Abstract
The use of psychotropic medication in pregnant women often requires a multifaceted risk–benefit analysis, taking into account the risks of the untreated illness for the mother and baby. Recent reviews by the Melbourne Perinatal Psychotropic Review Group into the prenatal use of antidepressants, mood stabilizers [1,2] and antipsychotics (in progress), have highlighted not only the challenges of working with limited, sometimes conflicting data, but also the need for more research into this area. Apart from the risk of teratogenesis, for which the emerging literature appears encouraging [3], atypical antipsychotic medication may present obstetric risks such as increased infant birth weight [4], and studying placental transfer of these medications may be a step towards understanding the mechanisms behind these complications. There are presently no data on placental transfer of aripiprazole, but a study by Newport et al. reported umbilical cord:maternal concentration ratios for some other atypicals [5].
We describe the outcome in a 27 year old mother with a 10 year history of schizophrenia, who took aripiprazole during pregnancy. She has had a number of psychotic relapses but had been stable in the 12 months leading up to the pregnancy. She was maintained on 10 mg aripiprazole and 20 mg citalopram daily. When she discovered that she was pregnant (at around 5 weeks of gestation), she ceased both medications due to concerns about their effects on the baby. She remained free of symptoms until 16 weeks of gestation, when she reported ‘poor sleep and paranoia’ (signs of early relapse) and following a risk–benefit analysis discussion with the treating team, she agreed to recommence both aripiprazole and citalopram. She had been previously trialled with other antipsychotic medications; however, they had either failed to demonstrate efficacy or induced intolerable side-effects such as significant weight gain. Her symptoms resolved in the following weeks and she remained on both medications for 5 weeks in total before ceasing them again without informing the treating team. She recommenced the aripiprazole 10 mg at 36.7 weeks gestation following a discussion about the heightened risk in the post-partum. She did not resume taking the citalopram due to concerns about the risk of neonatal discontinuation syndrome. Medical history of note included morbid obesity and benign intracranial hypertension, for which she was prescribed acetazolamide (250 mg twice daily). She reported compliance with this medication. The pregnancy was otherwise uncomplicated, and she underwent an elective caesarian section for breech presentation at 39.3 weeks. She gave written informed consent for a placental transfer study as well as breast milk study. Blood samples were taken from her and from the cord at the time of birth.
Aripiprazole and its predominant pharmacologically active metabolite dehydroaripiprazole in serum were measured by a validated high-performance liquid chromatographic method. The intra- and inter-day relative standard deviations for the assay (range 8-1000 μg/L) were <4% and <6% respectively for aripiprazole, and <2.3% and <3.4% respectively for dehydroaripiprazole. The patient had been taking aripiprazole for 19 days at the time of delivery and since it has a half-life of 75 h [6], she can be considered to be at steady state. The cord serum sample (8.6 h after maternal dose) contained 17 μg/L aripiprazole and 8 μg/L dehydroaripiprazole while the maternal serum (9.6 h after dose) contained 70 μg/L aripiprazole and 45 μg/L dehydroaripiprazole. The cord: maternal concentration ratios were therefore 0.64 for aripiprazole and 0.47 for dehydroaripiprazole.
The patient gave birth to a healthy baby girl weighing 3650 g, 49 cm in length and 35 cm in head circumference. Apgar scores were 9 at both her first and fifth min of life. Mild respiratory distress occurred at 10 min but resolved without intervention. On the third day post-delivery, the baby appeared slightly unsettled with poor feeding which improved by the following day. She was assessed by a neonatologist and also underwent a routine hearing test. Both examinations were unremarkable. The mother remained psychiatrically stable in the immediate post-delivery period. She has continued with aripiprazole 10 mg daily and also recommenced on 20 mg daily of citalopram post-delivery. She decided not to breastfeed, which was disappointing as we had hoped to investigate the transfer of aripiprazole and its metabolite into breast milk because published data on milk transfer are sparse [7]. Both mother and baby were discharged from the hospital 5 days after the birth.
This case highlights the uncertainties surrounding the use of novel atypical antipsychotics during pregnancy and their potential to impact compliance. To the best of our knowledge, this is the first report of the placental transfer of aripiprazole. The cord:maternal ratios of 0.64 for aripiprazole and 0.47 for dehydroaripiprazole can be compared with previous mean (95% confidence interval) data of 0.72 (0.47–0.98) for olanzapine, 0.66 (0.4–0.91) for haloperidol, 0.49 (0.14–0.85) for risperidone and 0.24 (0.19–0.3) for quetiapine [5]. While the extent of transfer of aripiprazole and dehydroaripiprazole in our patient is closest to the means for risperidone and haloperidol, there is very considerable inter-patient variability in cord:maternal ratios. The limitation of our study is that it is only a single case and that the infant's exposure to the drug was only for the first weeks of the pregnancy followed by 5 weeks in early second trimester and 19 days in late third trimester. With the potential increasing use of aripiprazole in pregnant women [8] possibly due to its lower metabolic risks compared to other atypicals [9], future studies of its influence on obstetric and neonatal outcomes are warranted. Investigation of its transfer into breast milk is also needed.