ORIGINAL CONTRIBUTION
Mirtazapine in Pregnancy and Lactation Data From a Case Series Mirte Smit, MD,* Hanneke J.M.B. Wennink, MD, PhD,* Marion M.H.B. Heres, MD, PhD,† Koert K.M. Dolman, MD, PhD,* and Adriaan Honig, MD, PhD‡ Abstract: Depression is a common disorder in pregnancy and associated with adverse effects for both mother and neonate. Pharmacological treatment and prevention options include mirtazapine. In a series of 56 cases, we investigated neonatal outcome after intrauterine exposure to mirtazapine and exposure through lactation in the first days postpartum. No increase in any neonatal complication was observed. None of the infants exposed to mirtazapine in the first trimester were born with a major malformation. Of the 54 infants exposed to mirtazapine in the third trimester, 14 were diagnosed with poor neonatal adaptation syndrome (PNAS). This incidence (25.9%) is similar to the incidence of PNAS after intrauterine exposure to other antidepressants. The incidence of PNAS after exposure to mirtazapine was significantly diminished in children who were partially or fully breastfed (18.6% versus 54.5%, P = 0.024). Key Words: mirtazapine, pregnancy, neonatal outcomes, teratogenicity, safety, neonatal abstinence syndrome, pharmacology (J Clin Psychopharmacol 2015;35: 163–167)
D
epression is a common disease in both pregnancy and postpartum. The estimated prevalence varies from 12.7% in pregnancy to 19.2% for the combined period.1–3 Studies suggest that depression during pregnancy might cause an increased risk for low birth weight, restricted fetal growth, and preterm birth.4–6 A correlation between depression, prenatal stress, and adverse neurodevelopmental outcome of the child has been shown recently.7–9 When indicated, the use of antidepressants for the treatment of depression and prevention of relapses is well established.10,11 Concerns on medication in pregnancy include increased risk for congenital malformation, neonatal withdrawal, or poor neonatal adaptation syndrome (PNAS) and possible transfer of medication through breast milk. Mirtazapine is a relatively new antidepressant, classified as a noradrenergic and specific serotonergic antidepressant. It affects both serotonin and norepinephrine systems in the central nervous system.12 A meta-analysis showed that, in adult population, mirtazapine is as effective as other antidepressants such as tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) at the end of the acute-phase treatment of depression.13 Mirtazapine use during pregnancy and lactation may have an advantage over other antidepressants because it exhibits sleep quality–enhancing properties.12 Although sleep-enhancing drugs such as benzodiazepines in the third trimester may pose problems with respect to the respiration of the neonate,14 mirtazapine may
From the Departments of *Pediatrics, †Gynecology and Obstetrics, and ‡Psychiatry, Sint Lucas Andreas Hospital, VU University Medical Center, Amsterdam, the Netherlands. Received January 1, 2014; accepted after revision December 9, 2014. Reprints: Adriaan Honig, MD, PhD, Department of Psychiatry, Sint Lucas Andreas Hospital, Jan Tooropstraat 164, 1061 AE Amsterdam, the Netherlands (e‐mail: [email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0271-0749 DOI: 10.1097/JCP.0000000000000279
prove to be an acceptable alternative. However, there is no consensus on its safety in pregnancy and lactation. Concerns on the use of mirtazapine in the first trimester of pregnancy include the possible risk for congenital malformations. When mirtazapine is used in the third trimester, neonatal withdrawal or PNAS may occur as well as adverse effects during breastfeeding. Up to now, we found a total of 372 cases exposed to mirtazapine either in utero or via lactation in PubMed. These data showed no evidence of increased risk for congenital malformation. Hitherto, reports on PNAS after in utero exposure to mirtazapine are limited to 1 case report.15 Nevertheless, a warning for PNAS is stated by the UK Teratology Information Service (uktis.org), with the suggestion to monitor exposed neonates postpartum for 2 days to detect possible adverse effects. Respiratory problems and hypoglycemia have been reported in 1 study in which mirtazapine had been given during pregnancy in combination with other psychopharmacological medication.16 Scarce information is available on mirtazapine and lactation. The aim of the present cases series was to describe birth outcomes in newborns who have been exposed to mirtazapine during gestation and in the first days postpartum, including neonatal complications, major malformations, PNAS, and feeding methods.
METHODS Setting The Psychiatry, Obstetrics, and Pediatrics (POP) clinic in Sint Lucas Andreas Hospital in Amsterdam, the Netherlands, is a specialized center for pregnant and planning women. For women with a psychiatric history and/or actual symptoms during pregnancy, the POP clinic offers 2 predelivery outpatient visits and an observation period for mother and child of at least 48 hours postpartum. Exposed babies are seen in pediatric outpatients for observation of possible congenital malformations 3 weeks postpartum. On a yearly basis, approximately 120 women participate in the complete protocol.
Inclusion Data were collected from a consecutive cohort of pregnant women who were prescribed with mirtazapine during pregnancy followed by an immediate postpartum observation together with their neonates on the maternity ward of at least 2 days between September 2007 and October 2012. When women had more than 1 pregnancy while exposed to mirtazapine during this study period, pregnancies were included as separate cases (n = 1). Use of mirtazapine and possible other medications was registered through self-report during the POP outpatient visits on admittance, during pregnancy, or during the observation period on the maternity ward. Use of comedication, including other psychopharmacological agents, was documented. In addition, use of alcohol, tobacco, and illicit drugs was registered every contact on the basis of self-report and reports by other medical professionals.
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Journal of Clinical Psychopharmacology • Volume 35, Number 2, April 2015
Smit et al
The patients were asked for dosage of their medications as well as the duration of its use. Use of medication was registered every trimester. Any concurrent use of medication that might influence mirtazapine serum concentration, such as CYP3A4 inducers (ie, carbamazepine), was documented as well.
Poor Neonatal Adaptation Syndrome The newborns were 8-hourly monitored on symptoms of PNAS by nurses trained in the Finnegan scoring list. This neonatal abstinence scoring system is validated for PNAS because of opiate use during pregnancy17; although the system is not validated for PNAS after intrauterine exposure to antidepressants, by default, it is generally used for the screening of PNAS.18–20 A Finnegan score of 4 or higher is considered suggestive of PNAS, although other causes such as infection can give a rise in Finnegan scores. Poor neonatal adaptation syndrome was therefore subsequently diagnosed by a pediatrician on the basis of the score as well as other clinical parameters.
Statistics The database was analyzed using Statistical Package for the Social Sciences 17.0. Fisher exact tests were used when different groups were compared on categorical end points.
RESULTS A total of 55 women who had used mirtazapine during 56 pregnancies participated in the study. During these pregnancies, 26 (46.4%) fetuses had been exposed to mirtazapine in the first trimester, 34 (60.7%) fetuses had been exposed in the second trimester, and 54 (96.4%) fetuses had been exposed to mirtazapine in the third trimester. The mean (SD) dosage of mirtazapine in the first trimester was 27.1 (12.1) mg/d (minimum, 7.5; maximum, 45; n = 23); in the second trimester, the mean (SD) dosage was 28.4 (12.0) mg/ d (minimum, 7.5; maximum, 45; n = 32); and in the third trimester, the mean (SD) dosage was 28.9 (12.1) mg/d (minimum, 7.5; maximum, 60; n = 54). During pregnancy, 18 (32.1%) women used other, nonpsychopharmacological medication. These medications were checked for known interactions with mirtazapine with the use of pharmacokinetic information as provided by manufacturers. No interactions were found. Almost half of the included pregnant women had 1 psychiatric diagnosis (26/56 women, 46.4%); the other patients had more than 1 diagnosis. Patient characteristics are shown in Table 1. Characteristics regarding the neonates are shown in Table 2. A total of 56 neonates were included in the study, of whom 24 (42.9%) were breastfed only, 20 (35.7%) were given mixed feeding (both breastfeeding and formula), and 12 (21.4%) were given formula feeding only. We saw no feeding problems or sleeping problems. An increased Finnegan score (≥4) was detected in 26 of the 54 neonates who were exposed in utero to mirtazapine in the third trimester (48.1%); 5 (9.3%) neonates showed a highly increased Finnegan score (≥8). Of these neonates, 14 (25.9%) neonates, all with a Finnegan score of 4 or higher, were diagnosed with PNAS by a pediatrician. Two (3.7%) neonates were admitted to the neonatal ward because of severe withdrawal symptoms. In the group of infants exposed in the third trimester, breastfed children, either exclusively or in combination with formula, showed less PNAS diagnosed by a pediatrician, compared with children who were formula fed only (8/43 [18.6%] versus 6/11 [54.5%], P = 0.024).
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Within the group of neonates who were exposed to mirtazapine in utero in the third trimester (n = 54), 19 (35.2%) newborns were also exposed to other psychopharmacological medication during the third trimester. There was no significant difference in the incidence of PNAS between this group (n = 19) and the neonates exposed only to mirtazapine (26.3% versus 25.7%, P = 0.603). Birth weight was below p10 in 5.4% of the neonates and above p90 in 12.5% of the neonates.
DISCUSSION This study on a consecutive cohort of 56 new cases of mirtazapine exposure in pregnancy attributes to the scarce information on safety of mirtazapine in pregnancy. However, because of the observational nature of this study, lacking any control group, no definitive conclusions can be drawn. Second, this study is a case series, so obviously, no incidence rates of either mirtazapine use in pregnancy and lactation or the absolute or relative chance of any problems associated with the use of mirtazapine in pregnancy or lactation can be given. Part of our results is in accordance with previously published data. However, our results on PNAS after exposure to mirtazapine
TABLE 1. Patient Characteristics of the Included Pregnant Women (N = 56) Characteristics Age, mean (SD), y
Mean (SD)/n (%)
Missing
31.89 (5.27) [minimum, 20; maximum, 41]
0
Marital status Married 30 (53.6%) Cohabiting 12 (23.2%) Not cohabiting 3 (5.4%) Single 7 (12.5%) Ethnicity White 11 (19.6%) Nonwhite 30 (53.6%) Psychiatric diagnosis Depressive disorder 45 (80.4%) Anxiety disorder 26 (46.4%) Other psychiatric disorder 17 (30.4%) No disorder diagnosed 1 (1.8%) Hard drugs during pregnancy 1 (1.8%) Soft drugs during pregnancy 2 (3.6%) Smoking during pregnancy 7 (12.5%) Alcohol during pregnancy 0 Other psychopharmacological medication None 28 (50.0%) During first trimester 24 (42.9%) During second trimester 22 (42.9%) During third trimester 21 (37.5%) During complete pregnancy 16 (28.6%) Other nonpsychopharmacological 18 (32.1%) medication
3 (5.4%)
15 (26.8%)
0
1 (1.8%) 5 (8.9%) 2 (3.6%) 7 (12.5%) 0
0
Table 1 states the patient characteristics of all pregnant women included in this study. The last column shows any missing information per characteristic.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Journal of Clinical Psychopharmacology • Volume 35, Number 2, April 2015
TABLE 2. Patient Characteristics of Neonates Characteristics Sex Method of birth Spontaneous, vaginal Assisted delivery Cesarean section AD, d Preterm birth (p90 SGA
Mirtazapine in Pregnancy and Lactation Data From a Case Series Mirte Smit, MD,* Hanneke J.M.B. Wennink, MD, PhD,* Marion M.H.B. Heres, MD, PhD,† Koert K.M. Dolman, MD, PhD,* and Adriaan Honig, MD, PhD‡ Abstract: Depression is a common disorder in pregnancy and associated with adverse effects for both mother and neonate. Pharmacological treatment and prevention options include mirtazapine. In a series of 56 cases, we investigated neonatal outcome after intrauterine exposure to mirtazapine and exposure through lactation in the first days postpartum. No increase in any neonatal complication was observed. None of the infants exposed to mirtazapine in the first trimester were born with a major malformation. Of the 54 infants exposed to mirtazapine in the third trimester, 14 were diagnosed with poor neonatal adaptation syndrome (PNAS). This incidence (25.9%) is similar to the incidence of PNAS after intrauterine exposure to other antidepressants. The incidence of PNAS after exposure to mirtazapine was significantly diminished in children who were partially or fully breastfed (18.6% versus 54.5%, P = 0.024). Key Words: mirtazapine, pregnancy, neonatal outcomes, teratogenicity, safety, neonatal abstinence syndrome, pharmacology (J Clin Psychopharmacol 2015;35: 163–167)
D
epression is a common disease in both pregnancy and postpartum. The estimated prevalence varies from 12.7% in pregnancy to 19.2% for the combined period.1–3 Studies suggest that depression during pregnancy might cause an increased risk for low birth weight, restricted fetal growth, and preterm birth.4–6 A correlation between depression, prenatal stress, and adverse neurodevelopmental outcome of the child has been shown recently.7–9 When indicated, the use of antidepressants for the treatment of depression and prevention of relapses is well established.10,11 Concerns on medication in pregnancy include increased risk for congenital malformation, neonatal withdrawal, or poor neonatal adaptation syndrome (PNAS) and possible transfer of medication through breast milk. Mirtazapine is a relatively new antidepressant, classified as a noradrenergic and specific serotonergic antidepressant. It affects both serotonin and norepinephrine systems in the central nervous system.12 A meta-analysis showed that, in adult population, mirtazapine is as effective as other antidepressants such as tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) at the end of the acute-phase treatment of depression.13 Mirtazapine use during pregnancy and lactation may have an advantage over other antidepressants because it exhibits sleep quality–enhancing properties.12 Although sleep-enhancing drugs such as benzodiazepines in the third trimester may pose problems with respect to the respiration of the neonate,14 mirtazapine may
From the Departments of *Pediatrics, †Gynecology and Obstetrics, and ‡Psychiatry, Sint Lucas Andreas Hospital, VU University Medical Center, Amsterdam, the Netherlands. Received January 1, 2014; accepted after revision December 9, 2014. Reprints: Adriaan Honig, MD, PhD, Department of Psychiatry, Sint Lucas Andreas Hospital, Jan Tooropstraat 164, 1061 AE Amsterdam, the Netherlands (e‐mail: [email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0271-0749 DOI: 10.1097/JCP.0000000000000279
prove to be an acceptable alternative. However, there is no consensus on its safety in pregnancy and lactation. Concerns on the use of mirtazapine in the first trimester of pregnancy include the possible risk for congenital malformations. When mirtazapine is used in the third trimester, neonatal withdrawal or PNAS may occur as well as adverse effects during breastfeeding. Up to now, we found a total of 372 cases exposed to mirtazapine either in utero or via lactation in PubMed. These data showed no evidence of increased risk for congenital malformation. Hitherto, reports on PNAS after in utero exposure to mirtazapine are limited to 1 case report.15 Nevertheless, a warning for PNAS is stated by the UK Teratology Information Service (uktis.org), with the suggestion to monitor exposed neonates postpartum for 2 days to detect possible adverse effects. Respiratory problems and hypoglycemia have been reported in 1 study in which mirtazapine had been given during pregnancy in combination with other psychopharmacological medication.16 Scarce information is available on mirtazapine and lactation. The aim of the present cases series was to describe birth outcomes in newborns who have been exposed to mirtazapine during gestation and in the first days postpartum, including neonatal complications, major malformations, PNAS, and feeding methods.
METHODS Setting The Psychiatry, Obstetrics, and Pediatrics (POP) clinic in Sint Lucas Andreas Hospital in Amsterdam, the Netherlands, is a specialized center for pregnant and planning women. For women with a psychiatric history and/or actual symptoms during pregnancy, the POP clinic offers 2 predelivery outpatient visits and an observation period for mother and child of at least 48 hours postpartum. Exposed babies are seen in pediatric outpatients for observation of possible congenital malformations 3 weeks postpartum. On a yearly basis, approximately 120 women participate in the complete protocol.
Inclusion Data were collected from a consecutive cohort of pregnant women who were prescribed with mirtazapine during pregnancy followed by an immediate postpartum observation together with their neonates on the maternity ward of at least 2 days between September 2007 and October 2012. When women had more than 1 pregnancy while exposed to mirtazapine during this study period, pregnancies were included as separate cases (n = 1). Use of mirtazapine and possible other medications was registered through self-report during the POP outpatient visits on admittance, during pregnancy, or during the observation period on the maternity ward. Use of comedication, including other psychopharmacological agents, was documented. In addition, use of alcohol, tobacco, and illicit drugs was registered every contact on the basis of self-report and reports by other medical professionals.
Journal of Clinical Psychopharmacology • Volume 35, Number 2, April 2015
www.psychopharmacology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
163
Journal of Clinical Psychopharmacology • Volume 35, Number 2, April 2015
Smit et al
The patients were asked for dosage of their medications as well as the duration of its use. Use of medication was registered every trimester. Any concurrent use of medication that might influence mirtazapine serum concentration, such as CYP3A4 inducers (ie, carbamazepine), was documented as well.
Poor Neonatal Adaptation Syndrome The newborns were 8-hourly monitored on symptoms of PNAS by nurses trained in the Finnegan scoring list. This neonatal abstinence scoring system is validated for PNAS because of opiate use during pregnancy17; although the system is not validated for PNAS after intrauterine exposure to antidepressants, by default, it is generally used for the screening of PNAS.18–20 A Finnegan score of 4 or higher is considered suggestive of PNAS, although other causes such as infection can give a rise in Finnegan scores. Poor neonatal adaptation syndrome was therefore subsequently diagnosed by a pediatrician on the basis of the score as well as other clinical parameters.
Statistics The database was analyzed using Statistical Package for the Social Sciences 17.0. Fisher exact tests were used when different groups were compared on categorical end points.
RESULTS A total of 55 women who had used mirtazapine during 56 pregnancies participated in the study. During these pregnancies, 26 (46.4%) fetuses had been exposed to mirtazapine in the first trimester, 34 (60.7%) fetuses had been exposed in the second trimester, and 54 (96.4%) fetuses had been exposed to mirtazapine in the third trimester. The mean (SD) dosage of mirtazapine in the first trimester was 27.1 (12.1) mg/d (minimum, 7.5; maximum, 45; n = 23); in the second trimester, the mean (SD) dosage was 28.4 (12.0) mg/ d (minimum, 7.5; maximum, 45; n = 32); and in the third trimester, the mean (SD) dosage was 28.9 (12.1) mg/d (minimum, 7.5; maximum, 60; n = 54). During pregnancy, 18 (32.1%) women used other, nonpsychopharmacological medication. These medications were checked for known interactions with mirtazapine with the use of pharmacokinetic information as provided by manufacturers. No interactions were found. Almost half of the included pregnant women had 1 psychiatric diagnosis (26/56 women, 46.4%); the other patients had more than 1 diagnosis. Patient characteristics are shown in Table 1. Characteristics regarding the neonates are shown in Table 2. A total of 56 neonates were included in the study, of whom 24 (42.9%) were breastfed only, 20 (35.7%) were given mixed feeding (both breastfeeding and formula), and 12 (21.4%) were given formula feeding only. We saw no feeding problems or sleeping problems. An increased Finnegan score (≥4) was detected in 26 of the 54 neonates who were exposed in utero to mirtazapine in the third trimester (48.1%); 5 (9.3%) neonates showed a highly increased Finnegan score (≥8). Of these neonates, 14 (25.9%) neonates, all with a Finnegan score of 4 or higher, were diagnosed with PNAS by a pediatrician. Two (3.7%) neonates were admitted to the neonatal ward because of severe withdrawal symptoms. In the group of infants exposed in the third trimester, breastfed children, either exclusively or in combination with formula, showed less PNAS diagnosed by a pediatrician, compared with children who were formula fed only (8/43 [18.6%] versus 6/11 [54.5%], P = 0.024).
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Within the group of neonates who were exposed to mirtazapine in utero in the third trimester (n = 54), 19 (35.2%) newborns were also exposed to other psychopharmacological medication during the third trimester. There was no significant difference in the incidence of PNAS between this group (n = 19) and the neonates exposed only to mirtazapine (26.3% versus 25.7%, P = 0.603). Birth weight was below p10 in 5.4% of the neonates and above p90 in 12.5% of the neonates.
DISCUSSION This study on a consecutive cohort of 56 new cases of mirtazapine exposure in pregnancy attributes to the scarce information on safety of mirtazapine in pregnancy. However, because of the observational nature of this study, lacking any control group, no definitive conclusions can be drawn. Second, this study is a case series, so obviously, no incidence rates of either mirtazapine use in pregnancy and lactation or the absolute or relative chance of any problems associated with the use of mirtazapine in pregnancy or lactation can be given. Part of our results is in accordance with previously published data. However, our results on PNAS after exposure to mirtazapine
TABLE 1. Patient Characteristics of the Included Pregnant Women (N = 56) Characteristics Age, mean (SD), y
Mean (SD)/n (%)
Missing
31.89 (5.27) [minimum, 20; maximum, 41]
0
Marital status Married 30 (53.6%) Cohabiting 12 (23.2%) Not cohabiting 3 (5.4%) Single 7 (12.5%) Ethnicity White 11 (19.6%) Nonwhite 30 (53.6%) Psychiatric diagnosis Depressive disorder 45 (80.4%) Anxiety disorder 26 (46.4%) Other psychiatric disorder 17 (30.4%) No disorder diagnosed 1 (1.8%) Hard drugs during pregnancy 1 (1.8%) Soft drugs during pregnancy 2 (3.6%) Smoking during pregnancy 7 (12.5%) Alcohol during pregnancy 0 Other psychopharmacological medication None 28 (50.0%) During first trimester 24 (42.9%) During second trimester 22 (42.9%) During third trimester 21 (37.5%) During complete pregnancy 16 (28.6%) Other nonpsychopharmacological 18 (32.1%) medication
3 (5.4%)
15 (26.8%)
0
1 (1.8%) 5 (8.9%) 2 (3.6%) 7 (12.5%) 0
0
Table 1 states the patient characteristics of all pregnant women included in this study. The last column shows any missing information per characteristic.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Journal of Clinical Psychopharmacology • Volume 35, Number 2, April 2015
TABLE 2. Patient Characteristics of Neonates Characteristics Sex Method of birth Spontaneous, vaginal Assisted delivery Cesarean section AD, d Preterm birth (p90 SGA
