Long-acting Injectable (LAI) Antipsychotic Use During Pregnancy

Basic premise:

Treatment of serious mental illness in women of childbearing age presents clinical challenges due to exacerbation of symptoms during pregnancy and postpartum.¹ Clinicians should be comfortable considering a long acting injectable (LAI) antipsychotic during pregnancy as they would consider them with a patient who was not pregnant. Generally, LAI use is associated with a more consistent drug plasma drug level, which may reduce fetal exposure to the highly fluctuating plasma drug levels associated with maternal oral antipsychotic use.² Research supports that LAIs are superior in preventing hospitalization and relapse of serious mental illness, are relatively safe, and have benefits of increased adherence and convenience.³ This is important during pregnancy because relapse of illnesses in schizophrenia and bipolar disorder increases the risk of poor outcomes (both mother and fetus). Current pregnancy safety data of oral antipsychotics is largely reassuring, with no increased risk of major congenital malformations after first trimester exposure.⁴

 Consider risks and benefits:

• Improved drug plasma profile
  • LAIs bypass first-pass metabolism and are associated with more stable blood plasma medication levels.³ This may reduce fetal exposure to fluctuating high plasma levels and lead to greater psychiatric stability during pregnancy.^3,8
  • It should be noted that antipsychotic medications are not generally associated with a significant increase in teratogenic effects.⁵
• Reduced risk of relapse
  • Women with history of severe psychiatric illness who are non-adherent to treatment during first trimester are twice as likely to relapse as women who are adherent.³
  • Relapses have poor outcomes, such as psychotic denial of pregnancy,³ malnutrition,⁵ deterioration of routine and behavior of the mother,⁵ and issues with follow up and obstetric care.^3,5
  • Untreated schizophrenia and bipolar pose a risk for congenital malformations.³ Women with schizophrenia are reported to be at increased risk for poor obstetrical outcomes including preterm delivery, infants with low birth weight and small for gestational age, still birth, infant death, and artificial abortion.⁶
  • Oral use implies lower teratogenic risk but is linked to increased treatment abandonment.⁵ LAIs are superior in preventing hospitalization and relapse.³
• Communication, adherence, and monitoring
  • Prescribing antipsychotics during pregnancy requires careful monitoring and supervision using a multidisciplinary approach.³
  • With LAI use, clinicians know that patients are medication adherent for longer dosing intervals and are at decreased risk for overdose. ³ There is also more frequent and standardized contact between patients and clinicians.
• Risk for unwanted/unplanned pregnancy in childbearing women
  • Consider the prevalence of serious mental illness in women of childbearing age. Bipolar disorder usually is diagnosed between ages 18-30, which affects a high number of childbearing women³.
  • Unplanned/unwanted pregnancies are more frequent in schizophrenia than the general population.¹
• Risk for immediate or late onset adverse effects
  • All antipsychotics cross the placenta.⁷
  • Some increased risks include metabolic issues and fetal macrosomia, but generally no increased risk of fetal malformations.⁵ However, the largest study to date examining pregnancy outcomes in 9991 women with first trimester antipsychotic exposure found no increased risk of major congenital malformations compared to nonusers of antipsychotics.⁴  There was a sensitivity analysis which demonstrated a possible dose dependent link with risperidone; however the number needed to harm would exceed 50 if one uses the relative risk of 1.46 from the sensitivity analyses.  Given the risks of bad outcomes due to nonadherence, use of risperidone (or paliperidone) appears reasonable, especially when an LAI is needed in a risperidone responder who doesn’t respond to or tolerate aripiprazole, haloperidol, or fluphenazine.⁴
  • Avoid administering LAIs to women at risk for preterm birth.³ Preterm infants are at risk for elevated plasma medication levels due to immature hepatic and renal systems.
  • Newborns should be observed for adverse effects at birth, such as extrapyramidal symptoms,⁸ as well as monitored for immediate and late onset teratogenicity.⁶
• May impact breastfeeding/lactation
  • Evidence is largely reassuring.³
  • Antipsychotics in general enter breastmilk in low concentrations but may have longer half-lives.⁹
  • Some studies recommend against breastfeeding,⁷ but other professionals argue that benefits outweigh the risks.⁹
  • Dopamine agonists impact prolactin by reducing levels, which may negatively impact lactation (e.g., aripiprazole).³
  • Dopamine antagonists cause increase in prolactin, with rare possibility of breastmilk overproduction and mastitis (e.g., risperidone).³

Historical factors that could indicate the patient is a good candidate for a long acting injectable (LAI):

• Medication nonadherence or requiring multiple emergent medications to achieve stability. ³
• Long or frequent hospitalizations, however women who have not been hospitalized are also candidates.³
• Psychiatric symptom recurrence, including psychosis, or substance use during previous pregnancies or postpartum periods.³

Process for selecting a long acting injectable (LAI) during pregnancy:

The process is same for non-pregnant women. Consider efficacy of oral medication, side effects, cost, and patient ability to be adherent during overlap period.

• Metabolic profile of individual
  • Choose LAIs with more favorable metabolic profiles since some antipsychotics have higher rates of causing or increasing risk of preeclampsia and eclampsia, as well as effects on mother and baby.³
• Need for increased dosage during pregnancy
  • The clinician should monitor need for temporary increase in medication due to pregnancy related pharmacokinetic changes.³
  • Decreased cytochrome P450 (CYP) 1A2 enzyme activity (e.g., reduced clearance of olanzapine or clozapine) or increased CYP2D6 activity (e.g., greater clearance of risperidone or aripiprazole) can occur.⁸
• Diagnosis and current oral medication
  • There are six antipsychotics with LAI formulations available in the United States: aripiprazole, fluphenazine, haloperidol, olanzapine, paliperidone, and risperidone.
  • In bipolar disorder, use risperidone or aripiprazole.³
• In women already taking LAIs who wish to become pregnant
  • The LAI should be continued unless there is compelling reason for discontinuation. ³ Engage in an informed consent process with patient (and ideally father of the baby) prior to conception.
  • Prolactin-elevating antipsychotic could potentially prevent pregnancy and a different antipsychotic may need to be considered¹⁰
• In women who are currently taking an LAI and discover they are pregnant
  • Continue unless clear contraindication to continue the antipsychotic and engage in informed consent discussion.³ Tailor the discussion to the week of pregnancy, since teratogenic concerns recede as pregnancy continues.

REFERENCES

1. Özdemir, A. K., Pak, Ş. C., Canan, F., Geçici, Ö., Kuloğlu, M., & Gücer, M. K. (2015). Paliperidone palmitate use in pregnancy in a woman with schizophrenia. Archives of women’s mental health, 18(5), 739–740. https://doi.org/10.1007/s00737-014-0496-6
2. Ereshefsky L, Mascarenas CA. (2003) Comparison of the effects of different routes of antipsychotic administration on pharmacokinetics and pharmacodynamics. J Clin Psychiatry, 64(suppl 16):18-23.    https://doi.org/10.4088/JCP.20ac13597
3. Reinstein, S. A., Cosgrove, J., Malekshahi, T., & Deligiannidis, K. M. (2020). Long-Acting Injectable Antipsychotic Use During Pregnancy: A Brief Review and Concise Guide for Clinicians. The Journal of clinical psychiatry, 81(6), 20ac13597. https://doi.org/10.4088/JCP.20ac13597
4. Huybrechts KF, Hernandez-Diaz S, Patorno E, et al. (2016).  Antipsychotic use in pregnancy and the risk for congential malformations.  JAMA Psychiatry, 73:938-46.  https://doi.org/10.1001/jamapsychiatry.2016.1520
5. Ballester-Garcia, I., Pérez-Almarcha, M., Galvez-Llompart, A., & Hernandez-Viadel, M. (2019). Use of long acting injectable aripiprazole before and through pregnancy in bipolar disorder: a case report. BMC pharmacology & toxicology, 20(1), 52. https://doi.org/10.1186/s40360-019-0330-x
6. Kim, S. W., Kim, K. M., Kim, J. M., Shin, I. S., Shin, H. Y., Yang, S. J., & Yoon, J. S. (2007). Use of long-acting injectable risperidone before and throughout pregnancy in schizophrenia. Progress in neuro-psychopharmacology & biological psychiatry, 31(2), 543–545. https://doi.org/10.1016/j.pnpbp.2006.09.017
7. Azevedo Avelar, R., Luengo Corbal, A., & Heitor, M. (2020). A case report of pregnancy and paliperidone palmitate 3‐monthly long‐acting injection. Clinical Case Reports, 8(12), 2592–2594. https://doi.org/10.1002/ccr3.3213
8. Clinebell, K., Gannon, J., Debrunner, S., & Roy Chengappa, K. N. (2017). Long-acting risperidone injections in a pregnant patient with bipolar disorder. Bipolar disorders, 19(7), 606–607. https://doi.org/10.1111/bdi.12572
9. Janjić, V., Milovanović, D. R., Zecević, D. R., Loncar, D., Laban, O., Stepanović, M., Varjaric, M., Obradović, S., Dejanović, S. D., & Janković, S. (2013). Zuclopenthixol decanoate in pregnancy: successful outcomes in two consecutive offsprings of the same mother. Vojnosanitetski pregled, 70(5), 526–529. https://doi.org/10.2298/vsp120208005j
10. Gentile S. (2010).  Antipsychotic therapy during early and late pregnancy.  A systematic review.  Schizophr Bull 36:518-544.  https://doi.org/10.1177/2042098614522682