Outcomes of long-acting injectable antipsychotics use in pregnancy: A literature review

Table 2 An overview of included publications/cases

No.	Ref.	Maternal age (yr)	Type of publication, No. of women/pregnancies	Psychiatric diagnosis	LAI-AP medication (dosage, duration of treatment during pregnancy); other medications used during pregnancy	Maternal treatment outcomes	Pregnancy and delivery outcomes (gestational age, gender, birth weight, Apgar score 1/5/10 min)	Neonatal and developmental outcomes
1	Donaldson and Bury[36], 1982	29	Case report, 1/1	Hebephrenic schizophrenia	Fluphenazine enanthate (25 mg/month, entire pregnancy); dicyclomine hydrochloride, doxylamine succinate and pyridoxine hydrochloride (from 45 to 101 d of gestation), ferrous sulphate, folic acid (from day 101 to near delivery), paracetamol (from day 165 to near delivery), sodium amytal (from day 250 to 255)	Her symptoms improved during pregnancy	Labor was induced surgically and proceeded to forceps delivery (36 wk, male, 2520 g, 9/NR/NR)	Born with a short sloping forehead, wide metopic suture, persistent metopic fontanelle, telecanthus, ocular hypertelorism, nystagmoid eye movements, bilateral cleft lip and palate, imperforate anus, rectourethral fistula, bifid scrotum, unusual penis with hypospadias, and neutrophil polymorphs with numerous nuclear projections. His overall progress was good, with the rectourethral fistula divided and anoplasty performed soon after delivery and the cleft lip and palate repaired at 7 months
2	Cleary[37], 1977	32	Case report, 1/1	Schizophrenia	Fluphenazine decanoate (2 cc every 3 wk, entire pregnancy); benztropine mesylate sporadically	Latent homicidal ideas were noted late in pregnancy, and her behavior continued to be bizarre, explosive, and unpredictable. Two months after delivery, she developed somatic delusions, became agitated and paranoid, and was readmitted to a psychiatric hospital. After discharge and some months later, she indicated the persistence of a schizophrenic thought disorder	Delivered by cesarean section 9 d after the expected date following the failure of oxytocin to induce labor (40 wk and 9 d, male, 3380 g, 8/10/NR)	Born healthy. Possible minor extrapyramidal manifestations 4 wk after delivery (or withdrawal symptoms from fluphenazine) that responded to diphenhydramine elixir. Apparently well-nourished, well-developed, and alert child at 24 months
3	O'Connor et al[38], 1981	22	Case report, 1/1	Schizophrenia	Fluphenazine decanoate (50 mg fortnightly from 14 to 24 wk /increased over three wk to this dose/, then 100 mg fortnightly from 24 wk to delivery); chlorpromazine (from 12th week of pregnancy to delivery)	Her suicidal behavior gradually abated after the LAI-AP dosage increase, but she continued to exhibit denial of pregnancy, extreme unpredictability, and total resistance to obstetric examination	Delivered by cesarean section after spontaneous onset of labor (39 wk, male, 3530 g, 10/10/NR)	Excellent condition at delivery. Initial progress was good. On the 21st d after birth, he developed many neurological signs (e.g., excessive irritability, choreiform and dystonic movements involving mainly the upper limbs, jittery behavior, and hypertonicity) which persisted for 9 months and were mainly treated with diphenhydramine. The symptoms were consistent with LAI withdrawal effects. Follow-up at 15 months of age revealed no abnormalities
4	Collins and Comer[39], 2003	35	Case report, 1/1	Schizoaffective disorder	Haloperidol decanoate (200 mg/2 wk, throughout the pregnancy – last dose 3 wk before delivery); not specified	She had an acute psychotic episode before induced delivery	Induced vaginal delivery (full term, female, 3880 g, 9/9/NR)	At birth was noted to be “jittery”, then developed diarrhea and metabolic acidosis, and was transferred to NICU at 3rd d. She became increasingly irritable, and on day 8 had an episode of tonic-clonic movements in all extremities with tongue thrusting and torticollis (possible tardive dyskinesia or withdrawal dyskinesia). Tonic-clonic episodes continued up to the 14th d of life (successfully treated with clonazepam). On day 21, she was discharged to foster care with no tremulous movements noted
5	Janjić et al[40], 2013	35 at 1st pregnancy, 38 at 2nd pregnancy	Case report, 1/2	Schizophrenia	Zuclopenthixol decanoate (in 1st pregnancy initially 400 mg/2 wk, then upon discovery of the pregnancy at 13 wks’ gestation dose was decreased to 200 mg/month and this dose was also used during entire 2nd pregnancy); not specified	Maternal psychiatric status during both pregnancies, after each delivery, and during the follow-up period was favorable (continued to be rated as “borderline mentally ill”), with no exacerbations	Delivery method not specified for both pregnancies. 1st pregnancy/child: (39 wk, female, 3750 g, 9/NR/NR); 2nd pregnancy/child: (40 wk, female, 3700 g, 9/NR/NR)	Both girls were healthy without obvious congenital malformations. The brain ultrasound of the first child revealed some clinically insignificant periventricular hyperechogenicity. Both had been normally developing 3.5 yr and 6 months after delivery
6	Ballester-Gracia et al[41], 2019	43	Case report, 1/1	Bipolar disorder	Aripiprazole LAI (400 mg/month for first 2-3 wk of pregnancy, then decreased to 300 mg/month, entire pregnancy); not specified (probably none)	No recurrence of her illness or significant mood fluctuations during pregnancy. Two days after hospital discharge after delivery, she came as an outpatient and was euthymic, so LAI-AP dose was increased to 400 mg/4 wk	Spontaneous vaginal delivery without complications (40 wk and 4 d, female, 3500 g, 9/10/10)	No congenital malformations at birth or development abnormalities at five months after delivery
7	Sole et al[49], 2020	30	Conference abstract, 1/1	Schizophrenia	Aripiprazole LAI (400 mg/28 d, entire pregnancy), not specified	No psychiatric complications due to pregnancy and puerperium were reported. No bounding disorder was detected	Delivered without obstetric complications (41 wk, female, 3465 g, 9/10/NR)	No neonatal complications
8	Fernández-Abascal et al[21], 2021	35 (table), 39 (text)	Case series, 1/1	Paranoid schizophrenia	Aripiprazole LAI (400 mg/28 d from beginning of pregnancy to 8th week, 300 mg/28 d from 8th week until delivery); not specified	Throughout pregnancy, the patient remained psychopathologically stable, and treatment adherence was maintained	Uncomplicated eutocic/vaginal delivery (38 wk and 5 d, gender?/male in text; female in table/, 3300 g, 9/10/NR)	During the first 6 wk of follow-up postural plagiocephaly and hypertonia were noted, that finally were resolved with physiotherapy. He developed normally during a 3-yr follow-up
9	Fernández-Abascal et al[21], 2021	29 (table), 32 (text)	Case series, 1/1	Schizophrenia, schizotypal personality disorder	Aripiprazole LAI (400 mg/28 d from beginning of pregnancy to 20th week, 300 mg/28 d from 20th week until delivery); not specified	Adherence was maintained throughout the pregnancy with psychopathological stability and good adherence. She had clinical worsening 3 months after delivery	Admitted to ED for spontaneous delivery – eutocic/vaginal delivery, right medial episiotomy (31 wk and 5 d, female, 1800 g, 10/10/NR)	Remained in an incubator for 1 month due to prematurity. No congenital malformations were observed at delivery or during the postpartum period. She developed normally during a 2-yr follow-up
10	Fernández-Abascal et al[21], 2021	35 (table), 36 (text)	Case series, 1/1	Paranoid schizophrenia	Aripiprazole LAI (400 mg/28 d from beginning of pregnancy to 5th week, 300 mg/28 d from 5th week until delivery); not specified	Psychopathological stability and proper treatment adherence were maintained throughout the pregnancy	Eutocic/vaginal delivery (39 wk and 6 d, male, 3140 g, 9/10/NR)	No congenital malformations were observed at birth, and the postpartum period proceeded without relevant events. Normal development at 2 months
11	Fernández-Abascal et al[21], 2021	31	Case series, 1/1	Schizophrenia	Aripiprazole LAI (160 mg/28 d from beginning of pregnancy until delivery); occasional budesonide inhalation	Throughout the pregnancy, the patient remained psychopathologically stable, and treatment adherence was maintained	Uncomplicated eutocic/vaginal delivery (39 wk and 5 d, male, 3102 g, 10/10/NR)	Born healthy. In the 2-yr follow-up he remained in good health and developed normally
12	Fernández-Abascal et al[21], 2021	38 (table), 39 (text)	Case series, 1/1	Schizophrenia	Aripiprazole LAI (300 mg/28 d from beginning of pregnancy until delivery); not specified	Throughout the pregnancy, she remained psychopathologically stable, and treatment adherence was maintained	Eutocic/vaginal delivery (39 wk, male, 2940 g, 8/10/NR)	Born healthy. In the 1-yr follow-up, he remained in good health and developed normally
13	Fernández-Abascal et al[21], 2021	30	Case series, 1/1	Schizophrenia	Aripiprazole LAI (400 mg/28 d from beginning of pregnancy to 8th week); when pregnancy was confirmed the prescription dose of benzodiazepines was adjusted downwards until they were withdrawn along 4 wk, levothyroxine	To ensure psychopathological stability and to detect warning signs of decompensation, the patient was closely monitored weekly during pregnancy (no worsening was reported)	Eutocic/vaginal delivery (40 wk, male, 3400 g, 9/10/NR)	Born healthy. He has been followed for 18 months, and no malformation, developmental abnormalities, or growth retardation were detected
14	Eleftheriou et al[33], 2023	38	Case series, 1/1	Bipolar or psychotic disorder (exact diagnosis not specified)	Aripiprazole LAI (400 mg/month, pregnancy started on LAI treatment, interruption of treatment at 23 wk); folic acid	Postpartum hospitalization for psychosis relapse	Cesarian section (31 wk, NR, 1995 g, 6/8/NR)	Down’s syndrome, fetal hydrops complicated by septic shock, massive anuria, and death in 10 d. This syndrome cannot be considered a drug-induced malformation
15	Eleftheriou et al[33], 2023	25	Case series, 1/1	Bipolar or psychotic disorder (exact diagnosis not specified)	Aripiprazole LAI (400 mg/month, pregnancy started on LAI treatment which was continued until delivery); folic acid	Postpartum hospitalization for psychosis relapse	Vaginal delivery (40 wk, female, 3300 g, 9/10/NR)	Live birth with no malformations. No adaptation disorders after delivery
16	Eleftheriou et al[33], 2023	31	Case series, 1/1	Bipolar or psychotic disorder (exact diagnosis not specified)	Aripiprazole LAI (200 mg/month, pregnancy started on LAI treatment, interruption of treatment at 14 wk); folic acid, haloperidol (first trimester)	No hospitalization for psychosis relapse	Spontaneous abortion (miscarriage) at 15th week	Not applicable
17	Eleftheriou et al[33], 2023	35	Case series, 1/1	Bipolar or psychotic disorder (exact diagnosis not specified)	Aripiprazole LAI (200 mg/month, pregnancy started on LAI treatment which was continued until delivery); folic acid, haloperidol (first trimester)	No hospitalization for psychosis relapse	Spontaneous abortion (miscarriage) at 9th week	Not applicable
18	Eleftheriou et al[33], 2023	34	Case series, 1/1	Bipolar or psychotic disorder (exact diagnosis not specified)	Aripiprazole LAI (200 mg/month, pregnancy started on LAI treatment which was continued until delivery); folic acid, carbamazepine (in first trimester, stopped at 10 wk)	Postpartum hospitalization for psychosis relapse	Cesarian section (40 wk, male, 2900 g, 9/10/NR)	Live birth with no malformations. No adaptation disorders after delivery
19	Eleftheriou et al[33], 2023	28	Case series, 1/1	Bipolar or psychotic disorder (exact diagnosis not specified)	Aripiprazole LAI (400 mg/month, pregnancy started on LAI treatment which was continued until delivery); folic acid, oral aripiprazole (in first trimester)	No hospitalization for psychosis relapse	Cesarian section (40 wk, female, 3140 g, 7/9/NR)	Live birth with no malformations. No adaptation disorders after delivery
20	Eleftheriou et al[33], 2023	43	Case series, 1/1	Bipolar or psychotic disorder (exact diagnosis not specified)	Aripiprazole LAI (400 mg/month, pregnancy started on LAI treatment which was continued until delivery); folic acid.	No hospitalization for psychosis relapse	Vaginal delivery (40 wk, male, 2300 g, 10/10/NR)	Live birth with no malformations. No adaptation disorders after delivery
21	Eleftheriou et al[33], 2023	31	Case series, 1/1	Bipolar or psychotic disorder (exact diagnosis not specified)	Aripiprazole LAI (400 mg/month, pregnancy started on LAI treatment which was continued until delivery); folic acid	No hospitalization for psychosis relapse	Vaginal delivery (40 wk, male, 3500 g, 8/10/NR)	Live birth with no malformations. No adaptation disorders after delivery
22	Eleftheriou et al[33], 2023	20	Case series, 1/1	Bipolar or psychotic disorder (exact diagnosis not specified)	Aripiprazole LAI (400 mg/month, pregnancy started on LAI treatment which was continued until delivery); folic acid, haloperidol (in first trimester)	Hospitalization for psychosis relapse after stillbirth	Stillbirth at 26th week	Not applicable
23	Eleftheriou et al[33], 2023	31	Case series, 1/1	Bipolar or psychotic disorder (exact diagnosis not specified)	Aripiprazole LAI (400 mg/month, pregnancy started on LAI treatment which was continued until delivery); folic acid, paroxetine (in first trimester)	No hospitalization for psychosis relapse	Vaginal delivery (38 wk, female, 3120 g, 9/10/NR)	Live birth with no malformations. No adaptation disorders after delivery
24	Manouilenko et al[42], 2018	35	Case report, 1/1	Psychosis	Olanzapine pamoate (405 mg/4 wk, from 25th week, reduced to 300mg/4 wk from 29th week and ultimately due to sedation to 210 mg/2 wk at 39th week, exposure until delivery); oral olanzapine for 4 d and promethazine injections before initiation of LAI-AP	Improved rapidly on LAI-AP, but she was hospitalized at pregnancy week 40 since she reported fatigue and depression	Vaginal delivery was induced by amniotomy (40 wk, female, 2930 g, 9/10/10)	Fully developed infant. The child’s somatic and psychomotor development up to 3 yr of age was normal
25	de Azevedo Avelar et al[43], 2020	26	Case report, 1/1	Schizophrenia	Paliperidone palmitate (263 mg every three months twice during pregnancy, the last one approximately 2 months before birth – exposure during entire pregnancy); none	She was doing well on this LAI-AP (asymptomatic on follow-up)	Presented to ED with abdominal pain, found to be in labor – pregnancy was not planned nor monitored (unknown gestational age, male, 2420 g, 9/10/10)	Approximately 1 yr after birth no health or developmental issues
26	Zamora Rodríguez et al[44], 2017	34	Case report, 1/1	Bipolar schizoaffective disorder	Paliperidone palmitate (100 mg/4 wk initially, then reduced to 50 mg/4 wk, she was pregnant for 2 wk when it was initiated, and dosage reduced at 5 wk of pregnancy and remained at this dosage until and after delivery); venlafaxine and clonazepam for first 5 wk, which were then changed to fluoxetine and lorazepam, omeprazole and yodocefol	No psychotic or affective symptoms except for a slight period of anxiety in the days immediately after discovering she was pregnant, and a mild and self-limited depressive relapse from days 7 to 9 after giving birth	Term birth, delivery mode not specified (40 wk, male, 2440 g, 9/10/10)	Clinical status of the newborn was normal. No diseases or malformations were detected in the first year of follow-up
27	Özdemir et al[45], 2015	37	Case report, 1/1	Schizophrenia	Paliperidone palmitate (100 mg monthly, from beginning until week 28 of gestation – last dose given at the 28th week); haloperidol orally from 29th week until delivery	Developed psychotic symptoms despite regular injections of LAI-AP 2 wk before a change to haloperidol was made (her symptoms subsided 3 wk afterwards)	Cesarean section without complications (39 wk, male, 3000 g, 9/NR/NR)	The baby has been followed for 4 months, and no malformation or growth retardation was detected
28	Binns et al[46], 2017	28	Case report, 1/1	Chronic paranoid schizophrenia	Paliperidone palmitate (150 mg/4 wk, entire pregnancy); not specified	Good control of psychosis was maintained	Pregnancy was complicated by polyhydramnios, induced labor followed by cesarean section due to fetal distress (39 wk, male, 3840 g, 9/9/NR)	Neonatal clinical examination confirmed a minor correctable congenital anomaly, bilateral talipes equinovarus, which was managed conservatively but was otherwise normal. The early postnatal course was uncomplicated
29	Iwata et al[34], 2021	30	Case report, 1/1	Schizophrenia	Paliperidone palmitate (150 mg/monthly, first dose was given at 34 wks' gestation, and she electively gave birth at 38 wks' gestation); initially from beginning of pregnancy olanzapine orally (problems with adherence) up to 32nd week, then risperidone orally for 7 d during 33rd week of pregnancy	Doing well on LAI-AP (after its initiation at the third trimester she had a notable improvement in positive and negative symptoms, and the delivery was performed without any issues)	Uneventful cesarean section (38 wk, male, NR, NR/NR/NR)	Transient tachypnea of the newborn that was managed with nasal continuous positive airway pressure. He was discharged 29 d after the delivery. Normal growth and neuropsychological development at 12 months after birth
30	Erdoğan et al[35], 2017	25	Case report, 1/1	Schizophrenia	Paliperidone palmitate (150 mg/monthly, from beginning of pregnancy, last dose given at 22nd week); not specified	She discontinued LAI-AP use without consultation with a clinician. At the 29th week of pregnancy, she was hospitalized with an acute psychotic attack	Normal vaginal delivery (40 wk, male, 3200 g, 9/10/NR)	Born healthy baby. Normal neurobehavioral development according to BSID-III (subscales of cognitive, motor, and language developments were in normal ranges at 2, 6, 12, 18, and 24 months of age)
31	Erdoğan et al[35], 2017	32	Case report, 1/1	Schizophrenia	Paliperidone palmitate (150 mg/monthly, entire pregnancy); not specified	No information about worsening of her condition during treatment. Four months after delivery she gave baby to ward of state	Normal vaginal delivery (41 wk, female, 2980 g, 9/10/NR)	Normal neurobehavioral development according to BSID-III (subscales of cognitive, motor and language developments were in normal ranges at 2, 6, 12, and 18 months of age)
32	Eleftheriou et al[33], 2023	26	Case series, 1/1	Bipolar or psychotic disorder (exact diagnosis not specified)	Paliperidone LAI (50 mg/month, pregnancy started on LAI treatment which was continued until delivery); folic acid, lorazepam (first trimester)	Postpartum hospitalization for psychosis relapse	Cesarian section (39 wk, female, 3020 g, 9/9/NR)	Live birth with no malformations. No adaptation disorders after delivery
33	Eleftheriou et al[33], 2023	32	Case series, 1/1	Bipolar or psychotic disorder (exact diagnosis not specified)	Paliperidone LAI (100 mg/month, pregnancy started on LAI treatment which was continued until delivery); folic acid	No hospitalization for psychosis relapse	Cesarian section (40 wk, male, 3250 g, 9/10/NR)	Live birth with no malformations. No adaptation disorders after delivery
34	Eleftheriou et al[33], 2023	30	Case series, 1/1	Bipolar or psychotic disorder (exact diagnosis not specified)	Paliperidone LAI (100 mg/month, pregnancy started on LAI treatment which was continued until delivery); folic acid	Postpartum hospitalization for psychosis relapse	Cesarian section (39 wk, male, 3650 g, 10/10/NR)	Live birth with no malformations. No adaptation disorders after delivery
35	Eleftheriou et al[33], 2023	25	Case series, 1/1	Bipolar or psychotic disorder (exact diagnosis not specified)	Paliperidone LAI (100 mg/month, pregnancy started on LAI treatment which was continued until delivery); folic acid	No hospitalization for psychosis relapse	Cesarian section (40 wk, female, 3255 g, 9/10/NR)	Live birth with no malformations. No adaptation disorders after delivery
36	Eleftheriou et al[33], 2023	33	Case series, 1/1	Bipolar or psychotic disorder (exact diagnosis not specified)	Paliperidone LAI (50 mg/month, pregnancy started on LAI treatment which was continued until delivery); folic acid, haloperidol (first trimester)	No hospitalization for psychosis relapse	Cesarian section (39 wk, female, 3100 g, 9/10/NR)	Live birth with no malformations. No adaptation disorders after delivery
37	Clinebell et al[47], 2017	32	Case report, 1/1	Bipolar disorder	Risperidone LAI (50 mg/2 wk, entire pregnancy); risperidone orally, citalopram, and benztropine (entire pregnancy)	She was doing well	Intrauterine growth restriction, and, due to concerns for placental insufficiency, she had induction of labor (35 wk, male, 2098 g, 8/8/9)	Born healthy, but with bilateral supernumerary nubs/digits on his hands that were removed after birth (this anomaly was a paternal family trait). The child has met developmental milestones at 16 months
38	Kim et al[48], 2007	35	Case report, 1/1	Schizophrenia	Risperidone LAI (25 mg/2 wk, entire pregnancy); not specified	Her psychotic symptoms improved markedly with LAI-AP treatment. No information about relapse	She delivered vaginally 3 h after premature rupture of membranes (36 wk and 6 d, female, 2230 g, 9/9/NR)	No evidence of congenital malformation at birth and no developmental abnormalities were found 8 months postnatally
39	Nguyen et al[20], 2022	Mean±SD: All: 30.3±5.5; FGA: 31.0±6.0; SGA: 29.1±4.5	Case series, 36/38	Schizophrenia (25/69.4%); Schizoaffective disorder (6/16.7%); Bipolar affective disorder (3/8.3%); Unspecified psychosis (2/5.6%)	FGA (24/38): zuclopenthixol– 12 (100 mg fortnightly– 2, 150 mg fortnightly– 2, 200 mg fortnightly– 5, 200 mg monthly– 1, 300 mg fortnightly– 1, 300 mg monthly– 1); flupentixol– 9 (20 mg fortnightly– 1, 30 mg fortnightly– 1, 40 mg fortnightly– 5, 40 mg monthly– 1, 100 mg fortnightly– 1); fluphenazine– 2 (50 mg fortnightly); haloperidol– 1 (dose missing). SGA (14/38): aripiprazole– 8 (300 mg monthly– 1; 400 mg monthly– 7), risperidone– 4 (37.5 mg fortnightly– 1; 37.5 mg monthly– 1, 50 mg fortnightly– 2); paliperidone– 2 (100 mg monthly). First trimester exposure data only on 35/38 pregnancies, with 1/38 having a third trimester exposure and first trimester data were missing for 2/38. Nearly half (n = 17, 44.7%) were on LAI-AP as the sole medication while the rest had exposures to other oral medications including olanzapine, quetiapine, diazepam, chlorpromazine, risperidone, benztropine, venlafaxine, aripiprazole, fluoxetine, escitalopram, desvenlafaxine, lamotrigine)	Psychiatric relapse reported in 9 (40.9%) pregnancies in women on FGA and 3 (27.3%) pregnancies in women on SGA LAI-AP. Note: Valid% reported due to missing data	All pregnancies: spontaneous delivery in 13 (34.2%), emergency cesarean section in 11 (28.9%), premature birth (< 37 wk) in 6 (15.8%). Induction in 16 (66.7%) on FGA and 7 (50.0%) on SGA, emergency cesarean section in 8 (33.3%) on FGA and 3 (21.4%) on SGA, premature birth (< 37 wk) in 5 (20.8%) on FGA and 1 (7.1%) on SGA. Note: Valid% reported due to missing data. For all babies the mean gestational age was 38.25 wk (SD = 2.19) and mean birth weight was 3.18 kg (SD = 0.76). Gender and Apgar score were NR	Admission to a special care nursery was reported in a total of 18 i.e., 47.4% of babies (13 i.e., 54.2% and 5 i.e., 35.7% whose mothers received FGA and SGA, respectively). Congenital malformations were recorded in 2 babies, and with data available on first-trimester exposure in only 35 pregnancies, this gives a 5.7% rate. One baby had undescended testes whose mother was treated with risperidone LAI, and the other was a patent ductus arteriosus in a baby of a woman who received flupentixol LAI. Both babies were managed conservatively. The authors were not able to assess for neonatal extrapyramidal syndrome (not recorded in their data)

AP: Antipsychotic(s); BSID-III: Bayley Scales of Infant and Toddler Development 3^rd Ed; ED: Emergency department; FGA: First-generation antipsychotics; LAI: Long-acting injectable; NICU: Neonatal intensive care unit; NR: Not reported; SD: Standard deviation; SGA: Second-generation antipsychotics.