Einarson, R.N.
Bumn Fatoye, M.D.
Moumita Sarkar, B.Sc.
Sharon Voyer Lavigne, M.Sc.
Christina Chambers, M.P.H.
Pierpaolo Mastroiacovo, M.D.
Antonio Addis, Pharm.D.
Doreen Matsui, M.D.
Lavinia Schuler, M.D., M.Sc.
Thomas R. Einarson, Ph.D.
Gideon Koren, M.D.
Objective: Because there are no studies available on the safety
of venlafaxine during pregnancy, the authors’ goal in this study
was to determine whether venlafaxine increases the risk for
Method: Data on 150 women exposed to venlafaxine during
pregnancy in seven pregnancy counseling centers were com-
pared with data from studies of pregnant women who 1) re-
ceived selective serotonin reuptake inhibitor antidepressants (SS-
RIs) (N=150) and 2) who received nonteratogenic drugs (N=150).
Results: Among the 150 women who were exposed to ven-
lafaxine during pregnancy, 125 had live births, 18 had sponta-
neous abortions, and seven had therapeutic abortions; two of
the babies had major malformations. There were no significant
differences between these women and the two comparison
groups on any of the measures analyzed.
Conclusions: These results suggest that the use of venlafaxine
during pregnancy does not increase the rates of major malfor-
mations above the baseline rate of 1%–3%.
(Am J Psychiatry 2001; 158:1728–1730)
T o date, to our knowledge there are no studies on the
safety of venlafaxine during human pregnancy. In animal
studies (rats and rabbits), venlafaxine did not cause mal-
formations in doses 11–12 times the maximum recom-
mended human daily dose (1). The manufacturer of ven-
lafaxine has a number of spontaneous case reports of
women exposed to venlafaxine during pregnancy, docu-
menting both birth defects and healthy babies with no
specific pattern of defects (2). It is important to recognize
the inherent bias of spontaneous reporting to drug com-
panies, as our group commented in a recent report (3), be-
cause companies are much more likely to receive reports
of adverse birth outcomes than healthy babies.
Data obtained by the U.K. Drug Safety Research Unit (4)
revealed known outcomes of the pregnancies of 39 women
who took venlafaxine. There were 26 live births, seven
spontaneous abortions, and six therapeutic abortions in
this group and no reports of malformations.
A substantial number of women of child-bearing age
suffer from depression. Coupled with the fact that at least
50% of pregnancies are unplanned (5), the likelihood of
depression during pregnancy means that women will use
this drug in early pregnancy. We have found that some
women may choose to abort a wanted pregnancy because
there is no information on the safety of a particular drug
(6). In another one of our studies (7), we found that a num-
ber of women elected to discontinue needed antidepres-
sants abruptly after their pregnancy was diagnosed be-
cause there was no information on the safety of the drugs.
Because of the paucity of information on venlafaxine,
we elected to carry out this study to assess its safety or risk
potential during pregnancy. Our main objective was to as-
certain whether venlafaxine use during pregnancy raised
the baseline risk of 1%–3% for major malformations. Sec-
ondary outcomes of interest included rates of spontane-
ous and therapeutic abortions, mean gestational age, and
The Motherisk Program and the other participating pregnancy
counseling centers provide similar services for pregnant and lac-
tating women and their health professionals. Information is given
on the safety or risk potential during pregnancy of drugs, chemi-
cals, radiation, and infectious diseases. For the purpose of this
study, we ascertained the outcome of the pregnancy of women
who had called each service requesting information about the
safety of venlafaxine when they were in the first trimester of the
On successful contact, information on each woman’s exposure
history and pregnancy outcome were obtained, along with other
measures of interest, with the aid of a structured questionnaire.
The exposure history included medical indication for drug use,
dose, and frequency and timing of administration, as well as ma-
ternal demographics and obstetrical history. At follow-up, women
were questioned regarding the course of their pregnancy, the
health of their child, and specific details of their exposure to ven-
lafaxine and any other drugs or exposure to other risk factors dur-
ing their pregnancy. Outcomes were confirmed by sending a let-
ter to the child’s primary care physician to corroborate the
The primary outcome of interest was the incidence of major
malformations, which are defined by the presence of any anom-
Am J Psychiatry 158:10, October 2001
aly that has an adverse effect on either the function or the social
acceptability of the individual (8). Secondary outcome measures
included the rates of spontaneous or therapeutic abortions, live
births and stillbirths, gestational age at birth, and birthweight. Ex-
posure was defined as occurring during organogenesis if the drug
was consumed between the fourth and 14th week of gestation.
Data from studies of pregnant women (9–14) were used to cre-
ate two comparison groups; all of the data in the studies were col-
lected in the same fashion. The first comparison group consisted
of women suffering from depression who were taking selective se-
rotonin reuptake inhibitors (SSRIs) (fluoxetine, sertraline, fluvox-
amine, and paroxetine) (9, 10). The second comparison group
consisted of women who were given nonteratogenic drugs (loper-
amide, echinacea, sumatriptan, and dextromethorphan) (11–14).
Age, smoking status, and alcohol use were compared in all three
groups. Most women were followed up between 6 and 12 months
after delivering their babies.
Outcomes of interest were compared among groups by using
chi-square analysis, Fisher’s exact test, and analysis of variance.
We received oral consent from each participant after the study
was fully explained over the telephone; the study was approved by
the Research Ethics Board of The Hospital for Sick Children.
We were able to ascertain the outcomes of 150 pregnan-
cies after exposure to venlafaxine from seven different
centers: Toronto (N=99), Farmington, Conn. (N=15), San
Diego (N=13), Rome (N=9), Milan, Italy (N=5), London,
Ont., Canada (N=5), and Porto Allegre, Brazil (N=4). All of
the women used the drug in the first trimester, and 34
used it throughout their pregnancy. There were no signifi-
cant differences in maternal characteristics among the
venlafaxine and comparison groups, although there were
more smokers in both the venlafaxine and SSRI groups.
However, the difference did not reach statistical signifi-
cance, and the amount of cigarettes smoked was relatively
light; most women reported having cut down to fewer
than 10 cigarettes/day during their pregnancy. There were
no differences in any outcome measures in smokers com-
pared with nonsmokers, including the rates of spontane-
The majority of the women in the venlafaxine group
(70% [N=105]) took 75 mg/day of venlafaxine (immediate
release form); the rest fell into a wide range of dosing be-
tween 37.5 and 300 mg/day.
Among the women who received venlafaxine, there
were 125 live births, 18 spontaneous abortions, and seven
therapeutic abortions; the mean birthweight of the chil-
dren in all three groups was 3,332 g (Table 1). Pregnancy
outcome did not differ among the three groups, including
preterm delivery rates, with the exception of the fact that
more spontaneous abortions were reported in the ven-
lafaxine group (this difference did not reach statistical sig-
nificance) (Table 1). There were two major malformations
(hypospadias and neural tube defect with club foot) in the
venlafaxine group, three (ventricular septal defect, pyloric
stenosis, and absent corpus callosum) in the SSRI group,
and one (congenital heart defect) in the nonteratogenic
To our knowledge, this is the first prospective controlled
study examining the effects of venlafaxine use during
pregnancy with a large group of women exposed to the
drug in the first trimester (N=150). However, this study
does not attempt to evaluate the potential neurobehav-
ioral effects of this drug.
The only difference among the venlafaxine group and
the two comparison groups was in the rates of spontane-
ous abortions, which was nonsignificantly higher in both
the venlafaxine group (12%) and the group receiving SSRIs
(11%) than in the group receiving nonteratogenic drugs
(7%) (Table 1). We found nonsignificantly higher rates of
spontaneous abortion in women receiving antidepres-
sants in two previous studies (9, 10). In a study of fluoxe-
tine (9), we found spontaneous abortion rates of 14% in
women exposed to fluoxetine, 12% in women exposed to
tricyclic antidepressants, and 7% in women not exposed
to antidepressants. In a later study of SSRIs (10), we found
that the rates of spontaneous abortion were 12% among
women exposed to SSRIs and 7% among the general
Motherisk population. The differences in both studies
were not statistically significant, and the rates for both the
TABLE 1. Pregnancy Outcomes of Depressed Women Given Venlafaxine, Selective Serotonin Reuptake Inhibitors (SSRIs), or
Nonteratogenic Drugs During Pregnancy
SSRIs Nonteratogenic Venlafaxine
MeanSDMeanSDMean SDF (df=2, 446)p
Gestation age at birth (weeks)
aOdds ratio between venlafaxine and SSRIs=0.66 (95% confidence interval=0.11–3.99); odds ratio between venlafaxine and nonteratogenic
drugs=2.21 (95% confidence interval=0.20–24.69).
bFisher’s exact test (two-tailed).
0.34 3,332609 3,429482 3,452602
Am J Psychiatry 158:10, October 2001
fluoxetine and SSRI groups were within the baseline rate
of up to 15% for spontaneous abortions in the general
To verify whether our findings regarding spontaneous
abortion were statistically significant, we combined the
results of the two previous studies with those of the cur-
rent study using a meta-analytical approach. This pro-
duced a weighted mean of 12.2% spontaneous abortions
(SE=1.4%) in the groups of women who received antide-
pressants compared with 7.7% (SE=1.1%) in the other
groups, with a summary odds ratio of 1.68 (95% confi-
These results raise the question of whether there may be
a possible association between depression and higher
rates of spontaneous abortion, which was one of the rea-
sons why we selected a comparison group of women who
were suffering from depression. Smoking has been found
to increase the rates of spontaneous abortion (15); how-
ever, we did not find higher rates among the smokers in
our study, probably because the vast majority of the
women who smoked had cut down their cigarette use in
pregnancy to fewer than 10 cigarettes/day. Chatenoud et
al. (15) reported that smoking more than 10 cigarettes/day
increased the rates of spontaneous abortion.
Women who have been diagnosed with depression be-
fore becoming pregnant and are being successfully treated
with medication should not feel that they automatically
have to stop their medications as soon as their pregnancy
is confirmed. If they do decide to discontinue the medica-
tion, it should be tapered off slowly to avoid abrupt dis-
continuation syndrome. Failure to treat depression during
pregnancy can have serious ramifications for both the
mother and the child, probably the most important being
inability to carry out maternal duties and difficulty bond-
ing with the child because of depression (16). A recent
study (17) also found that depression and anxiety in early
pregnancy are associated with a risk for subsequent preec-
The main limitation of this study is the number of sub-
jects, which is small for statistical purposes in that it has
only an 80% power to detect a four-fold increase in the rate
of malformations with an alpha of 0.05. Approximately 800
subjects in each group would be required to detect a two-
fold risk of relatively common malformations, and thou-
sands of subjects would be required to detect rare defects.
In summary, the results in 150 women exposed to ven-
lafaxine during pregnancy in the first trimester do not sug-
gest that there is a greater risk for major malformations
above the baseline rate of 1%–3%. This evidence-based in-
formation can be helpful to women and their health pro-
fessionals when making the decision whether to treat a de-
pression with venlafaxine during pregnancy.
Received Dec. 8, 2000; revised April 9, 2001; accepted May 3, 2001.
From The Motherisk Program, The Hospital for Sick Children, Univer-
sity of Toronto; the Pregnancy Riskline, University of Connecticut,
Farmington; the California Teratogen Information Service, University
of California, San Diego; the Birth Defects Unit, Pediatric Institute,
Catholic University, Rome; the Mario Negri Institute, Milan, Italy; the
FRAME Program, Children’s Hospital of Western Ontario, London,
Ont., Canada; Unitade de Genetica, Porto Allegre, Brazil; and the Fac-
ulty of Pharmacy, University of Toronto, Canada. Address reprint re-
quests to Ms. Einarson, The Motherisk Program, Division of Clinical
Pharmacology, The Hospital for Sick Children, 555 University Ave.,
Toronto, Ont. M5G 1X8, Canada; email@example.com (e-mail).
1. Effexor Product Monograph. Montreal, Wyeth-Ayerst, 1999
2. Global Safety Surveillance Program. Montreal, Wyeth-Ayerst,
3. Bar-Oz B, Moretti ME, Bishai R, Mareels GR, Van Tittleboom T,
Verspeelt J, Koren G: Reporting bias in retrospective ascertain-
ment of drug-induced embryopathy (letter). Lancet 1999; 354:
4. Shaikir S: Data. Southampton, UK, Drug Safety Research Unit,
5. Better news on population (notice board). Lancet 1992; 339:16
6. Einarson A, Bailey B, Jung C, Spizziri D, Bailley M, Koren G: Pro-
spective controlled study of hydroxyzine and cetirizine in preg-
nancy. Ann Allergy Asthma Immunol 1997; 78:183–186
7. Einarson A, Selby P, Koren G: Abrupt discontinuation of psycho-
tropic drugs due to fears of teratogenic risk and the impact of
counseling. J Psychiatry Neurosci 2001; 26:44–48
8. Marden PM, Smith DW, McDonald MJ: Congenital anomalies in
the newborn, including variations. J Pediatr 1964; 64:357–371
9. Pastuszak A, Schick-Boschetto B, Zuber C, Feldkamp M, Pinelli
M, Sihn S, Donnenfeld A, McCormack M, Leen-Mitchell M,
Woodland C, Gardner A, Hom M, Koren G: Pregnancy outcome
following first trimester exposure to fluoxetine. JAMA 1993;
10. Kulin N, Pastuszak A, Sage S, Schick-Boschetto B, Spivey G, Feld-
kamp M, Ormand K, Matsui D, Stein-Schechman AK, Cook l,
Brochu J, Reider M, Koren G: Pregnancy outcome following
maternal use of the new serotonin reuptake inhibitors: a pro-
spective multicenter study. JAMA 1998; 279:609–610
11. Einarson A, Mastroiacova P, Arnon J, Ornoy A, Addis A, Malm H,
Koren G: Prospective controlled, multicentre study of loperam-
ide in pregnancy. Can J Gastroenterol 2000; 14185–14187
12. Gallo M, Sarker M, Au W, Pietrzak K, Comas B, Smith M, Jeager
TV, Einarson A, Koren G: Pregnancy outcome following gesta-
tional exposure to echinacea: a prospective controlled study.
Arch Intern Med 2000; 160:3141–3143
13. Shuhaiber S, Pastuszak A, Schick B, Matsui D, Spivey G, Brochu
J, Koren G: Pregnancy outcome following first trimester expo-
sure to sumatriptan. Neurology 1998; 51:581–583
14. Einarson A, Lyszkiewicz DA, Koren G: The safety of dex-
tromethorphan in pregnancy: results of a controlled study.
Chest 2001; 119:466–469
15. Chatenoud L, Parazzini F, di Cintio E, Zanconata G, Benzi G,
Bortolus R, La Vecchia C: Paternal and maternal smoking hab-
its before conception and during the first trimester: relation to
spontaneous abortion. Ann Epidemiol 1998; 8:520–526
16. Buist A: Managing depression in pregnancy. Aust Fam Physi-
cian 2000; 29:663–667
17. Kurki T, Hiilesmaa V, Raitasalo R, Mattila H, Ylikorkala O: De-
pression and anxiety in early pregnancy and risk of preeclamp-
sia. Obstet Gynecol 2000; 95:487–490