4/26/06njm

**Background:**

**Paxil in Pregnancy Discussion 12/13/05**

Dear MCH listserv

We need to discontinue use of Paxil in the 1^st^ trimester of pregnancy
asap.

Also please stop it in women who plan to get pregnant

More information is available below, plus in the upcoming December CCC
Corner

#1

Paxil essentially increases their risk for overall congenital
malformations by two-fold, esp. ventricular septal defects

We can offer these patients a change to another agent.

(see UpToDate for choices below)

Please document that you counseled the patient

#2

All other pregnant patients outside of the 1^st^ trimester on Paxil
should be also be counseled, though their major risk period has passed

We need to document that we informed these patients of these new
findings.

#3

Please stop it in women who plan to get pregnant

Please document that you counseled the patient

NB:

While these new findings are confined to the 1^st^ trimester, we can
offer the possibility of changing to another agent, if patients wish

(see UpToDate for choices below)

Thanks

Neil

From: Murphy, Neil\
Sent: Saturday, December 10, 2005 6:53 PM\
To: MCH@LISTSERV.IHS.GOV\
Subject: Paroxetine's pregnancy category from C to D - Please
discontinue use of Paxil asap: In the 1st trimester of pregnancy and
women who plan to get pregnant

FDA MedWatch

**Paroxetine HCl - Paxil and generic paroxetine**

The FDA has determined that exposure to paroxetine in the first
trimester of pregnancy may increase the risk for congenital
malformations, particularly cardiac malformations. At the FDA's request,
the manufacturer has changed paroxetine's pregnancy category from C to D
and added new data and recommendations to the WARNINGS section of
paroxetine's prescribing information. FDA is awaiting the final results
of the recent studies and accruing additional data related to the use of
paroxetine in pregnancy in order to better characterize the risk for
congenital malformations associated with paroxetine.\
\
Physicians who are caring for women receiving paroxetine should alert
them to the potential risk to the fetus if they plan to become pregnant
or are currently in their first trimester of pregnancy. Discontinuing
paroxetine therapy should be considered for these patients. Women who
are pregnant, or planning a pregnancy, and currently taking paroxetine
should consult with their physician about whether to continue taking it.
Women should not stop the drug without discussing the best way to do
that with their physician.

Here is the link to the FDA Professional Ed page

<http://www.fda.gov/cder/drug/InfoSheets/HCP/paroxetineHCP.htm>

Here is the link to the FDA Patient Ed page

<http://www.fda.gov/cder/drug/InfoSheets/patient/paroxetinePT.htm>

Here is the link to

**Treatment of psychiatric disorders in pregnancy, UpToDate**

<http://www.uptodateonline.com/application/topic.asp?file=maternal/5976>

**TREATMENT OF DEPRESSION AND ANXIETY DISORDERS IN PREGNANCY**

**Fluoxetine** ---
[Fluoxetine](http://www.uptodateonline.com/application/topic.asp?file=drug_a_k/109136&drug=true)
is the most frequently studied SSRI in terms of safety and efficacy in
pregnancy and lactation. Over 1500 cases have been reported in the
literature and there is no evidence of teratogenicity. Data on neonatal
complications and neurodevelopmental effects was summarized elsewhere.

The CERHR Expert Panel from the National Toxicology Program of the
Department of Health and Human Services reviewed the data available, as
of 2004, on
[fluoxetine](http://www.uptodateonline.com/application/topic.asp?file=drug_a_k/109136&drug=true)
in pregnancy and lactation
\[[41](http://www.uptodateonline.com/application/abstract.asp?TR=maternal/5976&viewAbs=41&title=41)\].
Although the panel acknowledged the many methodological limitations of
the studies, it nonetheless concluded that fluoxetine may be associated
with \"developmental toxicity as characterized by an increased rate of
poor neonatal adaptation (eg, jitteriness, tachypnea, hypoglycemia,
hypothermia, poor tone, respiratory distress, weak or absent cry,
diminished pain reactivity, or desaturation with feeding) at typical
maternal therapeutic doses (20 to 80 mg/d orally). These effects appear
to result more readily from in-utero exposure late in gestation. The
observed toxicity may be reversible although long-term follow-up studies
have not been conducted to look for residual effects. The evidence
suggests that developmental toxicity can also occur in the form of
shortened gestational duration and reduced birth weight at term.\"

Despite this report, clinically it is clear that a fluoxetine-responsive
patient should not be switched to a different SSRI during pregnancy.
Likewise, if a pregnant patient who is off medications and has a strong
history of response to
[fluoxetine](http://www.uptodateonline.com/application/topic.asp?file=drug_a_k/109136&drug=true)
and relapses, she should be restarted on fluoxetine. The risk of not
responding to a different SSRI is high. Any medication switches between
SSRIs are best accomplished prior to, rather than during, pregnancy.

**Sertraline, paroxetine, fluvoxamine, citalopram, and escitalopram**
--- There are no reports of increased rates of major anatomical
malformations, stillbirths, miscarriages, prematurity, or negative
effects on birth weight
\[[23,42,43](http://www.uptodateonline.com/application/abstract.asp?TR=maternal/5976&viewAbs=23~42~43&title=23,42,43)\].

Pregnancy outcomes after exposure to
[sertraline](http://www.uptodateonline.com/application/topic.asp?file=drug_l_z/228347&drug=true),
[paroxetine](http://www.uptodateonline.com/application/topic.asp?file=drug_l_z/192110&drug=true),
and
[fluvoxamine](http://www.uptodateonline.com/application/topic.asp?file=drug_a_k/111378&drug=true),
were described in a series from nine Teratology Information Centers in
Canada and the United States
\[[42](http://www.uptodateonline.com/application/abstract.asp?TR=maternal/5976&viewAbs=42&title=42)\].
In this study, 147 women were exposed to sertraline, 97 to paroxetine,
and 26 to fluvoxamine during pregnancy. SSRI exposure was not associated
with an increased risk of major anatomical malformations, miscarriage,
stillbirth, or prematurity, or any significant differences in birth
weight or gestational age compared to a control group of pregnant women
exposed to only nonteratogenic agents during pregnancy. A large study
evaluating women using SSRIs other than
[fluoxetine](http://www.uptodateonline.com/application/topic.asp?file=drug_a_k/109136&drug=true)
showed no increase in the rate of congenital malformations in infants
exposed solely to
[citalopram](http://www.uptodateonline.com/application/topic.asp?file=drug_a_k/206740&drug=true)
(n= 364), paroxetine (n = 118), and sertraline (n = 32)
\[[43](http://www.uptodateonline.com/application/abstract.asp?TR=maternal/5976&viewAbs=43&title=43)\].
Reports of neonatal complications are discussed above.

Exposure to
[citalopram](http://www.uptodateonline.com/application/topic.asp?file=drug_a_k/206740&drug=true)
in 375 pregnancies (citalopram only = 364 pregnancies) has also been
documented by the Swedish Medical Birth Registry and the Lundbeck Safety
Database
\[[43](http://www.uptodateonline.com/application/abstract.asp?TR=maternal/5976&viewAbs=43&title=43)\].
The rates of congenital malformations were no higher than the expected
rate in the general population. A study of 11 infants exposed throughout
pregnancy found infant plasma concentrations of citalopram and its
metabolite at delivery were two-thirds of maternal concentration
\[[25](http://www.uptodateonline.com/application/abstract.asp?TR=maternal/5976&viewAbs=25&title=25)\].
Infant levels declined to very low or undetectable by two months
postpartum, even in breastfed infants. Both exposed and control infants
had normal neurologic development at the age of 12 months, and there
were no differences in weight.

There are no data available on the effects of isolated exposure to
[escitalopram](http://www.uptodateonline.com/application/topic.asp?file=drug_a_k/2538&drug=true),
which is the s-enatiomer of
[citalopram](http://www.uptodateonline.com/application/topic.asp?file=drug_a_k/206740&drug=true)
(a racemic mixture). The safety data on citalopram is considered to be
applicable to escitalopram.

Reports of neonatal complications are discussed above and an additional
study is presented below. Forty-six infants who had been exposed to
antenatal medications for active depression were compared with 23
control infants whose mothers were neither depressed nor on
antidepressants
\[[44](http://www.uptodateonline.com/application/abstract.asp?TR=maternal/5976&viewAbs=44&title=44)\].
Fourteen of the infants who had been exposed either to an SSRI alone or
to an SSRI plus
[clonazepam](http://www.uptodateonline.com/application/topic.asp?file=drug_a_k/62643&drug=true)
had transient neonatal symptoms, in contrast to two of the control
infants. The rate of transient neonatal symptoms was higher if the baby
had been exposed to multiple rather than single drug therapy. Infant
serum
[paroxetine](http://www.uptodateonline.com/application/topic.asp?file=drug_l_z/192110&drug=true)
levels were significantly higher in infants exposed to combination
therapy and in symptomatic infants than in infants exposed to SSRIs
alone and asymptomatic infants. Importantly, no developmental
abnormalities were seen at two and eight months follow-up, independent
of the history of transient neonatal complications.

**Venlafaxine** ---
[Venlafaxine](http://www.uptodateonline.com/application/topic.asp?file=drug_l_z/278088&drug=true)
is a serotonin-norepinephrine reuptake inhibitor (SNRI). A multicenter
prospective study reported on the safety of venlafaxine (average dose 75
mg/day, range 37.5 to 300 mg/day) in 150 women who were exposed during
pregnancy and followed for six to 12 months postpartum
\[[45](http://www.uptodateonline.com/application/abstract.asp?TR=maternal/5976&viewAbs=45&title=45)\].
Thirty-four patients were exposed throughout the pregnancy, and all were
exposed during the first trimester. The control groups consisted of
women with depression treated with SSRIs
([fluoxetine](http://www.uptodateonline.com/application/topic.asp?file=drug_a_k/109136&drug=true),
[sertraline](http://www.uptodateonline.com/application/topic.asp?file=drug_l_z/228347&drug=true),
[paroxetine](http://www.uptodateonline.com/application/topic.asp?file=drug_l_z/192110&drug=true),
and
[fluvoxamine](http://www.uptodateonline.com/application/topic.asp?file=drug_a_k/111378&drug=true))
and women taking other types of drugs not known to be teratogenic. The
rate of major malformations associated with venlafaxine use was
comparable to that in the other two groups, and no higher than the
baseline rate of birth defects in the general population, 1 to 3
percent. There were no differences in the preterm delivery rates.

There are very few reports of neonatal complications
\[[16](http://www.uptodateonline.com/application/abstract.asp?TR=maternal/5976&viewAbs=16&title=16)\],
but the same considerations regarding the SSRIs apply to this
serotonergic antidepressant. Some clinicians recommend tapering the drug
close to delivery if the dose is high (eg, above 225 mg/d) to lower the
theoretical risk of neonatal complications but as with the SSRIs, there
is no evidence to support this practice. In fact, this practice could be
particularly dangerous with
[venlafaxine](http://www.uptodateonline.com/application/topic.asp?file=drug_l_z/278088&drug=true)
as there is a high risk of bothersome withdrawal symptoms in the mother
when the medication is lowered in addition to the attendant risks of
precipitating a relapse of depression. Thus, it is advisable to maintain
the dose close to term until further information becomes available.

**Mon 12/12/2005 5:10 PM**

**Gilson, George J \[gjgilson@anmc.org\]**

Here is an excellent summary....

  -----------------------------------------------------------------------
  Agent Summary

  Quick take: Although experimental animal studies do not suggest an
  increased risk of congenital anomalies, a preliminary case-control
  study and 2 other independent studies presented in abstract or
  letter-form have suggested a 2-fold increase in cardiovascular defects
  in children exposed antenatally to paroxetine. Use of paroxetine late
  in pregnancy can be associated with a mild transient neonatal syndrome
  of central nervous system, motor, respiratory, and gastrointestinal
  signs.\
  \
  \* \* \*\
  \
  Paroxetine is a serotonin re-uptake inhibitor used in the treatment of
  depression. Other names include Paxil, Aropax, and Seroxat. Animal
  pregnancy testing has been performed in rats and rabbits (1). Rabbits
  given up to 5.1 mg/kg/d showed no increase in congenital abnormalities
  in the offspring. In rabbits, up to 43 mg/kg/d was given without an
  increase in offspring anomalies; however, there was a decrease in
  fertility and in viable pregnancies in rats given 13 mg/kg/d or more.\
  \
  According to one manufacturer (GlaxoSmithKline, Research Triangle Park
  NC), paroxetine did not produce adverse effects on the offspring of
  pregnant rats and rabbits treated with 50 and 6 times the recommended
  human dose on a mg/kg basis (10 and 2 times the dose on a mg/square
  meter basis). Adverse fertility effects were noted in mating rats given
  15 times the human dose on a mg/kg basis (4.4 times on a mg/square
  meter basis), with atrophy of the seminiferous tubules in males.\
  \
  A study in pregnant mice used an oral paroxetine dose of 30 mg/kg/d to
  produce serum drug concentrations similar to those achieved clinically.
  There was a transient decrease in conception rate and in pup weight,
  but no abnormality of pup development (6). Reproductive capability and
  the perinatal outcomes of the second-generation offspring were
  unaffected by paroxetine exposure. In a separate report, this group did
  not find differences in behavioral test data from pups born to and
  raised by dams treated with paroxetine compared to placebo (7).
  Reproductive function in the offspring was also normal.\
  \
  During clinical trials, 13 pregnancies occurred in women taking
  paroxetine. Five were terminated, 1 miscarried, and 7 resulted in the
  birth of apparently normal infants. A one-year postmarketing survey
  conducted in England identified 63 pregnancies that included first
  trimester exposure to paroxetine (2). Among the outcomes of these
  pregnancies there were nine spontaneous abortions, 12 elective
  terminations, and nine unknown outcomes. Of three sets of twins, one
  twin was stillborn. There were no congenital anomalies in the liveborn
  infants. Another series reported three pregnancies exposed to
  paroxetine, all of which resulted in normal infants (4). A larger
  report included 97 women who were followed prospectively after
  contacting a teratology information service regarding their use of
  paroxetine (5). The incidence of malformations in this population was
  comparable to that found in unexposed control subjects. The mothers
  were the source of information on pregnancy outcome, which limits the
  reliability of the study.\
  \
  A report on 330 pregnancies identified by a teratogen information
  service (286 involved first trimester paroxetine exposure) was
  published in abstract (12). Congenital anomalies were identified in
  5.1% of the pregnancies with first-trimester exposure to paroxetine,
  compared to 2.6% of a comparison group (RR 1.92, 95% CI 1.01-3.65).
  Cardiovascular anomalies occurred in 1.9% of the paroxetine-exposed
  group, compared to 0.6% of the comparison group (RR 3.46, 95% CI
  1.06-11.24). A case-control study from the CDC, also published in
  abstract, identified a possible excess of omphalocele in children with
  antenatal paroxetine exposure (OR 6.3, 95% CI 2.0-19.6) (27).\
  \
  An unpublished case-control study using an insurance data base and
  medical record review identified a possible association between
  prescription of paroxetine in the first trimester and congenital heart
  disease in offspring (28). This study was performed as part of an
  evaluation by the manufacturer of pregnancy effects of bupropion
  ([#1238](http://www.reprotox.org/Members/AgentDetail.aspx?a=1238)). In
  the evaluation of bupropion, other antidepressant medications were used
  as a comparator group and were examined individually. There were 14
  children with cardiovascular defects among 704 pregnancies with first
  trimester prescription of paroxetine (prevalence 2%), giving an odds
  ratio (95% CI) of 2.08 (1.09-3.96), using other antidepressants
  pregnancies as a reference group. Of the 14 children with cardiac
  defects, 9 included ventricular septal defect. Paroxetine prescription
  does not guarantee that exposure actually occurred. In addition, these
  data have not been published and are considered preliminary.\
  \
  A letter-to-the-editor (30) used the Swedish Medical Birth Register to
  investigate a possible association between paroxetine and congenital
  heart disease. The association for paroxetine was statistically
  significant with an odds ratio (95% CI) of 2.22 (1.39-3.55).
  Anti-depressants as a group and other individual antidepressants were
  not associated with congenital heart disease, with the exception of
  clomipramine
  ([#1262](http://www.reprotox.org/Members/AgentDetail.aspx?a=1262)), for
  which the odd ratio (95% CI) was 1.87 (1.16-2.99). Ventricular and
  atrial septal defects showed the strongest associations among the
  individual malformations.\
  \
  Adverse effects in neonates exposed to paroxetine and other serotonin
  re-uptake inhibitors prenatally have been described in a variety of
  reports, including individual cases, prospective studies, and a data
  mining investigation of the large WHO database of adverse drug
  reactions (11,13,15,17-24,26). The adverse effects describe include
  jitteriness, irritability, vomiting and convulsions. One small series
  identified four neonates who also developed necrotising enterocolitis,
  although all the infants in this report were also prenatally exposed to
  other drugs (15). Respiratory distress and other abnormalities of
  neonatal adaptation also appeared to be unusually frequent in
  paroxetine exposed infants (13,21). In one report, altered pain
  response was demonstrated in 14 of 46 newborn infants whose mothers
  were treated chronically with paroxetine during pregnancy (22).
  Although some infants have required intensified care, including
  treatment with chlorpromazine (18), in most cases, the reported
  symptoms have resolved without therapy. Among the serotonin re-uptake
  inhibitors, the largest number of reports on adverse postnatal effects
  have included paroxetine exposure (25). Some commentators have
  suggested that paroxetine has a peculiar receptor profile that includes
  potent noradrenergic and muscarinic blockade, giving rise to adverse
  neonatal effects (25). There is an ongoing debate about whether the
  adverse effects seen in some neonates are due to a withdrawal syndrome
  when paroxetine exposure ends or a manifestation of the altered
  serotonin levels subsequent to paroxetine exposure (16,25). The
  importance of this distinction involves defining appropriate therapy
  for paroxetine exposed infants, because a true withdrawal syndrome
  could be treated with readministration of paroxetine, but a serotonin
  syndrome could be worsened by continuing paroxetine (25). Most
  clinicians have allowed adverse effects in neonates to resolve without
  the administration of additional paroxetine. A summary of
  recommendations on the treatment of symptomatic infants was included in
  a review (26). They include supportive care and the use of
  anticonvulsants, fluid replacement and respiratory support for the most
  severe cases (26). Neonates exposed prenatally to paroxetine and other
  serotonin re-uptake inhibitors can be evaluated for signs of adverse
  effects, but the incidence and severity of these effects do not appear
  to be so frequent or severe that women should avoid using these
  medications in late pregnancy if they are otherwise indicated (25).\
  \
  Paroxetine is excreted in human milk in small amounts (3,8-10,14,29).
  It has been estimated that the mean dose of paroxetine received by the
  infants is 1.13% (range 0.5 to 1.7) of the weight-adjusted maternal
  dose, with a milk:plasma ratio of about 0.2 (10). In the serum of the
  suckling infants, the drug was either undetectable, or in one case,
  present in levels too low to be quantified (3,8-10,14,29). No adverse
  effects have described been described from lactational exposure to
  paroxetine.\
  \
  Selected References\
  \
  1. Baldwin JA, Davidson EJ, Pritchard AL, Ridings JE. The reproductive
  toxicity of paroxetine. Acta Psychiatr Scand Suppl 1989;350:37-39.\
  \
  2. Inman W, Kubota K, Pearce G, Wilton L: PEM report number 6.
  Pharmacoepidemiol Drug Safety 2:393-422, 1993.\
  \
  3. Spigset O, Carleborg L, Norstrom A, Sandlund M: Paroxetine level in
  breast milk. J Clin Psychiatry 57:39, 1996.\
  \
  4. 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.\
  \
  5. Kulin NA, Pastuszak A, Sage SR et al: Pregnancy outcome following
  maternal use of the new selective serotonin reuptake inhibitors. JAMA
  279:609-10, 1998.\
  \
  6. Rayburn WF, Gonzalez CL, Christensen HD, Kupiec TC, Jacobsen JA,
  Stewart JD: Effect of antenatal exposure to paroxetine (paxil) on
  growth and physical maturation of mice offspring. J Matern Fetal Med
  2000;9:136-41.\
  \
  7. Coleman FH, Christensen HD, Gonzalez CL, Rayburn WF. Behavioral
  changes in developing mice after prenatal exposure to paroxetine
  (Paxil). Am J Obstet Gynecol 1999;181:1166-71.\
  \
  8. Stowe ZN, Cohen LS, Hostetter A, Ritchie JC, Owens MJ, Nemeroff CB:
  Paroxetine in human breast milk and nursing infants. Am J Psychiatry
  2000;157:185-9.\
  \
  9. Ohman R, Hagg S, Carleborg L, Spigset O: Excretion of paroxetine
  into breast milk. J Clin Psychiatry 1999;60:519-23.\
  \
  10. Begg EJ, Duffull SB, Saunders DA, Buttimore RC, Ilett KF, Hackett
  LP, Yapp P, Wilson DA: Paroxetine in human milk. Br J Clin Pharmacol
  1999;48:142-7.\
  \
  11. Dahl ML, Olhager E, Ahlner J: Paroxetine withdrawal syndrome in a
  neonate. Br J Psychiatry 1997;171:391-2.\
  \
  12. Diav-Citrin O, Shechtman S, Weinbaum D et al: Paroxetine and
  fluoxetine in pregnancy: A multicenter, prospective, controlled study.
  Reprod Toxicol 2005;20:459.\
  \
  13. Costei AM, Kozer E, Ho T, Ito S, Koren G: Perinatal outcome
  following third trimester exposure to paroxetine. Arch Pediatr Adolesc
  Med 2002;156:1129-32.\
  \
  14. Hendrick V et al: Use of sertraline, paroxetine and fluvoxamine by
  nursing women. Br J Psych 179:163-6,2001.\
  \
  15. Stiskal JA, Kulin N, Koren G, Ho T, Ito S: Neonatal paroxetine
  withdrawal syndrome. Arch Dis Child Fetal Neonatal Ed 84:F134-F135,
  2001.\
  \
  16. Isbister GK, Dawson A, Whyte IM et al: Neonatal paroxetine
  withdrawal syndrome or actually serotonin syndrome? Arch Dis Child
  Fetal Neonatal Ed 85:F146-7, 2001.\
  \
  17. Nijhuis IJM, Kok-Van Rooij GWM, Bosschaart AN: Withdrawal reactions
  of a premature neonate after maternal use of paroxetine. Arch Dis Child
  Fetal Neonatal Ed 84:F77, 2001.\
  \
  18. Nordeng H, Lindemann R, Perminov KV, Reikvam A: Neonatal withdrawal
  syndrome after in utero exposure to selective serotonin reuptake
  inhibitors. Acta Paediatr 90:288-291, 2001.\
  \
  19. Casper RC, Fleisher BE, Lee-Ancajas JC: Follow-up of children of
  depressed mothers exposed or not exposed to antidepressant drugs during
  pregnancy. J Pediatr 2003; 142:402-8.\
  \
  20. Jaiswal S, Coombs RC, Isbister GK: Paroxetine withdrawal in a
  neonate with historical and laboratory confirmation. Eur J Pediatr
  162(10):723-724, 2003.\
  \
  21. Hendrick V, Smith LM, Suri R, Hwang S, Haynes D, Altshuler L: Birth
  outcomes after prenatal exposure to antidepressant medication. Am J
  Obstet Gynecol 188:812-815, 2003.\
  \
  22. Oberlander TF, Misri S, Fitzgerald CE, Kostaras X, Rurak D, Riggs
  W: Pharmacologic factors associated with transient neonatal symptoms
  following prenatal psychotropic medication exposure. J Clin Psychiatry
  2004;65:230-7.\
  \
  23. Zeskind PS, Stephens LE: Maternal selective serotonin reuptake
  inhibitor use during pregnancy and newborn neurobehavior. Pediatrics
  113:368-75, 2004.\
  \
  24. Sanz EJ, De-las-Cuevas C, Kiuru A, Bate A, Edwards R: Selective
  seratonin reuptake inhibitors in pregnant women and neonatal withdrawal
  syndrome: a database analysis. Lancet 2005;365:482-7.\
  \
  25. Ruchkin V, Martin A: SSRIs and the developing brain. Lancet
  2005;365:451-3.\
  \
  26. Moses-Kolko EL, Bogen D, Perel J, Bregar A, Uhl K, Levin B, Wisner
  KL. Neonatal sings after late in utero exposure to serotonin reuptake
  inhibitors. Literature review and implications for clinical
  applications. J Am Med Assoc 2005;293:2372-2383.\
  \
  27. Alwan S, Reefhuis J, Rasmussen S, Olney R, Friedman JM. Maternal
  use of selective serotonin re-uptake inhibitors and risk for birth
  defects. Birth Defects Research (Part A). 2005;73:291.\
  \
  28. Unpublished data accessible at http://ctr.gsk.co.uk/welcome.asp.\
  \
  29. Misri S, Kim J, Riggs KW, Kostaras X: Paroxetine levels in
  postpartum depressed women, breast milk, and infant serum. J Clin
  Psychiatry 2000;61:828-32.\
  \
  30. Kallen B, Olausson PO. Antidepressant drugs during pregnancy and
  infant congenital heart defect. Reprod Toxicol 2006;in press.
  -----------------------------------------------------------------------