Outcome of Infants Exposed to Olanzapine During Breastfeeding

Abstract

Objective:

This study evaluated the outcome of infants exposed to olanzapine during lactation.

Methods:

A prospective, controlled observational study design was used. Mothers who contacted Beilinson Teratology Information Service regarding use of olanzapine while breastfeeding were followed by phone interview. Data on lactation, neonatal symptoms, and outcome at the age of 1–2 years were obtained. Mother–infant groups were compared. Mothers breastfeeding while taking olanzapine (n = 22) were compared to two control groups of mothers who continued to take olanzapine but did not breastfeed (n = 15) and to breastfeeding mothers using a drug known to be safe during lactation (n = 51).

Results:

Follow-up was obtained for 37 of 70 women. Comparison of olanzapine-exposed breastfed versus control breastfed infants showed a similar duration of breastfeeding; however, early discontinuation of breastfeeding was more common in the olanzapine-exposed breastfed group (five of 22 vs. none of 51, p = 0.02). The rate of adverse outcomes in olanzapine-exposed breastfed infants did not differ from those of the control groups. Among the 30 newborns exposed in utero to olanzapine, no congenital birth defects were found. Neonatal symptoms were seen in six of 30 of olanzapine-exposed infants versus two of 51 of nonexposed infants (p < 0.05). A withdrawal syndrome was seen in three of 30 (10%) infants.

Conclusions:

No increase in adverse long-term outcomes in olanzapine-exposed breastfed infants were found. Our data in conjunction with previous estimates of very low drug exposure support continuation of breastfeeding in women treated with olanzapine. However, until additional long-term studies are available, infants exposed to olanzapine through breastmilk should be followed up.

Introduction

The postpartum period is associated with an increased risk of psychiatric disorders with up to 20% of mothers affected.¹ These disorders range from mild mood disorders to major depression and postpartum psychosis. Schizophrenia and related psychotic disorders occur in 1–2% of women, commonly during the years of childbearing potential.² While some women will require antipsychotic medication during pregnancy and thereafter, others will initiate therapy while breastfeeding. Thus information on safety of antipsychotic medications during lactation is essential.

Olanzapine is a new antipsychotic agent structurally similar to clozapine. It has a greater affinity for serotonin than for dopamine receptors, accounting for greater efficacy and effects on both positive and negative symptoms of schizophrenia and an improved extrapyramidal side effects profile.^3,4 Recent evidence suggests that olanzapine has potential for broader use in treating bipolar disorders, pathologic aggression, substance abuse disorders, additional affective disorders, and other conditions.⁵ Applying these indications may increase exposure in women of childbearing age.⁶

The aim of the present study was to evaluate the outcome of infants exposed to olanzapine during breastfeeding. A secondary objective was to obtain information on neonatal symptoms of infants exposed in utero to olanzapine.

Materials and Methods

A prospective, controlled observational study design was used to assess the safety of olanzapine use during lactation.^7,8 Data were obtained from the Beilinson Teratology Information Service (BELTIS), Rabin Medical Center, Petah Tiqwa, Israel, which is a free service accessible to the public for all questions related to drug effects during pregnancy and lactation. During the initial query information was obtained using a standard questionnaire. Items covered included maternal age, parity, number of gestations, smoking habits, alcohol or drug use, use of medications, gestational age, infant sex, birth weight, examination at birth and data regarding breast-feeding. During the initial call the mothers were told that information regarding olanzapine and breastfeeding was limited, but that the existing data supported infant safety during lactation because of a low relative infant dose and lack of reported side effects.^6,9–15 Lactation was permitted under close medical supervision of the mother and her infant. The mothers were specifically instructed to check for sufficient weight gain, changes in the infant's appetite, and the presence of somnolence or agitation. All queries were regularly followed up after obtaining maternal consent during the initial phone call. Mothers who sought information regarding use of olanzapine during the period 2005–2008 were contacted 1–2 years after their initial query for a follow-up telephone interview using a structured questionnaire focusing on possible adverse effects to the mothers and their infants. Data regarding duration of breastfeeding, drug dose, infant growth, and development were recorded. Early discontinuation of breastfeeding was defined as stopping breastfeeding within 3 weeks of initiation. The study group (n = 22), which was composed of breastfeeding mothers taking olanzapine and their infants, was compared to two control groups, one (n = 15) composed of non-breastfeeding mothers who were taking olanzapine and their infants and a second (n = 51) that included breastfeeding mothers who contacted BELTIS regarding use of a drug known to be safe during lactation (paracetamol) and their infants. The paracetamol control group was matched to the study group for year of birth, gestational age, and birth weight. The control groups were followed up similarly to the study group. The study was approved by the Rabin Medical Center Research Ethics Board.

Statistical analysis

Continuous variables were compared by group using analysis of variance with Bonferroni's correction for multiple comparisons. Discrete variables were compared by group using Pearson's χ² test. A p value of <0.05 was considered statistically significant. The data were analyzed using BMDP Statistical Software (Chief Editor, W.J. Dixon, University of California Press, Los Angeles, CA, 1993).

Results

During the study period 70 women contacted BELTIS regarding use of olanzapine during lactation. Of the 70 women, 33 could not be included (nine refused to participate, six did not take olanzapine, and 18 were lost to follow-up). Of the remaining 37 women, 22 breastfed while taking olanzapine, whereas 15 women elected not to breastfeed.

Maternal characteristics are described in Table 1. The maternal characteristics were similar in most respects; however, multiple drug therapy was more common among women who used olanzapine but decided not to breastfeed. Thirty women used olanzapine during their pregnancy including 18 of 22 in the olanzapine-exposed breastfed group and 12 of 15 in the olanzapine-exposed non-breastfed group. No congenital birth defects were identified in the 30 infants exposed in utero to olanzapine.

Table 1.

Maternal and Perinatal Characteristics of Infants Exposed to Olanzapine During Breastfeeding Versus Nonexposed Infant Control Groups

Characteristic	Olanzapine, breastfed (n = 22)	Olanzapine, non-breastfed (n = 15)	Acetaminophen, breastfed (n = 51)	p value
Mean maternal age (years) (SD)	31.3 (5.6)	30.7 (5.3)	31.9 (4.4)	NS
Mean number of pregnancies (SD)	2.7 (2.0)	2.3 (2.2)	2.0 (1.4)	NS
Mean number of deliveries (SD)	2.7 (2.0)	2.3 (2.2)	2.0 (1.3)	NS
Pregnancy duration (weeks) (SD)	38.7 (2.5)	37.6 (3.1)	39.6 (1.3)	0.003^a
Alcohol use during pregnancy	1	0	2	NS
Tobacco smoking during pregnancy	0	0	1	NS
Mean daily olanzapine dose (mg) (SD)	6.25 (4.10)	5.68 (2.25)	NR	NS
Olanzapine use during pregnancy (%)	18 (82%)	12 (80%)	0 (0%)	NS
Additional drug use during lactation (%)	6 (27%)	10 (67%)	0 (0%)	<0.001
Birth weight (g) (SD)	3,293 (574)	3,133 (652)	3,253 (501)	NS
Male gender (%)	8 (36%)	7 (47%)	21 (42%)	NS

Comparison of olanzapine-exposed non-breastfed to acetaminophen group.

NR, not relevant; NS, not significant.

Fifteen women treated with olanzapine did not breastfeed because of difficulties in initiating breastfeeding (two women), fear of infant drug effects (four women), medical advice (five women), initiation of new drug (three women), and unknown cause (one woman). Early discontinuation of breastfeeding was more common in the olanzapine-exposed breastfed group versus the control breastfed group (five of 22 vs. none of 51, p = 0.02). The duration of breastfeeding was similar in the olanzapine-exposed breastfed and control breastfed infants (22.4 ± 20.2 weeks vs. 24.9 ± 6.4 weeks, p = 0.4). The reasons for early discontinuation of breastfeeding were difficulty in breastfeeding (one woman), fear (one woman), medical advice (one woman), and initiation of drug for which lactation was prohibited (two women).

Neonatal symptoms in infants prenatally exposed to olanzapine and in nonexposed control infants were also recorded. Neonatal symptoms were seen in eight of 30 (27%) of olanzapine-exposed infants versus one of 51 (2%) of control infants (p = 0.001). Neonatal symptoms recorded in olanzapine-exposed infants included respiratory distress (two), hypotonia (one), poor sucking or feeding difficulty (two), and a withdrawal syndrome (three). It is of note that six of the eight symptomatic olanzapine-exposed infants were in the non-breastfed group, whereas only two were in the olanzapine-exposed breastfed group (p = 0.1).

Adverse long-term outcomes in olanzapine-exposed breastfed, olanzapine-exposed non-breastfed, and paracetamol control groups are described in Table 2. Adverse long-term outcomes were seen in three of 22 (14%) of olanzapine-exposed breastfed infants compared to one of 15 (7%) of olanzapine-exposed non-breastfed infants and four of 51 (8%) of control infants. The study and control groups did not differ significantly in the rate of adverse outcomes.

Table 2.

Adverse Long-Term Outcomes in Olanzapine-Exposed Versus Nonexposed Infants

Characteristic	Olanzapine, breastfed (n = 22)	Olanzapine, non-breastfed (n = 15)	Acetaminophen breastfed (n = 51)	p value
Any adverse outcomes (%)^a	3 (14%)	1 (7%)	4 (8%)	NS
Feeding problems	0	0	1	NS
Speech delay	1	0	0	NS
Motor developmental delay	1	0	0	NS
Failure to gain weight	2	0	3	NS
Small head circumference	0	1	0	NS

Some infants had multiple adverse outcomes.

Discussion

Data regarding use of olanzapine during breastfeeding is scarce, based only on four case reports and two case series (16 subjects) and an additional case series giving limited information from a pharmaceutical company registry (23 subjects)^6,9–15 (Table 3). The present study showed that the rate of adverse outcomes in olanzapine-exposed breastfed infants did not differ from control groups, supporting the relative safety of maternal olanzapine therapy during breastfeeding.

Table 3.

Reports on Maternal Use of Olanzapine During Breastfeeding

Study	Number of patients	Follow-up	Dose	Maternal drug levels	Breastmilk drug levels	Infant drug levels	Long-term adverse outcomes
Kirchheiner et al.¹⁰	1	11 months	10 mg/day	33.4–39.5 ng/mL	NA	Below detection	None
Goldstein et al.^6,9^a	23	NA	7.5 mg/day	NA	NA	NA	Somnolence associated with diarrhea (1)
							Lethargy and poor sucking (1)
Croke et al.¹¹	5	NA	2.5–10 mg/day	8–31 mg/L	<1–21 ng/mL	<1 ng/mL	None
Gardiner et al.¹²	7	NA	5–20 mg/day	3–15 ng/mL	1.2–22.7 ng/mL	<1–<5 ng/mL	Drowsiness (1)
							Developmental delay (1)^b
Friedman and Rosenthal¹³	1	6 months	5 mg/day	NA	NA	NA	None
Lutz et al.¹⁴	1	2 months	15 mg/day	24 ng/mL	11.5–12.2 ng/mL	<5 ng/mL	None
Whitworth et al.¹⁵	1	8 months^c	5–15 mg/day	3.7–27 ng/mL	0.4–5 ng/mL	0–11 ng/mL	None
Present report	22	1–2 years	2.5–10 mg/day	NA	NA	NA	Speech delay (1)
							Motor development delay (1)
							Failure to gain weight (2)

Based on pharmaceutical company registry.

Treated by multiple medications.

Breastfed at the ages of 3–8 months.

NA, not available.

Breastfeeding while taking antipsychotic drugs is controversial because of possible adverse effects on the breastfeeding infant. Breastfeeding has well-known proven benefits enabling normal infant development, which should be weighed against the potential risks to the baby from exposure to medications through breastmilk, including adverse drug effects and undetermined long-term effects on neurobehavioral development.

Olanzapine is secreted in small amounts into breastmilk, with the highest levels detected in breast milk 5 hours after last maternal dose. The median milk-to-plasma ratio for olanzapine was 0.38, and the median dose ingested through breastmilk was 1–1.6% of the weight-adjusted maternal dose.^11,12 However, despite ingestion of small amounts of drug through breastmilk, serum levels of olanzapine were undetectable in most infants tested.^10–12,14 It is of note that a single case report showed variation in infant plasma drug levels attributed to an immature hepatic transformation system.¹⁵ This infant was asymptomatic, and with time drug levels decreased to an undetectable value. These data suggest that infant exposure to olanzapine through breastmilk is small and that olanzapine may be a relatively safe drug to use while breastfeeding.^11,12,16,17

In our study we compared a group of breastfeeding women using olanzapine and their infants to two control groups, one composed of non-breastfeeding mothers taking olanzapine and their infants and a second including breastfeeding mothers using a drug known to be safe during lactation and their infants. The three groups were similar in most respects; however, discontinuation of breastfeeding was more common in the olanzapine-exposed breastfeeding group compared to the breastfeeding control group, mostly because of fear or medical advice.

Neonatal effects (poor sucking, respiratory difficulties, sedation) described were similar to those published in earlier studies.^6,9–15 It is of note that most neonatal symptoms were seen in a subgroup of women who either breastfed only for a short period or did not breastfeed at all, thus possibly influencing their motivation to breastfeed. Three newborns exposed in utero to olanzapine suffered from a withdrawal syndrome. All three were born to mothers taking multiple drugs (clopixol, paroxetine, lithium); thus we cannot determine which drug or drug combination caused the withdrawal syndrome.

Despite the lack of identifiable drug-related adverse outcomes, some study limitations should be acknowledged. Although this is the largest long-term study to date, the sample size is relatively small. Our data are based on maternal reporting, and the duration of follow-up may lead to a possible recall bias. The follow-up period is insufficient to identify minor developmental difficulties. Because of the study design maternal plasma and milk and neonatal plasma drug levels were not obtained and could not be correlated with possible adverse drug effects.

In conclusion, long-term follow-up of infants exposed to olanzapine during breastfeeding was not associated with an increased rate of adverse outcomes compared to control infants. Our data in conjunction with previous estimates of very low drug exposure through breastmilk support continuation of breastfeeding in women requiring treatment with olanzapine. However, until additional long-term follow-up studies are available, caution should be exercised when using olanzapine: The lowest dose that is effective for the mother should be used, and infant follow-up by a pediatrician should be considered.

Footnotes

Disclosure Statement

No competing financial interest exist.

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