Antipsychotic
PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >> Embryo–Fetal Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity
PREGNANCY SUMMARY
Although no structural malformations attributable to quetiapine or other agents in this subclass have been reported, the number of exposures is too low to fully assess the embryo–fetal risk. In addition, there is a risk of extrapyramidal and/or withdrawal symptoms in the newborn if the drug is used in the 3rd trimester. Nevertheless, quetiapine is indicated for severe debilitating mental disease and the benefits to the mother appear to outweigh the potential embryo–fetal risks. Because of the limited human pregnancy experience with atypical antipsychotics, the American College of Obstetricians and Gynecologists does not recommend the routine use of these agents in pregnancy, but a risk–benefit assessment may indicate that such use is appropriate (1). However, the benefits to the mother appear to outweigh the unknown risk to the embryo-fetus (2). A 1996 review on the management of psychiatric illness concluded that patients with histories of chronic psychosis or severe bipolar illness represent a high-risk group (for both the mother and the fetus) and should be maintained on pharmacologic therapy before and during pregnancy (3). Folic acid 4 mg/day has been recommended for women taking atypical antipsychotics because they may have a higher risk of neural tube defects due to inadequate folate intake and obesity (4). A 2010 review of antipsychotic use in pregnancy concluded that most studies reported no adverse effects, including congenital anomalies in the offspring of mothers who had taken quetiapine during pregnancy (5).
FETAL RISK SUMMARY
Quetiapine is an atypical antipsychotic agent that is indicated for the treatment of schizophrenia. The drug is an antagonist of histamine H1 and adrenergic α1-receptors and may cause somnolence and orthostatic hypotension, respectively. Other antipsychotic agents in the same subclass of dibenzapine derivatives are asenapine, clozapine, loxapine, and olanzapine. The drug is extensively metabolized to primarily inactive metabolites and one active metabolite. Plasma protein binding to albumin is 83% and the mean terminal half-life is about 6 hours (6).
Reproduction studies have been conducted in rats and rabbits. No evidence of teratogenicity was observed in pregnant rats or rabbits at oral doses up to 2.4 times the maximum human dose based on BSA (MHD) during organogenesis. However, minor soft-tissue malformations (carpal/tarsal flexure) were noted in rabbit fetuses at 2.4 times the MHD. Embryo–fetal toxicity was observed in both species but the doses used (in rats only with the highest dose and in rabbits with all doses) also caused maternal toxicity (decreased weight gain and/or death). Delays in skeletal ossification were observed in rats at doses equivalent to 0.6 and 2.4 times the MHD. Similar fetal effects were observed in rabbits at doses 1.2 and 2.4 times the MHD. Reduced fetal body weights were noted at the highest doses in both species. No drug-related effects were noted in rat offspring in a perinatal/postnatal study using oral doses that were 0.1–0.24 times the MHD (6).
Quetiapine decreased mating and fertility in male rats given oral doses up to 1.8 times the MHD. Adverse effects (increased interval to mate and number of matings required for successful impregnation) continued to be observed in the high-dose group 2 weeks after treatment had been stopped. In male rats, the no-effect dose for impaired mating and fertility was 0.3 times the MHD. Quetiapine also adversely effected mating and fertility in female rats. At an oral dose 0.6 times the MHD, drug effects included decreases in mating and in matings resulting in pregnancy, and increases in the interval to mate and in irregular estrus cycles (also noted at 0.1 times the MHD). The no-effect dose in female rats was 0.01 times the MHD (6).
In an in vitro study using dually perfused human placentas, small amounts (about 4%) of quetiapine crossed from the maternal side to the fetal venous outflow (7). This is consistent with the molecular weight (about 767 for the free base), moderate protein binding, and the moderately long elimination half-life. In another study, 21 women taking a staple dose (mean 336.9 mg/day) of quetiapine for a mean 28.9 weeks before delivery had maternal and cord concentrations of the drug determined at birth (8). The cord blood concentration was 24.1% of the maternal concentration. The pregnancy outcomes include one premature infant (<37 weeks) and one growth-restricted infant (<2500 g). The mean Apgar scores were 7.6 and 8.9 at 1 and 5 minutes, respectively. There were nine neonatal complications, two cardiovascular and 7 respiratory (complications were not further described), and two infants were admitted to the neonatal intensive care unit (reasons not provided) (8).
A 38-year-old woman with paranoid-type schizophrenia was started on quetiapine (300 mg/day) after an unsuccessful trial with zuclopenthixol (9). After a marked improvement in her symptoms, she conceived with her pregnancy being diagnosed at 17 weeks’ gestation when she reported amenorrhea. At 20 weeks’ her dose was lowered to 200 mg/day, and then 2 weeks later to 150 mg/day. She eventually gave birth to a healthy 3120-g male infant with Apgar scores of 9 and 10 at 1 and 5 minutes, respectively. Birth length was 48 cm. The infant was developing normally at 6 months of age (9).
A 33-year-old woman with psychosis was treated with quetiapine (300 mg/day) beginning 2 weeks before conception and continuing during gestation (10). The dose was decreased to 200 mg/day at week 21. The dose was further reduced by 50 mg/day each week starting 4 weeks before her estimated due date to enable breastfeeding. At 39 weeks’ gestation, she gave birth to a healthy, 3.61-kg female infant with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively. The infant was doing well in the first month after birth (10).
A woman took quetiapine (200 mg/day) throughout pregnancy and gave birth to a term, male infant (11). No information was provided on the pregnancy outcome, but the mother planned to continue the drug while breastfeeding her infant (see below).
A 2005 study, involving women from Canada, Israeli, and England, described 151 pregnancy outcomes in women using atypical antipsychotic drugs (12). The exposed group was matched with a comparison group (N = 151) who had not been exposed to these agents. The drugs and number of pregnancies were olanzapine (N = 60), risperidone (N = 49), quetiapine (N = 36), and clozapine (N = 6). In those exposed, there were 110 live births (72.8%), 22 spontaneous abortions (14.6%), 15 elective abortions (9.9%), and 4 stillbirths (2.6%). Among the live births, one infant exposed in utero to olanzapine had multiple anomalies including midline defects (cleft lip, encephalocele, and aqueductal stenosis). The mean birth weight was 3341 g. There were no statistically significant differences, including rates of neonatal complications, between the cases and controls, with the exceptions of low birth weight (10% vs. 2%, p = 0.05) and elective abortions (9.9% vs. 1.3%, p = 0.003). The low birth weight may have been caused by the increased rate of cigarette smoking (38% vs. 13%, p ≤0.001) and heavy/binge alcohol use (5 vs. 1) in the exposed group (12).
A 2006 report mentioned three women treated with quetiapine and other agents during gestation (13). The drug therapy was continued during breastfeeding (see below).
In a second 2006 report, a 33-year-old woman with severe psychotic depression was treated with quetiapine (400 mg/day) and fluvoxamine (200 mg/day) (14). After appropriate counseling, she continued this therapy and conceived; after a normal pregnancy, she delivered a healthy, 2600-g, length 49 cm, female infant with Apgar scores of 9 and 10 at 1 and 5 minutes, respectively. The infant was developing normally a 3 months (14).
A 26-year-old woman was treated with quetiapine for resistant depression with comorbid chronic pain (15). She took 300 mg/day during the 1st trimester. The dose was increased to 400 mg/day in the 4th month and continued for the remainder of her pregnancy. Other drugs taken throughout pregnancy included oxycodone (20 mg 3 times daily) and fluoxetine (40 mg daily). She delivered a 3.4-kg (50th percentile) male infant at 37 weeks’ gestation, but other details were not provided. She continued the three drugs during breastfeeding (see below) (15).
A 2006 review of prophylactic therapy of bipolar disorder briefly described the effects in pregnancy and breastfeeding of a number of drugs, including (16). Untreated pregnant and nursing women with the disorder are at an increased risk of poor obstetrical outcomes and relapse of affective symptoms. Although the limited data prevented conclusions on the relative safety of the drugs, the author did state that each case needed to be considered separately (16).
A 17-year-old pregnant adolescent with bipolar disorder was treated throughout gestation with quetiapine 300 mg/day, venlafaxine 75 mg/day, and trazodone 150 mg/day (17). In the 1st, 2nd, and 3rd trimesters, plasma concentrations of quetiapine were –27%, –42%, and –18%, respectively, of the concentrations at 6 months postpartum. She gave birth to a healthy 3-kg male infant with Apgar scores of 9, 10, and 10. The infant had jitteriness during the first 4 days of life that did not require intervention. He was seen monthly and met developmental milestones during the first year (17).
A woman with schizophrenia was treated with quetiapine 250 mg/day throughout two consecutive pregnancies (18). In the first pregnancy, she gave birth at term to a healthy 2.5-kg female infant. She conceived again about 1 year later and again delivered a healthy 2.4-kg female infant. Both infants were breastfed while the mother continued quetiapine. Both girls were healthy, the first one at about 2 years of age and the other at about 9 months (18).
A 2014 case study described the use of phenelzine (105 mg/day), lithium (900 mg/day), and quetiapine (600 mg/day) in a 31-year-old woman with bipolar affective disorder (19). She was also taking metformin (1 g/day) for polycystic ovarian syndrome with oligomenorrhea. Despite her oligomenorrhea, a pregnancy was confirmed at 17 weeks’ gestation. A glucose tolerance test was negative at 26 weeks’. Lithium was suspended 24–48 hours before induction of labor at 39 weeks’. Because of obstructed labor, a cesarean section was performed to give birth to a 4.2-kg male infant with Apgar scores of 5 and 9 at 1 and 5 minutes, respectively. The baby required initial resuscitation during the first 10 minutes. The baby was discharged home with the mother at 5 days. At 10 weeks of age, the baby’s growth and development were normal (19).
BREASTFEEDING SUMMARY
Consistent with its molecular weight (about 767 for the free base), protein binding (83%), and mean terminal half-life (about 6 hours), quetiapine is excreted into breast milk. A 36-year-old woman took quetiapine (200 mg/day) throughout gestation and planned to continue the drug while breastfeeding her term, male infant (11). However, the infant was initially given formula because it was not known how much of the drug was excreted in milk. At 3 weeks postpartum, manually expressed milk samples were obtained before a dose and again at 1, 2, 4, and 6 hours after a dose. The average milk AUC over 6 hours was 13 mcg/L, with a maximum concentration of 62 mcg/L measured at 1 hour. At 2 hours, the milk concentrations were almost predose levels. Based on a milk intake of 150 mL/kg/day, it was estimated that an exclusively breastfed infant would ingest 0.09% of the weight-adjusted maternal dose. Even at the maximum concentration, the estimated infant dose was only 0.43% of the maternal dose. When the mother was told of these findings, she began exclusive breastfeeding at 8 weeks. No adverse effects of quetiapine were reported and the infant was developing normally at 4.5 months (11).
A 2006 report described six women treated with quetiapine and other agents during lactation (13). In three cases, therapy was started before or during pregnancy (gestational age shown in parentheses): quetiapine (50 mg) and paroxetine (40 mg) (18 weeks); quetiapine (75 mg), trazodone (75 mg), and venlafaxine (75 mg) (before conception); and quetiapine (100 mg) and venlafaxine (225 mg) (35.5 weeks). In the other three cases, quetiapine was added after delivery (postpartum weeks shown in parentheses): quetiapine (25 mg), paroxetine (60 mg), and clonazepam (0.5 mg) (16.5 weeks); quetiapine (25 mg) and paroxetine (12.5 mg) (3 weeks); and quetiapine (400 mg) and paroxetine (50 mg) (10.5 weeks). Breast milk samples, drawn at variable times after the dose, were obtained between 6.5 and 18.5 weeks postpartum. Quetiapine was not detected (<30 nmol/L) in the breast milk of four women (doses 25–75 mg). The estimated infant exposures in these four cases were <0.01 mg/kg/day. In the two women taking 100 or 400 mg doses, the quetiapine milk levels were 32 and 264 nmol/L, respectively, and the estimated infant exposures were <0.01 and <0.10 mg/kg/day, respectively. Milk levels for the other agents were clonazepam (not detected), paroxetine (not detected in three; 776 nmol/L in one; estimated infant exposure <0.26 mg/kg/day), trazodone (108 nmol/L; estimated infant exposure <0.01 mg/kg/day), and venlafaxine (371 and 1179 nmol/L; estimated infant exposure <0.01 mg/kg/day for both) (13).
At 9–18 months of age, infant behavior was evaluated using the Bayley Scales of Infant Development, Second Edition (13). Four scored within normal limits, whereas two showed mild developmental delay (evaluated at 9 and 12.72 months, respectively). Both infants were exposed to quetiapine and paroxetine; one from 18 weeks’ gestation and the other starting at 3 weeks postpartum. Neither agent was detected in the breast milk of the mothers. Based on the limited sample, the authors concluded that there appeared to be no association between developmental outcomes and exposure to the drugs in breast milk (13).
In a case described in the Fetal Risk Summary section, a woman took quetiapine 400 mg/day and fluvoxamine 200 mg/day throughout a normal pregnancy (14). She continued this therapy while attempting to breastfeed her healthy female infant. Because of insufficient milk production, formula supplementation was required. The infant was developing normally and meeting all milestones at 3 months of age (14).
Another case, also described in the Fetal Risk Summary section, involved a 26-year-old mother taking quetiapine 400 mg/day, oxycodone 60 mg/day, and fluoxetine 40 mg/day during pregnancy and while breastfeeding her 3-month-old male infant (15). The infant’s weight, 3.4 kg (50th percentile) at birth, was now 5.6 kg (25th percentile). Blood and milk samples were collected before the night quetiapine dose was administered and at various times over a 24-hour period. Sixteen milk samples were collected by manual expression at regular feeding times. The average milk concentration of quetiapine was 41 mcg/L and the milk:plasma ratio was 0.29. Using 150 mL/kg/ day as an estimated milk intake, the infant’s dose was 0.09% of the maternal weight-adjusted dose. The infant’s plasma level, 1.4 mcg/L, was about 6% of the corresponding maternal plasma concentration. No adverse effects were noted in the infant. The results of a Denver developmental assessment were consistent with the chronologic age (15).
The long-term effects of these exposures on nursing infants are unknown. The manufacturer recommends women receiving quetiapine should not breastfeed (6). Moreover, the American Academy of Pediatrics classifies other antipsychotics (e.g., see Clozapine) as drugs whose effect on the nursing infant is unknown but may be of concern (20).
References
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