Fluoxetine (Prozac ®, Sarafem™)
Antidepressant, antiobsessive-compulsive, and antibulimic. Also used for
premenstrual dysphoric disorder. Selective serotonin reuptake inhibitor (SSRI).
Molecular weight: 345.79
Reproduction studies in rats and rabbits, following administration of up
to 1.5 and 3.6 times the maximum recommended human dose on a mg/m 2
basis (MRHD), respectively found no evidence of teratogenicity. However, in rat reproduction studies, an increase in stillborn pups, a
decrease in pup weight, and an increase in pup deaths during the first 7
days postpartum occurred following maternal exposure to 1.5 times the MRHD during gestation or
0.9 times the MRHD during gestation
and lactation. There was no evidence of developmental neurotoxicity in the
surviving offspring of rats treated with 12 mg/kg/day during gestation .
Fluoxetine appears to cross the human placenta at term. In a study that
included 15 women taking fluoxetine 10 to 60 mg per day the mean cord to maternal
serum concentrations of fluoxetine and norfluoxetine were 0.64 (range 0.32 to 1.36 )
and 0.65 (range 0.12 to 1.58 ) respectively .
A meta-analytical review of epidemiological studies concluded
that the use of fluoxetine during the first trimester of pregnancy is not
associated with significant teratogenic effects in humans .
Studies including over 1200 women exposed to fluoxetine during the first
trimester did not demonstrate an increase in the rate of major malformations
above the expected baseline rate [4-7]. Only one of these studies noted a trend toward a higher percentage of
miscarriages in fluoxetine treated patients which was not statistically
Amongst the human studies included above Chambers et al. noted an increased
incidence of three or more minor anomalies in the infants of 228 fluoxetine-treated
mothers. The authors suggested that the presence of
three or more minor anomalies increased the risk of having an
occult malformation such as defects in brain development not recognizable at
However, Goldstein et al. found no consistent or recurring pattern of
abnormalities after first-trimester exposure to fluoxetine in 796 pregnancies
. Studies by Mattson et
al. and Nulman et al. found no adverse neurobehavioral development in 106
preschool and early-school aged children who had been exposed in utero to
Casper et al. compared birth outcomes and postnatal neurodevelopmental
functioning between ages 6 and 40 months in 13 children whose mothers were
diagnosed with major depressive disorder in pregnancy and elected not to take
medication with 31 children of depressed mothers treated with SSRIs.The Bayley mental developmental indexes were similar in both groups.
Children exposed to SSRIs during pregnancy had lower APGAR scores and scored
lower on the Bayley psychomotor development indexes and the motor quality
factor of the Bayley Behavioral Rating Scale than unexposed children .
Chambers et al. also found that infants exposed to fluoxetine during the latter part of pregnancy (after 25
weeks) demonstrated an increased rate of prematurity, special care nursery admission,
poor neonatal adaptation, and persistent pulmonary hypertension compared to infants with only early pregnancy
Birth weight was also lower in the exposed-late group. However, when
maternal weight gain was considered the latter result was
no longer statistically significant .
Cohen LS, et al. also found SSRI exposure during pregnancy to be a risk
factor for special care nursery admission , and
Simon GE et al. reported higher rates of preterm birth amongst women exposed
to SSRIs . However,
a study by Goldstein was unable to confirm an increase in neonatal problems
after third trimester exposure to fluoxetine in 115 infants . It
should also be noted that underlying maternal depression also appears to play a
role in the above complications [14,15].
BREAST FEEDING: Fluoxetine and its active metabolite norfluoxetine
are excreted into human milk.
Reported milk:plasma ratio for fluoxetine = 0.14 to
Reported milk:plasma ratio for norfluoxetine =
0.09 to 0.82 [16-19]
In a study that included 10 nursing women taking a mean maternal dose
of 0.39 mg/kg/day ( range 0.17 to 0.85 mg/kg/day ) Taddio et al. reported peak milk concentrations of 293 ng/mL
and 379.1 ng/mL
fluoxetine and norfluoxetine respectively. The authors of the study
estimated the average infant doses of fluoxetine and norfluoxetine, for an
exclusively breast-fed infant ingesting 1000 mL of milk per day, were 0.077 mg
and 0.084 mg respectively. The total dose of fluoxetine and norfluoxetine
(expressed as fluoxetine equivalents) was 0.165 mg, which was equivalent to
10.8% of the maternal dose, adjusted on a mg/kg basis in a 4-kg infant .
Yoshida et al. studied four mothers who took fluoxetine and their breast-fed
infants. Fluoxetine and norfluoxetine were detected in all
samples of maternal plasma (range of total concentration 138-427 ng/ml) and
in breast-milk (range 39-177 ng/ml). Amounts of both fluoxetine and
norfluoxetine in infants' plasma and urine were below the lower limit of
detection. All infants were observed to be developing normally and showed no
abnormal findings on neurological examination .
A retrospective cohort study of infants breastfed by
26 mothers taking fluoxetine( 20 mg to 40 mg per day)
demonstrated a growth curve significantly below that of infants who were
breastfed by mothers who did not take the drug. The average deficit in
measurements taken between 2 weeks and 6 months of age was 392 g .
Irritability, decreased sleep, vomiting and watery stools were reported in one
nursing mother while taking fluoxetine .
The manufacturer recommends that fluoxetine not
be used by nursing mothers in accordance with a 1994 FDA advisory .
The American Academy of Pediatrics has classified fluoxetine as a drug "for which the effect on nursing infants is unknown but may be of concern"
A review by Nordeng et al. of the literature on selective serotonin reuptake
inhibitors and excretion in breast milk concluded
the relative dose to the breastfed infant is lowest for fluvoxamine and
sertraline, somewhat higher for paroxetine and
highest for citalopram and fluoxetine. Fluoxetine
should not be the first line alternative. High doses of citalopram should also
be used with caution. However, when the use of an SSRI is clearly indicated
in a breastfeeding woman, available data generally indicate that the positive
effects of breast-feeding outweigh the risks for pharmacological effects in the
NEONATAL SIDE EFFECTS:
Nordeng H, et al. have reported symptoms suggestive of medication withdrawal
within a few days after birth in one infant whose mother had taken fluoxetine
20 mg daily during pregnancy. Symptoms included irritability, constant crying,
shivering, increased tonus, eating and sleeping difficulties and convulsions.
In another case report central nervous system toxicity in a term
newborn was attributed to measurable cord blood levels of fluoxetine and
norfluoxetine. The mother had been taking 20 mg /day throughout her pregnancy.
Symptoms included continuous crying, tachypnea, increased muscle tone, tremors,
and hyperactive Moro reflex. The total drug concentration in cord blood was 80 ng/mL. The fluoxetine
level, 26 ng/mL, is below the adult therapeutic level; the norfluoxetine cord
blood level, 54 ng/mL, is at the adult therapeutic level. At 96 hours the
fluoxetine level was not measurable and the norfluoxetine level was 55 ng/mL. The
neonate was asymptomatic at 96 hours of age.
SSRIs prescribed for the treatment of
depression have the potential to cause abnormal hemostasis by blocking serotonin
reuptake in platelets. In one study pregnant
rats were administered 5.62 mg/kg fluoxetine by oral gavage beginning on day
7 of gestation and ending the day of birth. At birth, fluoxetine
exposed pups showed a statistically higher frequency of skin hematomas
when compared to controls .
Mhanna et al. described a newborn delivered at term from a woman treated
with fluoxetine 60 mg/day. The infant was jittery and had scattered
petechiae on the face and trunk as well as a cephalohematoma.
Serum fluoxetine and norfluoxetine concentrations were 129ng/mL and 227ng/mL
Reports of abnormal bleeding in infants following in utero exposure to
fluoxetine appear to be otherwise uncommon . It is possible that
bleeding events may occur as an idiosyncratic reaction to fluoxetine treatment
or in infants predisposed to bleeding.
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Prozac (Fluoxetine) and Pregnancy
2001 Organization of Teratology Information Services
Fluoxetine Expert Panel Report
The Center for the Evaluation of Risks to Human Reproduction (CERHR)