Preclinical studies suggest a harmful effect of lithium on motor activity, developmental milestones and reflexes, spatial memory and brain weight |
Only three clinical cohort studies on the development of children with in utero exposure to lithium are published in the literature. They report normal development. |
Most preclinical studies found a harmful effect of intrauterine exposure to antipsychotics on motor activity, developmental milestones and reflexes and spatial memory |
Clinical studies suggest a delay in motor functioning of children with in utero exposure to antipsychotics. In several studies, this delay appeared to be transient |
Introduction
Methods
Search strategy for systematic review
Study selection
Data extraction
Assessment of the risk of bias and the quality of studies
Procedure for meta-analysis
Results
Study selection
Study characteristics
Author (year) | Species/strain | Lithium dosage | Control medication | Exposed period | Follow-up time | Measurements | Results |
---|---|---|---|---|---|---|---|
Brain (1986) [35] | Mice/SW | 0.1 or 0.2 mEq s.c. | n.r. | Last 4 days of gestation until PND 4 | 36 days | Standard opponent test: social, defensive, threatening and aggressive behaviour | No difference |
Messiha (1986) [34] | Mice/SD | Lithium 1 mEq solution | Distilled water | G1 until PND 23 | 37 days | Brain weight | Decrease in brain weight (8.6% female, 8.2% male) |
Sechzer (1986) [29] | Rats/SD | 2.0 or 4.0 mEq/kg/day in orange juice solution | Orange juice solution | G1 until PND 28 | 4 months | Eye and ear opening, startle response, depth perception, open field activity | Delayed eye and ear opening, startle response and maturation of depth perception. Less spontaneous activity at 4 months |
Rider (1978) [33] | Rats/n.r. | 15 mEq/L water | Water and low protein diet | During gestation and lactation (days not specified) | 4.5–5.5 months | T-maze performance, avoidance response | Decreased performance on the T-maze, decreased avoidance response |
Teixeira (1995) [32] | Rats/W | 10 mM in tap water | Tap water (restricted) Tap water ad libitum | Whole gestation period or G1 until PND 21 | 21 days | Righting reflex, eye opening, cliff avoidance test, motor coordination (rota-rod test) | Delayed righting reflex and eye opening, decreased cliff avoidance, no difference in motor coordination |
Abu-Taweel 2012 [30] | Mice/SW | 15 or 30 mg/kg/day in water | Distilled water | G1 until PND 15 | 22 days | Eye opening. Righting reflex, cliff avoidance, rotating reflex, locomotor activity test | Delayed eye opening. Inhibitory dose-dependent effect on sensory motor reflexes and locomotor activity |
Nery (2014) [31] | Zebrafish/Daniorerio | 0.05 mM, 0.5 mM, 5 mM | System water | G3 | 10 days | Locomotor activity | Dose-dependent locomotor deficit |
Author (year) | Species/strain | Experimental medication (dosage) | Control medication | Exposed period | Follow-up time | Measurements | Results |
---|---|---|---|---|---|---|---|
Jewett (1966) [59] | Rats/SD | Cpz 2 mg/ml or Inj 0.1 ml/100 g body weight 3× daily | Distilled water Inj 3× daily or no treatment | G4–G7 | 75 days | Spontaneous motor activity (photoelectric cell activity cage), audiogenic seizures | Cpz: decreased motor activity day 30–33; no difference day 23–26. Increased susceptibility to audiogenic seizures |
Ordy (1966) [63] | Mice/C57BL/10 | Cpz 4 or 16 mg/kg/day orally | Placebo | G6–PND0 | 60 days | Open field test, wheel running activity, shock-elicited escape avoidance conditioning | Delayed open field latency to move to middle square. Fewer rotations in wheel running. Fewer avoidances in conditioning |
Hoffeld (1968) [58] | Rats/SD | Cpz 6.0 mg/kg/day | Distilled water | G5–G8 (I) G11–G14 (II) G17–G20(III) | 97 days | Rotary activity wheel, emotionality testing (faecal boluses), stress reaction (stomach ulcers) | Increased activity. More activity in 2nd and 3rd than in 1st trimester exposed pups. No difference in emotionality and stress response |
Clark (1970) [61] | Rats/SD | Cpz 3 mg/kg/day s.c. | Vehicle | G12–G15 | 60 days | Open field test, T-maze, mother-goal maze, operant conditioning | Locomotor activity reduced on day 13 but enhanced on day 18. Maze learning: shorter latencies, higher error scores in mother-goal maze; no differences in T-maze. Operant conditioning: one more session needed to acquire bar-press response |
Robertson (1979) [60] | Rats/CR | Cpz 1, 3 or 9 mg/kg/day by gavage | Vehicle | G6–G 15 | 13 weeks | Open field test in week 3,7,13, brain weight in week 15 | Increased open field activity and decreased latency time in week 3 and 13 in the 3 and 9 mg group. No difference in brain weight |
Spear (1980) [50] | Rats/SD | Hal 0.25 mg/kg/cc in water | Distilled water | G1–PND21 | 54 days | Open field test, open field hole-poking, response to amphetamine and haloperidol | Increased locomotor activity, hole-poking and response to amphetamine. Accentuated response to haloperidol in early life and young adulthood but not in adolescence |
Umemura (1983) [62] | Rats/SD | Cpz 2 or 8 mg/kg/day s.c. | Saline | G17–PND21 | 15 weeks | Spontaneous motor activity (magnatic field activity counter) and light–dark discrimination learning test | No difference in spontaneous activity. Impairment of reversal learning |
Hull (1984) [52] | Rats/LE | Hal 2.5 mg/kg/d i.p. | Saline i.p. (4 groups with Hal and saline pre- and postnatally) | G7–PND21 | 79 days | Open field test, eye opening, haloperidol-induced catalepsy | No difference in open field ambulation, eye opening or haloperidol-induced catalepsy |
Szkilnik (1987) [64] | Rats/W | Cpz 1 or 5 mg/kg/d s.c. | Saline 1 ml/kg/day s.c. | G1–PND21 | 3 months | Lats’ test, open field test, hole test, chlorpromazine-induced catalepsy, conditional avoidance learning | No difference in Lats’ test. Lower number of trespassings and lookings outside. Increased excitability. Fewer dippings in hole test. Increased catalepsy. No difference in conditional avoidance learning |
Bruses (1989) [45] | Rats/SD | Hal 2.5 mg/kg/day i.p. | Saline 200 µl i.p. | G5–G20 | 38 days | Surface righting reflex, negative stereotaxis test, T-maze spatial learning, circling training | Delayed surface righting reflex, fewer turns on circling training, no difference in T-maze spatial learning test |
Scalzo (1989) [55] | Rats/SD | Hal 2,5 or 5 mg/kg/day s.c. | Vehicle | G6–G20 | 62 days | Milk induced behavioural activation (day 6), SPWC (day 9,11,13,15,17), stimulant induced behavioral stereotypes (SIBS) (day 30), duration of barbiturate anesthesia (day 34, 62) | SPWC duration reduced on day 9 + 11 but not later. Reduced total anesthesia duration at day 62 in 5 mg group. No difference in milk induced behavior or SIBS |
Myslivecek (1991) [57] | Rats/W | Cpz 2.5 mg/kg/day Inj | Saline Inj | G15, 18, 20 | 4 months | Eye opening, righting reflexes, hanging, passive avoidance learning paradigms (neonatal, 2 months, 4 months) | No difference in eye opening. Delayed righting reflexes. Impaired hanging. Impaired passive avoidance learning |
Archer (1992) [47] | Rats/n.r. | Hal 2.5 µmol/kg/day by gavage | Vehicle | G6–G21 | 25 days | Radial arm maze and circular swim maze. Response to low dose d-amphetamine | Increased locomotion, rearing, and total activity. Rearing behavior reduced 90 min after d-amphetamine, potentiation after 120 min. Potentiation of stimulatory effect of d-amphetamine on locomotion. Retardation of spatial learning. |
Williams (1992) [56] | Rats/SD | Hal 5 mg/kg/d s.c. | Vehicle | G6–G20 | 100 days | Brain weight | Decreased brain weight |
Singh (1997) [49] | Rats/CF | Hal 0.1 mg/kg/day i.p. | Vehicle | G13–G20 | 7–8 weeks | Open field test, tunnel-entry test, elevated zero maze test, elevated plus-maze test | Increased ambulation and rearing. Decreased scratching, licking and washing behavior in open field. Tunnel: decreased time in centre of cage. Zero-maze: less time in open arms. Plus maze: fewer entries and less time in open arms |
Singh (1998) [54] | Rats/n.r. | Hal 0.1 mg/kg/d i.p. | Vehicle | G13–G21 | 8 weeks | Foot shock induced aggressive behaviour test | Increased number of fighting bouts. No difference in fighting latency |
Rosengarten (2002) [48] | Rats/SD | Hal 2 mg Qtp 10 mg Olz 2 mg Ris 1 mg/kg/day in water | Vehicle | G8–G18 | 2 months | Radial arm maze: spatial learning and short term retention | Hal,Ris,Qtp: impaired spatial learning, Hal, Ris: impaired short-term retention, Olz: no differences in spatial learning or short-term retention |
Singh (2002) [51] | Rats/CF | Hal 2.5 mg/kg/day i.p. | Vehicle | G12–G20 | 56 days | Open field test, elevated plus-maze test, zero-maze test (anxiety patterns) | Increased ambulation, rearing and defecation. Plus-maze: fewer entries and less time in open arms, more entries and time in closed arms. Zero-maze: fewer head dips and stretch attend postures |
Wolansky (2004) [46] | Rats/SD | Hal 2.5 mg/kg i.p. | Vehicle | G5–G18 | 90 days | Circling training test | Decreased circling activity, but effect disappeared when exposure was continued during lactation |
Zuo (2008) [68] | Rats/SD | Ris 2 mg/kg, Sul 200 mg/kg in water | Saline in drinking water | G6–G18 | 60 days | Righting reflex, Open field test, Morris water maze | Ris: increased rearing. No difference in water maze tests or righting reflex. Sul: impaired cue response in visual task performance (Morris water maze). Reduction in spontaneous activity. No difference in righting reflex |
Singh (2015) [66] | Rats/W | Qtp 55 or 80 mg/kg/day orally | Vehicle | G6–G21 | 70 days | Morris water maze; passive avoidance learning task | Impaired (dose-dependent) spatial learning. Impaired retention capability |
Singh (2016) [67] | Rats/W | Ris 0.8 mg/kg/day; 1.0 mg/kg/day; 2.0 mg/kg/day in water | Saline | G6–G21 | 10 weeks | Open field test, elevated plus-maze, brain weight | Increased ambulation and rearing. Anxiety-like exploratory behavior. Dose-dependent reduction in brain weight |
Author (year) | Study design | Sample size | Lithium daily dosage | Treatment indication | Follow-up time | Measurements | Results | NOS |
---|---|---|---|---|---|---|---|---|
Schou (1976) [36] | Prospective cohort study | Exposed = 60 Controls = 57 | n.r. | n.r. | Mean: 7 years | Developmental questionnairea | No difference in rate of abnormal development | 7 |
Jacobson (1992) [37] | Prospective cohort study | Exposed = 22 Controls = n.r. | Mean: 927 mg | Major affective disorders | Mean: 61 weeks, range: 1-9 years | Telephone interview on the attainment of developmental milestones | No difference | 3 |
vd Lugt (2012) [38] | Cohort study | Exposed = 15 No controls | n.r. | Bipolar disorder | 3–15 years | Development questionnairea IQ by BSID or WPPSI/WISC Hempel or Touwen neurological examination Child Behavior Checklist* | MND (n = 1). Low V–IQ + T–IQ normal P–IQ (n = 1) Subclinical anxiety problems (n = 2). Subclinical oppositional problems (n = 1) | 6 |
Author (year) | Study design | Sample size | Medication (daily dosage) | Treatment indication | Follow-up time | Measurements | Results | NOS |
---|---|---|---|---|---|---|---|---|
Slone (1977) [77] | Prospective cohort study | Exposed = 2141 Controls = 26.217 | Phenothiazine antipsychotics (n.r.) | n.r. | 4 years | IQ scores | No difference | 5 |
Platt (1989) [73] | Prospective cohort study | Exposed = 192 D+ Med− = 116 | Antipsychotic neuroleptics (n.r.) | Psychotic neurotic disorders | 7 years | Motor development in newborn period, at 8 months, 4 and 7 years | Newborn: increased abnormal motor activity; 8 months: trend towards more failures on BSID (not sign.) | 6 |
Stika (1990) [76] | Cohort study | Exposed = 66 Controls = 66 | Chlorpromazine (10–25 mg) or chlorprotixene (5 mg) | n.r. | 10 years | Teacher questionnaire | No difference in behavioural score | 5 |
Auerbach (1992) [69] | Cohort study | Exposed = 14 Controls = 26 D+ Med − = 18 | Phenothiazine antipsychotics (varied) | SMI | 14 days | NBAS at day 3 and day 14 | Reduced autonomic stability and higher abstinence score. | 8 |
Mortensen (2003) [71] | Register study | Exposed = 63 Controls = 755 | Neuroleptics (n.r.) | n.r. | 7–10 months | Boel test | Adjusted OR abnormal Boel test in exposed children = 4.1 (95% CI 1.3–13.0) | 7 |
Johnson (2012) [70] | Prospective cohort study | Exposed = 21 Controls = 78 ADD exposed = 183 | Antipsychotics combined (n.r.) | Anxiety and Mood Disorders | 6 months | INFANIB | Lower INFANIB scores after exposure to antipsychotics | 7 |
Peng (2013) [72] | Prospective cohort study | Exposed = 76 Controls = 76 | 33 Clz (178 mg), 16 Ris (2 mg), 13 Sul (461 mg), 8 Olz (8 mg), 6 Qtp (550 mg) | Schizophrenia | 12 months | BSID at 2, 6, 12 months | 2 months: lower on cognitive, motor, social-emotional and adaptive behavior scale, 6 months: lower on social-emotional and adaptive behavior scale, 12 months: no difference | 7 |
Shao (2015)a [80] | Post hoc analysis (Peng 2013) | Exposed = 63 | 33 Clz (178 mg), 30 other AP (16 Ris (2 mg), 8 Olz (8 mg), 6 Qtp (550 mg)) | Schizophrenia | 12 months | BSID at 2, 6, 12 months | 2 and 6 months: lower adaptive behavior scores for Clz exposed children compared to other AP, 12 months: no difference | |
Hurault-Delarue (2016) [74] | Register study | Exposed = 70 Controls = 32.303 | Neuroleptics (n.r.) | n.r. | 24 months | Pediatric examination | 9 months: higher prevalence of motor deficits, no difference in mental development, 24 months: no difference | 7 |
Petersen (2016) [75] | Register study | Exposed = 290 Controls = 210.966 D+ Med− = 492 | Antipsychotics (n.r.) | SMI | 9 months to 5 years | NDBD reported in health record | No difference in relative risk of NDBD after adjustment for confounders [RRR 1.22 (95% CI 0.80–1.84)] | 8 |