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Depression is common in women, especially during pregnancy and the postpartum period. Untreated depression is associated with many adverse gestational outcomes. It is therefore important to know about the safety of different antidepressant drugs during pregnancy and lactation so that informed decisions can be made regarding treatment. This article summarizes published literature on the subject with regard to duloxetine, an antidepressant with serotonin-norepinephrine reuptake inhibition properties. In general, it appears that the use of duloxetine during pregnancy is associated with an increase in the risk of spontaneous abortion, but no increase in other adverse outcomes, such as major fetal malformations. Late-pregnancy exposure to duloxetine may be associated with poor neonatal adaptation syndrome, but the magnitude of this risk is not known. Infant exposure to duloxetine in breast milk is less than 1% of the maternal weight-adjusted dose, suggesting that duloxetine can be safely administered to a woman who is breastfeeding her infant. In general, the very limited data available on the subject do not uncover a signal that the use of duloxetine during pregnancy or lactation increases the risk of adverse outcomes.
J Clin Psychiatry 2014;75(12):e1423-e1427 (doi:10.4088/JCP14f09631).
© Copyright 2014 Physicians Postgraduate Press, Inc.
Ms K is a 29-year-old woman with a 7-year history of recurrent depressive illness. She has been euthymic on duloxetine (80 mg/d) for the past 18 months. She wishes to conceive. She recognizes that duloxetine has stabilized her life. She knows that she is at increased risk of relapse into depression during pregnancy and the postpartum period and that continuation of duloxetine could protect her against relapse. However, she is concerned about the possible adverse effects of duloxetine on her child. What information is available on the subject?
Pregnancy is associated with a unique combination of physical, physiologic, and psychological stresses, and women are at increased risk of depression during pregnancy and the postpartum period1-3; this is especially so if they have a previous history of depression and if they discontinue effective antidepressant treatment before conceiving or after discovering that they are pregnant.4
Depression is associated with neuroendocrinologic changes, immunologic impairments, abnormal eating patterns, nutritional disorders, neglect of health, poor adherence to medical regimens, smoking and drinking, impulsive behavior, deliberate self-harm, and other behaviors, all of which can harm not only the mother but also the unborn child. These factors may explain why untreated depression during pregnancy is associated with several adverse maternal and offspring outcomes, including preterm birth, low birth weight, perinatal complications, decreased initiation of breastfeeding, poor mother-child bonding, etc.3,5-7 There is therefore an increasing trend to advocate the continuation of effective antidepressant treatment during pregnancy and lactation, especially in women with more severe forms of illness,8-10 and this is reflected by an increasing prevalence of antidepressant use during pregnancy.11-13
In a single case report,14 umbilical cord serum concentration of duloxetine was found to be only 12% of that in maternal serum, and the ratio of duloxetine in infant plasma to maternal plasma was just 0.81% during lactation. If these findings can be generalized, they suggest that fetal and neonatal exposure to duloxetine is low when this drug is used during pregnancy and lactation. Case reports, however, are not evidence. This article therefore examines what is known about the use of duloxetine during pregnancy and lactation. The contents of this article are based on a PubMed search conducted on November 2, 2014, with the search terms duloxetine combined singly with pregnancy, malformations, teratogenicity, lactation, breastfeeding, and milk. Searches were also conducted for duloxetine paired with specific adverse pregnancy outcomes.
Duloxetine and Pregnancy Outcomes
Duloxetine is a serotonin-norepinephrine reuptake inhibitor that is classified as a Pregnancy Category C drug by the US Food and Drug Administration (FDA)15; that is, there are no adequate and well-controlled studies of duloxetine in pregnant women. What do the available data show?
In a multicenter, prospective, observational study, Einarson et al16 followed 208 women who had directly or through their health care providers inquired about the safety of duloxetine during pregnancy. Of these, 206 women (99.0%) took duloxetine before conception and during early pregnancy, 51 (24.5%) used it all through pregnancy, and 2 took it only during the second or third trimesters. These women were compared with 208 randomly selected women who had inquired about the use of other antidepressants during pregnancy and 208 women who had inquired about the use of substances not considered to be teratogenic. The 3 groups were matched for age and for alcohol and tobacco use. There were 165 live births and 3 (1.8%) major malformations (clubfoot, hydronephrosis, kidney agenesis) in the duloxetine group. The rate of major malformations did not differ significantly across the 3 groups (P = .99). Although the sample was underpowered for confident conclusions, it is reassuring that the malformation rate was not elevated above the 2%-3% rate that is expected in the general population. Readers may note that to identify a doubling of malformation risk from 3% to 6%, a sample of 750 women would have been required in each of the groups. Other pregnancy outcomes were not reported in this study.16
Hoog et al17 reported on 400 cases of duloxetine exposure during pregnancy for which pregnancy outcome information was available. These cases were identified from the Eli Lilly Safety System database. There were 233 prospectively recorded cases, of which 170 were spontaneous reports, 58 were from clinical trials, and 5 were from postmarketing studies. The mean age of the women was 32 years. Most (74%) women had received duloxetine for the indication of depression. There were 41 (18%) spontaneous abortions, 19 (8%) premature births, 25 (13%) perinatal or postnatal conditions (not further described), 6 (3%) congenital malformations, 3 (1%) ectopic pregnancies, 3 (1%) intrauterine deaths or stillbirths, and 1 postterm delivery. Relative to women with normal pregnancy outcomes (n = 140; 61%), women with abnormal outcomes (n = 90; 39%) were more likely to have used potentially unsafe medications such as benzodiazepines, nonsteroidal anti-inflammatory drugs, and anticonvulsants during pregnancy (13% vs 26%, respectively; P = .02). Also, relative to women with normal outcomes, women with abnormal outcomes were more likely to have had a past or current history of medical issues such as miscarriage, smoking, and substance abuse (17% vs 30%, respectively; P = .03). It is therefore uncertain whether the abnormal outcomes recorded were due to duloxetine use, the depression, the medical issues, the concurrent medications, or combinations of these factors. In any case, with the possible exception of spontaneous abortion, the rates of adverse outcomes were largely similar to those in the general population.
Hoog et al17 noted that the Eli Lilly database also contained 167 retrospectively reported cases, which included 120 (72%) abnormal outcomes. These outcomes were not further described by the authors, perhaps because retrospective identification is known to be biased toward adverse findings. Finally, Hoog et al17 observed that analysis of data from the FDA Adverse Event Reporting System database did not demonstrate disproportionality of adverse outcomes (congenital anomaly, spontaneous abortion, induced abortion, ectopic pregnancy, and stillbirth) in women treated with duloxetine as compared with all other drugs or with selected antidepressants.
In an analysis of data from population-based registries, Kjaersgaard et al18 reported that exposure to duloxetine during pregnancy was associated with a trebled risk of spontaneous abortion (relative risk = 3.12; 95% CI, 1.55-6.31) in women diagnosed with depression.
No information is available about duloxetine and other pregnancy outcomes such as preterm delivery, low birth weight, persistent pulmonary hypertension of the newborn, and other perinatal complications.
Duloxetine, Poor Neonatal Adaptation Syndrome, and Other Infant Outcomes
Late-pregnancy exposure to antidepressant drugs has been associated with the development of the poor neonatal adaptation syndrome (PNAS), also known as the neonatal behavioral syndrome. The clinical features of PNAS include 1 or more of the following: lethargy, hypoactivity, shaking, shivering, tremors, excessive crying, jitteriness, irritability, agitation, poor feeding, excessive weight loss, rapid respiration, respiratory distress, hypothermia, hypoglycemia, increased or decreased muscle tone, and seizures.6,19
The odds of PNAS are 5 times as high in antidepressant-exposed infants as in unexposed infants.19 The clinical features of PNAS develop hours to days after birth and resolve days to (rarely) weeks later.6 It is unclear to what extent PNAS is due to antidepressant withdrawal and to what extent it is due to antidepressant toxicity resulting from an inability of the neonate to capably metabolize the drug that is present in the circulation at birth.19
Poor neonatal adaptation syndrome, including probable seizures, was reported in a child born at 38 weeks after late-pregnancy exposure to duloxetine (90 mg/d). However, at a 2-year follow-up, the child was healthy with consistently normal neurobehavioral development.20 Another case of neonatal withdrawal syndrome was described after late-pregnancy exposure to duloxetine (90 mg/d) in a woman who was receiving insulin for gestational diabetes; because the woman was also receiving lamotrigine (100 mg/d) and quetiapine (800 mg/d), it is uncertain to what extent duloxetine contributed to the PNAS.21
Bellantuono et al22 described a 42-year-old woman with a past history of major depressive illness and comorbid panic disorder who received duloxetine (60 mg/d) throughout pregnancy; she delivered a healthy baby at 37 weeks of gestation. There was no malformation, perinatal complication, or abnormal neurobehavioral outcome in the child on prospective follow-up to age 9 months. Briggs et al23 and Boyce et al14 also described completely uneventful exposure to duloxetine (60 mg/d) during the second half of pregnancy and all through pregnancy, respectively.
Other than the case reports described above, there is no published information about duloxetine exposure during pregnancy and long-term neurobehavioral outcomes.
Transfer of Duloxetine Across the Placenta
At least 2 case reports have presented duloxetine levels in cord blood, which is a proxy measure of transplacental transfer of the drug. Briggs et al23 found that, in a woman who received duloxetine (60 mg/d) during the latter half of pregnancy, the concentration of the drug in cord plasma was 65 μg/L; the sample was obtained 14 hours after a 60-mg extended-release dose. A corresponding maternal plasma sample was not obtained. However, the concentration of duloxetine in maternal plasma was slightly lower, at 53 μg/L, on the same dose and with sampling conducted 32 days after delivery, with the blood sample drawn 6 hours after dosing.
Boyce et al14 found that the concentration of duloxetine in cord serum was 18 μg/L and that the corresponding concentration of the drug in maternal serum was 151 μg/L. The transplacental transfer ratio, therefore, was just 0.12 (12%).
Transfer of Duloxetine Into Breast Milk
Briggs et al23 studied a breastfed infant whose mother was receiving duloxetine (60 mg/d). They found that the peak concentration of duloxetine in milk was double that of the trough concentration (64 vs 31 μg/L, respectively) and that the milk-to-plasma ratios at the milk peak and milk trough were 1.21 and 1.29, respectively. The theoretical infant dose was calculated to be 7.1 μg/d, corresponding to a relative infant dose that was just 0.82% that of the mother’s weight-adjusted dose. Duloxetine was not detected in the infant’s plasma with a limit of detection of 1 μg/L.
Boyce et al14 found that, with duloxetine dosed at 60 mg/d, the average concentration of duloxetine in milk was 51 μg/L across a 24-hour period. Thus, an infant consuming 150 mL of milk daily would receive 7.7 μg of duloxetine per day. When the dose of duloxetine was adjusted for body weight, the relative infant dose was estimated at 0.81% of the maternal dose. The concentrations of duloxetine in infant and maternal plasma, assessed 7.6 hours after the morning dose of the drug, were 2 and 245 μg/L, respectively; the infant concentration was 0.82% that of the maternal concentration. The concentration of duloxetine in hindmilk was 1.4 to 2.0 times that in foremilk, depending on the time of sampling.
Lobo et al24 administered duloxetine 40 mg twice daily to 6 healthy women who were weaning their infants and who stopped nursing during the course of the study. All women were at least 12 weeks postpartum. Paired milk and blood samples were obtained at steady state. The mean concentration of duloxetine in milk was in the 10-20 μg/L range, while the mean concentration of the drug in maternal plasma was in the 30-60 μg/L range. The ratio of duloxetine in milk to plasma was 0.25 (95% CI, 0.18-0.35) for the 12-hour area under the curve. The mean quantity of duloxetine in breast milk was 7.4 (range, 4-15) μg/d. The predicted infant exposure was 1.7 (range, 0.6-3.1) μg/kg/d, which was 0.14% (range, 0.06%-0.25%) of the maternal weight-adjusted dose.
These findings are reassuring, given that infant exposure that is < 10% of the maternal dose is generally considered acceptable.25
There is only a small body of information available on the safety of duloxetine in pregnancy and lactation. From the literature that has been reviewed, the following broad conclusions can be drawn:
Practical Notes About Dosing
Here are some practical suggestions for dosing duloxetine during pregnancy. These suggestions are based on clinical knowledge of pharmacodynamics and pharmacokinetics, rather than on specific evidence.
It needs to be recognized that although 60 mg/d is the standard antidepressant dose for duloxetine, some patients may require higher doses. In this context, Waldschmitt et al32 found that depressed patients who were very much improved with duloxetine had higher serum levels of the drug than those with moderate, minimal, or no improvement (mean, 93 vs 47 ng/mL, respectively); however, daily doses of duloxetine did not differ significantly between duloxetine responders and nonresponders (mean, 76 vs 83 mg/d, respectively). It is difficult to know what to make of these findings, but whereas the dose could have been unnecessarily high in the responders, it was clearly inadequate in the nonresponders with low serum levels. In other words, patients who fail to respond to approved doses of duloxetine may require higher-than-approved doses to bring their serum duloxetine levels within a more therapeutic range.
For a more general discussion of recommendations regarding the use of antidepressants in pregnancy and lactation, readers are referred to available reviews on the subject.6,10,33
Each month in his online column, Dr Andrade considers theoretical and practical ideas in clinical psychopharmacology with a view to update the knowledge and skills of medical practitioners who treat patients with psychiatric conditions.
Department of Clinical Psychopharmacology and Neurotoxicology, National Institute of Mental Health and Neurosciences, Bangalore, India (firstname.lastname@example.org).
Financial disclosure and more about Dr Andrade.
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