Adverse effects and short-term developmental outcomes of infants exposed to atypical antipsychotics during breastfeeding.

BACKGROUND: Postpartum period in women is vulnerable to the occurrence and exacerbation of psychiatric disorders. Mothers with postpartum psychosis or bipolar disorder need treatment with psychotropic medications, especially atypical antipsychotics. However, many mothers and families will have reservations about the use of psychotropics during the perinatal period, particularly during breastfeeding because of its presumed side effects and adverse developmental outcomes of the child. Since there are limited data in this area, the present study aimed to examine the adverse effects, if any, and the short-term developmental outcome of infants exposed to atypical antipsychotics during breastfeeding.
METHODS: The study involved infants of postpartum women (n = 28) who were admitted in the mother and baby inpatient psychiatry unit of a tertiary care center in India. The medication side effects were checked every alternate day for 1-2 weeks using a checklist based on common side effects that infants may experience due to lactation exposure of atypical antipsychotics. Developmental assessments of the infants were done using the Developmental Assessment Scales for Indian Infants and through anthropometric measurements such as weight, length, head circumference, and chest circumference in follow-up when they came as an outpatient after 1-3 month interval.
RESULTS: The occurrence of adverse side effects was quite low (17.85%). The main side effects directly attributable to atypical antipsychotics were constipation and sedation. Of the 17 infants who attended follow-up, 52.9% (n = 9) showed some form of developmental delay at the time of the first follow-up. However, low birth weight, higher maternal age (>35 years), and exposure to medications (quetiapine and phenytoin) during pregnancy may be confounding risk factors.
CONCLUSIONS: The acute adverse effects of atypical antipsychotics such as sedation and constipation in the infant through breast milk were seen in less than a fourth of the sample. Developmental delay was noted in a proportion of infants; however, this may be due to other risk factors. Copyright:

INTRODUCTION

The postpartum period is a difficult period which causes biological, physical, social, and emotional changes in women. Pregnant women and their families have lots of aspirations which are fulfilled by the joyful arrival of a new baby in the postpartum period. The postpartum period in women is vulnerable to occurrence and exacerbations of psychiatric disorders. Postpartum psychosis and bipolar disorder are the two major psychiatric disorders during this period, and usually, they necessitate the use of an antipsychotic drug. Postpartum psychosis occurs in approximately 1–2/ 1000 childbirth.[12] Postpartum period has increased the risk of recurrence or new episodes of bipolar disorder, especially in those who discontinue treatment. Postpartum women are 2.9 times more likely to have recurrences of mood episodes than nonpregnant women on discontinuation of medication during pregnancy.[3] Severe postpartum psychiatric disorders pose a significant challenge to the bonding and attachment between mother and infant as well as the cognitive and behavioral development of the infant.[4] Psychotic symptoms at postpartum onset may increase the risk of neglect and harm of self and the infant.[56] Thus, mothers with postpartum psychosis or bipolar disorder need treatment with psychotropic medications, especially antipsychotics.

Recently, atypical antipsychotics are more commonly used for postpartum psychosis and bipolar disorder because they are more effective and have less extrapyramidal adverse effects than the typical antipsychotics.[7] However, if the mother is on psychotropic medication and is nursing the infant, the drugs can pass onto the infant through breastfeeding. Since the mother's milk is the best source of nutrition for the infants up to the first 6–12 months of life,[8] antipsychotic medication has specific implications for both mother and child. It is clear from the literature that atypical antipsychotics can cause increased sedation in mothers, but the impact on nursing infants is not very robust. One of the common questions asked by the families in our clinical setting is, “whether there are any side effects of the medication to the infant because of breastfeeding?” However, there are no robust data to address these concerns. Hence, there is a need for safety data on adverse effects and developmental outcomes of infants exposed to atypical antipsychotics through breastfeeding. Much of the current information on adverse effects and developmental outcome of antipsychotics come from single-case studies. Barring a few studies,[8] there are no prospective studies to understand the adverse effects and developmental outcome of infants exposed to atypical antipsychotics through breastfeeding. In this context, the present study aimed to examine the adverse effects and short-term developmental outcomes of infants exposed to atypical antipsychotics through breastfeeding.

MATERIALS AND METHODS

The study was conducted at the mother–baby inpatient unit in India. The unit is managed by a multidisciplinary team of psychiatrists, psychologists, psychiatric social workers, and nurses. A lactation expert is available on call to respond to breastfeeding difficulties, and pediatric support is available from a neighboring pediatric hospital. All mother–infant dyads are assessed for their suitability to admission under mother–baby unit (MBU) facility. Based on the risks, necessary decisions are made about joint admissions, with precautions to ensure the safety of the mother and the infant. Mothers and infants are admitted with a family member (usually a woman). The majority of the mothers (80%) stayed for 3–4 weeks, and the mean duration of hospital stay was 17.23 ± 14.56 days.[9] The study was approved by the Institute Ethical Committee. Infants of the mothers with postpartum psychiatric illness (n = 28), who were admitted in the mother and baby inpatient psychiatry ward of the hospital and had been started on atypical antipsychotics during the period of January 2016–November 2016, were recruited for the study after obtaining written informed consent from the mothers [Figure 1].

Figure 1

Recruitment process of participants

Inclusion criteria for the study were as follows: (1) mother and baby dyads admitted to the MBU, (2) all full-term infants who are being breastfed (partial or exclusive) by a mother who is on antipsychotics, (3) and infants age <6 months of age. Exclusion criteria for the study were (1) preterm delivery, (2) birth weight <2kg, (3) major neonatal complications (needing neonatal intensive care unit stay), (4) major congenital anomaly, (5) major medical or surgical illness, and (6) mother taking medication for any other medical illness.

Tools

Intake proforma

A structured proforma was designed to record minimum sociodemographic data of mother and infant dyads. Clinical details included the pregnancy exposure to psychotropics, medication for any medical/surgical illnesses, term, type of delivery, complications during delivery, birth weight of infant, major congenital anomalies, major medical/surgical illnesses of the dyads, lactation details, and postpartum medication details.

Adverse effects checklist

A checklist was prepared based on standard textbooks in psychiatry, pediatrics and latest data available on the adverse effects of atypical antipsychotics during breastfeeding.[1011] It included common adverse effects such as sedation, irritability, tremor, insomnia, rigidity, constipation, rashes, diarrhea, excessive cry, jitteriness, seizure, myoclonic jerks, lethargy, difficulty in sucking, urinary retention, cyanosis, abdominal colic, vomiting, fever, jaundice, and hypersalivation.

Developmental Assessment Scale for Indian Infants

Developmental Assessment Scale for Indian Infants (DASII)[12] is a standardized test of developmental assessment for Indian infants which is based on the Bayley Scale of Infant Development. The normative values on DASII have been established based on a sample of Indian children. It assesses the development of children from birth to 30 months of age and provides a measure of motor development and mental development as motor development quotient (DQ) and mental DQ, respectively.[13] Although the published literature on it is limited, it is commonly used in India.[14] Developmental delay is defined on DASII as DQ score ≤70 in either the mental or motor scale.

Anthropometric measurements

It included measurement of weight, length, head circumference, and chest circumference. Any score less than three percentile of the population norm was considered as a significant deviation. The details of the assessment are as follows:

Weight

A digital weighing scale was used to measure the weight of infants at follow-ups. Shoes, bulky clothing, ornaments, and any other objects the infant may be carrying were removed. The weighing scale was placed on a flat surface. Readings were recorded in kilograms to the nearest decimal fraction.

Length

The child was placed supine on the flat table. The head was held firmly, and the legs were straightened, keeping the feet at right angles to the legs with the toes pointing upward. The length was measured from the feet to the crown of the head.

Head circumference

The maximum circumference of the head from the occipital protuberance to the supraorbital ridges on the forehead was recorded.

Chest circumference

The chest circumference was measured at the level of the nipples, midway between inspiration and expiration, while the child was in a recumbent position.

Procedure

The mother–infant dyads were recruited in the study after obtaining written informed consent from the mother. Relevant sociodemographic and clinical details were noted using the intake pro forma. Medication side effects were checked every alternate day for 1–2 weeks using the checklist mentioned above. Developmental assessments (using DASII and specified anthropometric measurements) were carried out after the infant's age was >3 months and the mother and infant followed up in the outpatient department except for one infant who was assessed at 1.5 months of age because the mother was unable to come for follow-up later. Half of the infants (47.05%) were followed 1–3 months of exposure to atypical antipsychotics when they came as an outpatient. Infant's weight and height were compared with the 3rd and 50th percentile curve of growth chart of the Indian infant to determine the developmental delay in weight and height.[11] DASII rating was done in consensus with one of the guides. Data were analyzed using the Statistical Package for Social Sciences for Windows (Version 20.0. 0, Computer software, Chicago, IL: IBM).

RESULTS

The mean age of mothers (n = 28) during the study was 26.5 years (Standard deviation [SD] = 6.56 years). Only three mothers (10.72%) were >34 years of age. Most women who were selected for the study were educated up to class ten (35.71%), four (14.29%) were educated less than the tenth standard, and six (21.43%) were graduates. Twenty-one (75%) women were from low socioeconomic status and 7 (25%) women were of middle socioeconomic status. Half of the women were from a rural background (n = 15; 53.57%). International Statistical Classification of Diseases 10 diagnosis included acute and transient psychotic disorder (n = 5), schizophrenia (n = 7), bipolar affective disorder (n = 8), schizoaffective disorder (n = 2), and severe depression (n = 2).

The infants' mean age was 10.36 weeks (SD = 6.32), with majority being around 12 weeks of age (n = 20; 71.43%). The mean birth weight of the infants was 3.01 kg (SD = 0.52).

Twenty-four infants (85.71%) were on supplementary breastfeeding, whereas only four (14.29%) infants were on exclusive breastfeeding. Of 28 infants, 15 infants (53.57%) were exposed to olanzapine. The minimum dose of olanzapine given to mother was 2.5 mg/day, whereas the maximum dose of olanzapine given to mother was 30 mg/day. Eleven infants (39.29%) were exposed to risperidone through breastfeeding, with a maternal dose ranging from 4 mg/day to 8 mg/day. Two infants were exposed to quetiapine through breastfeeding, with a maternal dose range of 25 mg/day–200 mg/day. Among the infants who were exposed to olanzapine and risperidone through breastfeeding, 7.14% had constipation and 10.71% had sedation.

Three infants were found to have rashes during their hospital stay. The first infant had a rash on back of the head from the day of admission, the second infant's rash subsided with calamine lotion, whereas the third infant had a perianal rash which was found during diarrhea and it subsided with it, so direct causation with atypical antipsychotics could not be established [Table 1].

Table 1

Side effects noted in infants during exposure to atypical antipsychotics through breastfeeding (n=28)

Variable Side effects	Frequency, n (%)
Rash	3 (10.71)
Sedation	3 (10.71)
Diarrhea	2 (7.14)
Constipation	2 (7.14)
Excessive cry	1 (3.57)
Jitteriness	1 (3.57)

Three infants had developed sedation during the hospital stay in which one infant's mother was on olanzapine 20 mg and chlorpromazine 100 mg; another infant's mother was on olanzapine 10–15 mg/day, whereas the third infant's mother was on risperidone 4 mg and lorazepam 2 mg when sedation happened, but it was not seen on the last day when lorazepam was stopped. Thus, it appears that olanzapine and risperidone could cause sedation independently, but the risk increases with the use of adjuvant benzodiazepines or another antipsychotic used to sedate the mother.

Two infants developed diarrhea. One of these infants' mother was on risperidone 4 mg and lorazepam 6 mg and the other was on olanzapine 10 mg. However, diarrhea subsided in 2–3 days, so it seems that diarrhea may not be because of atypical antipsychotics, but other factors could have contributed to the etiology.

Two infants developed constipation during the hospital stay. In the two infants who developed constipation during the hospital stay, one infant's mother was on risperidone 4 mg, Trihexyphenidyl 2 mg, and electroconvulsive therapy, whereas other infant's mother was on olanzapine 20 mg, ranitidine 300 mg, and cough syrup.

One infant was noted to be excessively crying, but this behavior was reported to be present even before atypical antipsychotics were prescribed.

One infant was found to have jitteriness which subsided on the addition of Vitamin D, so it seems that jitteriness was because of Vitamin D deficiency and not because of atypical antipsychotics.

Therefore, these results indicate that olanzapine and risperidone's exposure through breastfeeding may cause constipation in infants. Olanzapine exposure through breastfeeding may cause sedation in infants, but it is not clear whether the same will happen with risperidone.

All mothers consented for follow-up, but only 17 came for follow-up. Most infants (47.05%) were followed up after 1–3 months of discharge from the inpatient stay. Three out of 17 (17.65%) infant's weight were <3rd percentile of population norm. Of these three infants, the first infant's mother was on phenytoin during pregnancy, the second infant had lower birth weight (2.25 kg) than mean birth weight of our sample (3 kg), whereas the third infant did not have any other risk factors [Table 2].

Table 2

Short-term developmental outcomes of infants exposed to atypical antipsychotics during breastfeeding

Diagnosis (ICD-10)	Age of mother (years)	Birth weight of infant (kg)	Medication during pregnancy	Atypical antipsychotics	Developmental outcome
					Weight	Height	DASII
Delirium	30	3	No	Olanzapine	Normal	Normal	Normal
Mania with psychotic symptoms	19	3.5	No	Olanzapine	Normal	Normal	Normal
BPAD, current episode manic with psychotic symptoms	20	2.7	No	Olanzapine	Delay	Normal	Normal
BPAD, current episode severe depression with psychotic symptoms	39	3	No	Risperidone	Normal	Normal	Normal
BPAD, current episode manic without psychotic symptoms	32	2.7	Quetiapine	Quetiapine	Normal	Normal	Motor and mental delay
Other nonorganic psychotic disorder	21	2.5	No	Risperidone	Normal	Normal	Normal
BPAD, current episode manic without psychotic symptoms	36	3.75	No	Risperidone	Normal	Normal	Motor and mental delay
OCD with soft bipolar symptoms	22	3.5	No	Quetiapine	Normal	Normal	Normal
BPAD, current episode manic with psychotic symptoms	23	2	No	Olanzapine	Normal	Delay	Normal
Organic mood disorder	19	2.8	Phenytoin	Olanzapine	Delay	Normal	Normal
Severe depressive episode with psychotic symptom	20	2.45	No	Olanzapine	Normal	Normal	Normal
Acute and transient psychotic disorders	22	2.7	No	Olanzapine	Normal	Normal	Motor and mental delay
BPAD, current episode manic with psychotic symptoms	21	2.25	No	Risperidone	Delay	Normal	Mental delay
Schizophrenia	44	3	No	Risperidone	Normal	Delay	Normal
BPAD, current episode manic with psychotic symptoms	23	3	No	Olanzapine	Normal	Normal	Normal
Schizophrenia	30	2.7	No	Risperidone	Normal	Normal	Normal
Acute and transient psychotic disorders	24	2	No	Risperidone	Normal	Normal	Motor and mental delay

DASII – Developmental Assessment Scales for Indian Infants; BPAD – Bipolar affective disorder; OCD – Obsessive Compulsive Disorder; ICD – International Statistical Classification of Diseases; Motor or Mental delay in DASII- Development Quotient (DQ) score ≤70 in motor or mental scale. Weight or Height delay- Weight or Height Score less than three percentile of the population norm

Similarly, two of 17 (11.76%) infant's height was <3rd percentile of population norm. In these two infants, one infant's mother was 44 years old, whereas other infant birth weight was 2 kg which is less than the mean birth weight of our sample.

So though five out of seventeen (29.41%) infants had a delay in weight or height; four of these five infants had other risk factors like low birth weight, higher mothers age, and mother being on antiepileptic medication during pregnancy.

Based on DASII scores four out of 17 (23.52%) infants had a delay in both motor and mental milestones. Among the four infants with delay, first infant's mother was on Quetiapine during pregnancy, second infant's mother age was 36 years, whereas third infant birth weight was 2 kg. One infant (5.88%) had delay in only mental milestone, his birth weight was 2.25 kg.

Hence, though five of 17 infants had a delay based on the DASII scores, four of these five had other risk factors such as low birth weight, higher maternal age, or mother on psychotropic medication during pregnancy.

Infants who had <3rd percentile of normal population norm of weight and height and infants who were found to have delay in DASII were different except one infant who had weight <3rd percentile of normal population norm and had a delay in Mental milestone in DASII also.

Of the 17 infants who were followed up, 9 infants (52.9%) showed some form of developmental delay. However, of these 9 infants who showed some form of developmental delay, 7 were found to be associated with other risk factors.

DISCUSSION

The study was undertaken to check the adverse effects and short-term developmental outcome of infants exposed to atypical antipsychotics during breastfeeding. The present study was a hospital-based study with a prospective design. Only inpatients were recruited in the study. In our study, 7.14% of the infants developed constipation, whereas 10.71% of the infants developed sedation on exposure to atypical antipsychotics, but no other adverse effects such as diarrhea, irritability, poor sucking, or extrapyramidal symptoms were noted. Infants exposed to atypical antipsychotics during breastfeeding may develop adverse effects because the mother's plasma medication reaches the infant's plasma through breast milk. However, the relative infant dose of most atypical antipsychotics was quite low; therefore, no serious adverse effects were noted. The findings of our study are similar to a systematic review conducted by Brunner et al., 2013,[10] in which 15.6% of babies developed side effects. In contrast,few case series have reported lesser side effects.[1516171819] The slightly higher rates in our study may be related to poor infant health and nutrition which may make the infant more susceptible to these effects. Furthermore, sometimes, it might be challenging to say if the infant's medical problems were contributing to the problem or the mother's medication. The high rates of supplementary feeding in the present sample also indicate the difficulty in breastfeeding among mothers with psychosis and this may also have influenced the nature and severity of side effects. However, higher rates of adverse effects were not found among mothers who were exclusively breastfeeding.

Of 17 infants on whom anthropometric measurement and developmental assessment were done in follow-up, three infants were found to have low weight, two infants were found to have low height, four infants were found to have a delay in both motor and mental milestones, whereas one infant was found to have only delay in mental milestones, but low weight, height, and delay in developmental milestones were found to be associated more with low birth weight, higher maternal age, and exposure to medications (phenytoin and quetiapine) during pregnancy which is itself a risk factor of developmental delay. This is similar to earlier studies in which developmental delay could not be attributable directly to atypical antipsychotics.[202122]

This study has specific limitations. The sample size was small which precluded any detailed statistical analysis and inferences. We were, hence, not able to control for the various confounding variables which might contribute to adverse effects and developmental delay. There was no control group for comparison of developmental assessments. Although these data were collected systematically, statistical analysis could not be performed due to a lack of power. The nature of feeding the baby at follow-up was also not assessed. Other atypical antipsychotics like clozapine and aripiprazole were not included as they are not routinely prescribed in our MBU. (Olanzapine and quetiapine are categorized as acceptable for breastfeeding. Chlorpromazine, haloperidol, risperidone, and zuclopenthixol are categorized as possible for breastfeeding under medical supervision. Breastfeeding cannot be currently recommended for the following medications: aripiprazole, asenapine, chlorprothixene, clozapine, droperidol, fluphenazine, flupenthixol, iloperidone, lurasidone, paliperidone, perphenazine, pimozide, trifluoperazine, thiothixene, and ziprasidone.)[23]

The study also has several merits. This is a prospective study; hence, there is no recall bias. Information from multiple people such as the baby's mother, relative, and nursing staff along with examination was used to determine side effects. Structured and standardized developmental assessment (DASII) used earlier in the Indian population has been used. Adverse effects were checked multiple times during the hospital stay. The student doing the thesis received training in the developmental assessment, and one of the co-guides independently rated all the assessments to ensure the reliability of rating. Other factors that might have led to developmental delay such as infants who had obstetric risk factors, congenital problems, or major medical illnesses were excluded from the study.

CONCLUSION

In this sample of 28 infants of mothers admitted with postpartum psychiatric illness we found some side effects such as sedation and constipation with atypical antipsychotics occurred in 17.85%. Follow up in a subsample of 17 infants, 52.9% (n = 9) showed developmental delay.

However,these may also be due to the presence of other factors such as low birth weight,higher mother age (>35 years) and exposure to medications (quetiapine and phenytoin) during pregnancy. More studies with larger sample sizes and controlling for factors such as birth weight, nutritional status needed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.