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 [1].

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 [2].

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 [3].

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 significant [5].

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 birth [6].

However, Goldstein et al. found no consistent or recurring pattern of abnormalities after first-trimester exposure to fluoxetine in 796 pregnancies [7]. 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 fluoxetine [8,9]. 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 [10].

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 exposure [6]. 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 [6].

Cohen LS, et al. also found SSRI exposure during pregnancy to be a risk factor for special care nursery admission [11], and Simon GE et al. reported higher rates of preterm birth amongst women exposed to SSRIs [12]. However, a study by Goldstein was unable to confirm an increase in neonatal problems after third trimester exposure to fluoxetine in 115 infants [13]. 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 0.88  [16-19]
     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 [19].

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 [20].

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 [21].

Irritability, decreased sleep, vomiting and watery stools were reported in one nursing mother while taking fluoxetine [22].

The manufacturer recommends that fluoxetine not be used by nursing mothers in accordance with a 1994 FDA advisory [23].

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" [24].

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 infant [25].

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[26].

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[27].

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 [28].

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 respectively.  Reports of abnormal bleeding in infants following in utero exposure to fluoxetine appear to be otherwise  uncommon [29]. It is possible that bleeding events may occur as an idiosyncratic reaction to fluoxetine treatment or in infants predisposed to bleeding.

SEARCH LITERATURE

1. Physicians Desk Reference 57th ed. Montvale, NJ: Thomson PDR; 2004: 1841-43
2. Hendrick V, et. al. Placental passage of antidepressant medications. Am J Psychiatry. 2003;160:993-6. MEDLINE
3. Addis A and Koren G.Safety of fluoxetine during the first trimester of pregnancy: a meta-analytical review of epidemiological studies.Psychol Med. 2000;30:89-94. MEDLINE
4.Rosa F. Medicaid antidepressant pregnancy exposure outcomes. Reprod Toxicol 1994;8:444-445.
5.Pastuszak A, et al. Pregnancy outcome following first-trimester exposure to fluoxetine (Prozac)JAMA. 1993 5;269:2246-8. MEDLINE
6.Chambers CD, et al. Birth outcomes in pregnant women taking fluoxetine. N Engl J Med 1996;335:1010-1015. MEDLINE
7. Goldstein DJ, et al.. Effects of first- trimester fluoxetine exposure on the newborn. Obstet Gynecol 1997;89:713-8.21. MEDLINE
8. Mattson, SN et al.  "Neurobehavioral Follow-up of Children Prenatally Exposed to Fluoxetine." Teratology.1999  59:376
9. Nulman I, et al.. Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: a prospective, controlled study. Am J Psychiatry. 2002;159:1889-95. MEDLINE
10.Casper RC,et al Follow-up of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy.J Pediatr. 2003;142:402-8. MEDLINE
11. Cohen LS, et al: Birth outcomes following prenatal exposure to fluoxetine. Biol Psychiatry 2000;48:996-1000. MEDLINE
12.Simon GE et al., Outcomes of prenatal antidepressant exposure. Am J Psychiatry. 2002;159:2055-61. MEDLINE
13. Goldstein DJ. Effects of third trimester fluoxetine exposure on the newborn.J Clin Psychopharmacol. 1995;15:417-20. MEDLINE
14.Steer RA, et al Self-reported depression and negative pregnancy outcomes. J Clin Epidemiol. 1992;45:1093-9. MEDLINE
15.Orr ST and Miller CA. Maternal depressive symptoms and the risk of poor pregnancy outcome. Review of the literature and preliminary findings.Epidemiol Rev. 1995;17:165-71. MEDLINE
16. Burch KJ and Wells BJ Fluoxetine/norfluoxetine concentrations in human milk. Pediatrics. 1992;89:676-7. MEDLINE
17. Isenberg KE. Excretion of fluoxetine in human breast milk.J Clin Psychiatry. 1990;51:169. MEDLINE
18. Kristensen JH, et al. Distribution and excretion of fluoxetine and norfluoxetine in human milk. Br J Clin Pharmacol. 1999;48:521-7. MEDLINE
19. Taddio A, et al Excretion of fluoxetine and its metabolite, norfluoxetine, in human breast milk. J Clin Pharmacol. 1996;36:42-7. MEDLINE
20. Yoshida K, et al. Fluoxetine in breast-milk and developmental outcome of breast-fed infants. Br J Psychiatry. 1998;172:175-8. MEDLINE
21. Chambers CD, et al. Weight gain in infants breastfed by mothers who take fluoxetine.Pediatrics. 1999;104:e61. MEDLINE
22. Lester BM, et al. : Possible association between fluoxetine hydrochloride and colic in an infant.J Am Acad Child Adolesc Psychiatry. 1993 Nov;32(6):1253-5. MEDLINE
23. Nightingale SL. Fluoxetine labeling revised to identify phyenytoin interaction and to recommend against use in nursing mothers. JAMA 1994;271:1067. MEDLINE
24. Transfer of drugs and other chemicals into human milk. Pediatrics. 2001 Sep;108(3):776-89.
25. Nordeng H,et al. [The transfer of selective serotonin reuptake inhibitors to human milk]Tidsskr Nor Laegeforen. 2001;121:199-203. MEDLINE
26. Nordeng H, et al. Neonatal withdrawal syndrome after in utero exposure to selective serotonin reuptake inhibitors. Acta Paediatr. 2001;90:288-91. MEDLINE
27. Spencer MJ. Fluoxetine hydrochloride (Prozac) toxicity in a neonate. Pediatrics. 1993;92:721-2. MEDLINE
28. Stanford MS and  Patton JH In utero exposure to fluoxetine HCl increases hematoma frequency at birth.Pharmacol Biochem Behav. 1993;45:959-62. MEDLINE
29. Mhanna MJ et al Potential fluoxetine chloride (Prozac) toxicity in a newborn.Pediatrics. 1997 ;100:158-9. MEDLINE

ADDITIONAL READING:

Prozac (Fluoxetine) and Pregnancy (PDF file)
2001 Organization of Teratology Information Services

Fluoxetine Expert Panel Report (PDF file)
The Center for the Evaluation of Risks to Human Reproduction (CERHR)

Created: 11/17/2000
 Updated: 11/30/2002
 Updated: 1/17/2004
 Updated: 10/17/2004