Drug Safety Site.com Taking Paroxetine during pregnancy and breastfeeding

• Home
• Index
• Appendix
• Instructions

PAROXETINE

Fetal Risk Summary

Paroxetine is thought to manifest its antidepressant activity as a selective serotonin reuptake inhibitor (SSRI), thereby potentiating the activity of serotonin in the brain. Its chemical structure is unrelated to other antidepressants, including those classified as SSRI agents. Paroxetine is metabolized to inactive metabolites.

All the antidepressant agents in the SSRI class (citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) share a similar mechanism of action, although they have different chemical structures. These differences could be construed as evidence against any conclusion that they share similar effects on the embryo, fetus, or newborn. In the mouse embryo, however, craniofacial morphogenesis appears to be regulated, at least in part, by serotonin. Interference with serotonin regulation by chemically different inhibitors produces similar craniofacial defects (1). Regardless of the structural differences, therefore, some of the potential adverse effects on pregnancy outcome may also be similar.

In reproduction studies with rats and rabbits, paroxetine was not teratogenic at doses up to 50 mg/kg/day and 6 mg/kg/day, respectively (2). These doses were equivalent to 9.7 and 2.2 times, respectively, the maximum recommended human dose based on mg/m2 (MRHD) for depression and social anxiety disorder (DSAD), and 8.1 and 1.9 times, respectively, the MRHD for obsessive compulsive disorder (OCD). In rats dosed at 0.19 times the MRHD for DSAD and 0.16 times the MRHD for OCD, there was an increase in pup deaths when paroxetine was used during the last trimester and continued during lactation. The cause of the deaths was not known (2). In another study, no embryotoxic or teratogenic effects were observed in either of these species at doses up to 43.0 mg/kg and 5.1 mg/kg, respectively (3).

In a 1999 abstract and a full report in the same year, the effects of paroxetine on behavioral changes in developing mice was studied (4,5). The drug was administered for 2 weeks before conception and throughout gestation. A similar group of mice were administered placebo for comparison. The daily dose (30 mg/kg/day) was known to achieve levels in the mouse serum equivalent to the upper human therapeutic level and to obtain levels in the fetal mouse brain equivalent to those in the adult mouse (5). No drug-induced facial abnormalities were seen, nor were any differences between the exposed and control groups in terms of pregnancy duration, litter size, and sex ratio. Body weights, however, were significantly lower for the exposed pups (both male and female) at least through postnatal day 5. Most of the behavioral tests showed no differences between the groups, but subtle differences in anxiety testing and adult male aggressiveness were noted. Although stating that these findings require confirmation, the investigators speculated that these effects may have resulted from the effect of paroxetine on the development of the postsynaptic serotonin (1A) receptors (5).

No reports describing the transfer of paroxetine across the human placenta have been located. The molecular weight (about 329 for the free base) of the drug is low enough, however, that transfer to the fetus should be expected.

The FDA has received 10 reports of birth defects, including 4 involving clubfoot and 2 cases of cutaneous hemangioma (personal communication, F. Rosa, FDA, 1995).

The results of a postmarketing survey of paroxetine, conducted in England between March 1991 and March 1992, were published in 1993 (6). A total of 137 pregnancies were identified, including 66 in which the drug was stopped before the last menstrual period. In this group there were 12 deliveries, 9 spontaneous abortions, 5 elective terminations, and 40 unknown outcomes. Among the remaining 71 pregnancies, 63 were known to be exposed during the 1st trimester, but the dates of exposure were uncertain in 8. The outcomes in the combined exposed group were 44 newborns (3 sets of twins; 1 twin stillborn, cause not specified), 9 spontaneous abortions, 12 elective terminations, and 9 unknown outcomes. There were no congenital anomalies in the liveborn infants (data not provided for the abortions or stillborn).

Two of the authors of the above study were also co-authors of a 1998 non-interventional observational cohort study that described the outcomes of pregnancies in women who had been prescribed one or more of 34 newly marketed drugs by general practitioners in England (7). Data were obtained by questionnaires sent to the prescribing physicians one month after the expected or possible date of delivery. In 831 (78%) of the pregnancies, a newly marketed drug was thought to had been taken during the 1st trimester, with birth defects noted in 14 (2.5%) singleton births of the 557 newborns (10 sets of twins). In addition, two birth defects were observed in aborted fetuses. However, few of the aborted fetuses were examined. Paroxetine was taken during the 1st trimester in 63 pregnancies. The outcomes of these pregnancies included 8 spontaneous abortions, 11 elective abortions, 1 intrauterine death, 2 stillborns (twins), 3 cases lost to follow-up, 41 normal infants (3 premature plus 2 sets of full term twins). No birth defects were noted in any of the outcomes (7).

A prospective, multicenter, controlled cohort study published in 1998 evaluated the pregnancy outcomes of 267 women exposed to one or more of three SSRI antidepressants during the 1st trimester: fluvoxamine (N=26); paroxetine (N=97); and sertraline (N=147) (8). The women were combined into a study group without differentiation as to the drug they had consumed. All of the women had contacted a teratogen information service about their use of the drugs during pregnancy. A randomly selected control group (N=267) was formed from women who had contacted one service after exposure to nonteratogenic agents. The pregnancy outcomes were determined, in most cases, 6 to 9 months after delivery. The study group was significantly more likely to smoke cigarettes and to have had a previous elective abortion but less likely to be primigravid. Other characteristics, such as a previous spontaneous abortion, alcohol consumption, and maternal age at conception, did not differ between the groups. As for pregnancy outcomes, no significant differences were measured in the number of live births, spontaneous or elective abortions, stillbirths, major malformations, birth weight, or gestational age at birth. Nine major malformations were observed in each group. The relative risk for major anomalies was 1.06 (95% confidence interval [CI] 0.43–2.62). No clustering of defects was apparent. In the study group, no differences were found in the pregnancy outcomes of smokers compared to nonsmokers. In addition, the outcomes of women who took an antidepressant throughout gestation were similar to those who took an antidepressant only during the 1st trimester (8). One of the investigators, in response to subsequent correspondence regarding the study (9,10), clarified that all of the 267 women in the study group had taken an antidepressant during embryogenesis (11). Other concerns relating to the outcomes and sample size were also addressed.

In 1999, the Swedish Medical Birth Registry published the results of a study on the use of antidepressants in early pregnancy and delivery outcome for the years 1995–1997 (12). During the period, 281,728 infants were registered, 531 of whom had been exposed in utero to SSRI antidepressants, 15 to SSRIs plus a non-SSRI antidepressant, and 423 to non-SSRI antidepressants. Of the 122 women who used paroxetine, 118 used it alone, 1 used it in combination with sertraline, and 3 used it in combination with non-SSRI antidepressants (clomipramine, amitriptyline, or nortryptyline). There was no significant differences in relative risk (RR=observed/expected) for birth defects between those exposed to any depressant (total 39; RR 1.13), SSRIs only (total 21; RR 1.12), and non-SSRIs only (total 18; RR 1.15). Similarly, no significant differences in infant survival were observed among the groups. A shorter gestational duration (<37 weeks) was observed for any antidepressant exposure (odds ratio [OR] 1.43, 95% CI 1.14–1.80), but no difference between SSRI and non-SSRI antidepressants. Moreover, antidepressant exposure was not associated with an increased risk of low birth weight (defined as <2500 g) among singletons as the crude OR 1.32, 95% CI 0.96–1.80, decreased to 1.03 after adjustment for confounders (12).

A 2001 case report described complications consistent with neonatal withdrawal in four neonates exposed during pregnancy to paroxetine (13). The infants were delivered at 37–38 weeks' gestation and one mother breast fed her infant. The maternal medications were: paroxetine (10 mg/day); paroxetine (60 mg/day from early pregnancy to 35 weeks, then 120 mg/day to delivery as a result of a dispensing error, then decreased to 60 mg/day during breast feeding) plus desipramine (150 mg/day); paroxetine (20 mg/day) plus buspirone (30 mg/day); and paroxetine (20 mg/day) plus trazodone (50 mg/day) and diphenhydramine (25 mg each night). Neonatal withdrawal has also been reported with diphenhydramine (see Diphenhydramine). The symptoms in the four infants included jitteriness, irritability, lethargy, myoclonus, vomiting, and hypothermia. In one infant, serum levels of paroxetine and desipramine on days 5 and 15 of age were 48 and 70 ng/mL, respectively, and <10 and <10 ng/mL, respectively. In a second infant, the serum paroxetine concentration on day 2 was 66 ng/mL, whereas trazodone was undetectable. Two infants were hypoglycemic (one shortly after birth and one at 40 hours of age), but both mothers had gestational diabetes mellitus and no details of their disease were given. The hypoglycemia in at least one of these infants may have resulted from the mother's condition, because gestational diabetes has been associated with newborn hypoglycemia occurring within a few hours of birth (14). Necrotizing enterocolitis was also observed in two infants. The authors speculated that this condition may have been related to rebound activation of platelets after discontinuance of paroxetine exposure resulting in a hypercoagulable state. The withdrawal symptoms in one infant resolved over a few days, but some symptoms in the other three were still apparent at discharge on days 5, 22, and 24 of age, respectively (13).

In summary, the animal reproductive data and limited human pregnancy experience does not appear to indicate that paroxetine poses a major teratogenic risk. However, the available human studies lack the sensitivity to identify minor anomalies because of the absence of standardized examinations. Late-appearing major defects may also have been missed in at least two of the studies because of the short time frame (i.e., one month) between delivery and follow-up. Withdrawal symptoms were reported in four infants exposed to paroxetine during gestation, but other drug exposures may have contributed to the conditions. Of interest, no studies have examined the effects of in utero paroxetine exposure on human central nervous system development. At least one study has demonstrated that a drug in this class (see Fluoxetine) can induce long-term, perhaps permanent, changes in the brain of rats exposed in utero. Therefore, even though the clinical significance of this is unknown, the potential for behavioral teratogenic effects cannot be excluded. Because of these uncertainties, both short- and long-term studies of exposed infants, including neonatal withdrawal, are warranted.

Breast Feeding Summary

Paroxetine is excreted into human breast milk (15,16,17,18 and 19). A brief 1996 correspondence described a 39-year-old, 60-kg woman with a recurrent depressive and obsessive disorder who was started on paroxetine 20 mg/day (333 µg/kg/day) 3 days after delivery (15). One week later, analysis of a milk sample for paroxetine revealed a concentration of 7.6 ng/mL. Assuming that the infant ingested 0.15 L/kg of milk per day, the authors estimated that the daily weight-adjusted dose was 0.34% of the mother's dose. The minimum milk:plasma ratio (obtained 4 hours after a dose) was estimated to be 0.09. No data were available on the effects of this exposure on the nursing infant (15).

Breast milk concentrations of paroxetine in seven lactating women were reported in a 1999 publication (16). In six women receiving a paroxetine dose of 10–40 mg/day, milk and maternal serum samples were obtained 4–7 hours and 24 hours after a dose. The samples corresponded to either close to peak milk concentrations or trough levels. Based on area under the curve (AUC) calculations, the mean estimated daily infant dose was 1.4% (range 0.7%–2.9%) of the weight-adjusted maternal dose. The mean milk:serum ratio was 0.69 (range 0.39–1.11). In a seventh woman, frequent sampling during two 24-hour periods (one at 20 mg/day and one at 40 mg/day, 7 weeks apart) resulted in estimated daily infant doses of 1.0% and 2.0%, respectively, of the weight-adjusted maternal dose. The milk:serum ratios were 0.69 and 0.72, respectively. The study also measured paroxetine concentrations in foremilk and hindmilk at two steady-state doses (20 and 40 mg/day) in one subject. Drug levels in hindmilk were a mean 78% (range 16%–169%) higher than those in foremilk. The increase paralleled the increase in milk triglycerides and was thought to be consistent with the lipophilic properties of the drug. No adverse effects of the exposure were observed in the seven nursing infants (16).

In a two-phase study published in 1999, the dose of paroxetine received by 10 nursing infants from breast milk was estimated (17). In six subjects sampled over 24 hours, the mean daily estimated infant dose was 1.13% (range 0.5%–1.7%) of the weight-adjusted maternal dose (based on AUC). The mean milk:plasma ratio was 0.39 (range 0.32–0.51). In the second phase, milk and serum samples were obtained from four subjects around a normal infant feeding time. In this case, the mean infant dose was 1.25% (range 0.38%–2.24%) of the maternal dose and the mean milk:plasma ratio was 0.96 (range 0.31–3.33). The milk:plasma ratio was similar for fore and hind milk. Paroxetine was detected (limit 2 ng/mL) in the plasma of one of the eight infants tested, but the concentration was below the level of quantification for the assay (4 ng/mL). No adverse effects were noted in any of the infants (17).

A 2000 study described the excretion of paroxetine into breast milk (18). Sixteen women on a stable paroxetine dose (mean 23.1 mg/day; range 10–50 mg/day) were studied during the postpartum period (range 4–55.2 weeks). Seven of the women had continued their prenatal paroxetine, four had started the antidepressant postpartum, and data were not available for five subjects. Milk samples were collected after a dose at 4- to 6-hour intervals over a 24-hour period. The mean milk concentration was 41.6 ng/mL (range 2–101 ng/mL). Paroxetine concentrations were higher in hindmilk than in foremilk. No detectable levels of paroxetine (all <2 ng/mL) were found in the infants serum, including the 10 infants who were exclusively breast fed. No adverse effects in the nursing infants were reported by the mothers upon direct interview (18).

In another 2000 report, maternal serum, breast milk, and infant serum samples were obtained from 24 mother-infant pairs (mean infant age 4.5 months) 6 hours after a paroxetine dose (19). In 13 of the pairs, the infants were exclusively breast fed. All of the mothers were on a stable dose of paroxetine (10–40 mg/day for at least 30 days). One mother-infant pair was tested twice, once at 10 mg/day and again at 40 mg/day. The mean maternal serum, breast milk, and infant serum concentrations (ng/mL) were 45.2, 19.2, and not detectable (<0.1 ng/mL), respectively. The mean milk:plasma ratio, infant dose, and percent of maternal dose were 0.53, 2.88 µg/kg/day, and 1.1%, respectively. No adverse effects of the drug exposure were noted in the nursing infants, but the investigators recognized the need for follow-up studies to evaluate the potential for long-term effects (19).

A recent review of SSRI agents concluded that if there were compelling reasons to treat a mother for postpartum depression, a condition in which a rapid antidepressant effect is important, the benefits of therapy with SSRIs would most likely outweigh the risks (20). However, because the long-term effects of exposure to SSRI antidepressants in breast milk on the infant's neurobehavioral development are unknown (no such adverse effects have been identified to date but research is needed), stopping or reducing the frequency of breast feeding should be considered if therapy with these agents is required. Avoiding nursing around the time of peak maternal concentration (about 4 hours after a dose) may limit infant exposure. The American Academy of Pediatrics classifies antidepressants as drugs whose effect on a nursing infant is unknown but may be of concern (21). The mother should be provided all of this information so that she can actively participate in any decision.

References

1. Shuey DL, Sadler TW, Lauder JM. Serotonin as a regulator of craniofacial morphogenesis: site-specific malformations following exposure to serotonin uptake inhibitors. Teratology 1992;46:367–78.
2. Product information. Paxil. SmithKline Beecham Pharmaceuticals, 2000.
3. Baldwin JA, Davidson EJ, Pritchard AL, Ridings JE. The reproductive toxicology of paroxetine. Acta Psychiatrica Scand Suppl 1989;350:37–9.
4. Coleman F, Christensen D, Gonzalez C, Rayburn W. Behavioral changes in developing mice after prenatal exposure to paroxetine (Paxil) (abstract). Am J Obstet Gynecol 1999;180:S61.
5. 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.
6. Inman W, Kubota K, Pearce G, Wilton L. PEM report number 6. Paroxetine. Pharmacoepidemiol Drug Safety 1993;2:393–422.
7. Wilton LV, Pearce GL, Martin RM, Mackay FJ, Mann RD. The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England. Br J Obstet Gynaecol 1998;105:882–9.
8. Kulin NA, Pastuszak A, Sage SR, Schick-Boschetto B, Spivey G, Feldkamp M, Ormond K, Matsui D, Stein-Schechman AK, Cook L, Brochu J, Rieder M, Koren G. Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors. A prospective controlled multicenter study. JAMA 1998;279:609–10.
9. Grush LR. Risk of fetal anomalies with exposure to selective serotonin reuptake inhibitors. JAMA 1998;279:1873.
10. Witlin AG. Risk of fetal anomalies with exposure to selective serotonin reuptake inhibitors. JAMA 1998;279:1873.
11. Koren G. In reply. Risk of fetal anomalies with exposure to selective serotonin reuptake inhibitors. JAMA 1998;279:1873–4.
12. Ericson A, Kallen B, Wiholm BE. Delivery outcome after the use of antidepressants in early pregnancy. Eur J Clin Pharmacol 1999;55:503–8.
13. Stiskal JA, Kulin N, Koren G, Ho T, Ito S. Neonatal paroxetine withdrawal syndrome. Arch Dis Child Fetal Neonatal Ed 2001;84:F134–5.
14. Conway DL, Gulinson SM, Langer O. Predictors of neonatal hypoglycemia in pregnancies complicated by gestational diabetes (abstract). Am J Obstet Gynecol 2000;182:S82.
15. Spigset O, Carleborg L, Norstrom A, Sandlund M. Paroxetine level in breast milk. J Clin Psychiatry 1996;57:39.
16. Ohman R, Hagg S, Carleborg L, Spigset O. Excretion of paroxetine into breast milk. J Clin Psychiatry 1999;60:519–23.
17. 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.
18. 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.
19. 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.
20. Edwards JG, Anerson I. Systematic review and guide to selection of selective serotonin reuptake inhibitors. Drugs 1999;57:507–33.
21. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.
    
    

Q&A about Paroxetine

Index

A  B  C  D  E  F  G  H  I  K  L  M  N  O  P  Q  R  S  T  U  V  W  Z

Popular Meds

• Acyclovir
• Allopurinol
• Alprazolam
• Amiodarone
• Amitriptyline
• Amoxicillin
• Atenolol
• Atorvastatin
• Azithromycin
• Bupropion
• Buspirone
• Butalbital
• Carisoprodol
• Cefixime
• Celecoxib
• Cephalexin
• Cetirizine
• Ciprofloxacin
• Clomiphene
• Clonazepam
• Clonidine
• Codeine
• Cyclobenzaprine
• Diazepam
• Diethylpropion
• Diltiazem
• Doxycycline
• Enalapril
• Ephedrine
• Erythromycin
• Estradiol
• Fluconazole
• Fluoxetine
• Furosemide
• Gitalin
• Hydrocodone
• Lorazepam
• Losartan
• Metformin
• Metronidazole
• Minoxidil
• Naproxen
• Ondansetron
• Oxycodone
• Pantoprazole
• Passion Flower
• Phendimetrazine
• Phentermine
• Pioglitazone
• Pravastatin
• Propranolol
• Pseudoephedrine
• Quinine
• Ramipril
• Ranitidine
• Rosiglitazone
• Sertraline
• Simvastatin
• Sumatriptan
• Tamoxifen
• Terbinafine
• Tetracycline
• Thyroid
• Tramadol
• Trazodone
• Valerian
• Vitamin C
• Zolpidem

Copyright © 2003-2008 DRUGSAFETYSITE.COM All rights reserved.