Valproate (Epilepsy) updated on 06-15-2026

Table   Graphic     exposition period:

Congenital malformations
Adverse outcome OR 95%CII2k No. casesNo. exposedpublication biasROBE-value
All congenital malformations (majors, minors, majors and minors, or unspecified)3.10 [2.64, 3.64]13%33 studies1,1096,009low ROB5.65 [4.72; .]
Major congenital malformations2.95 [2.45, 3.55]20%26 studies9255,561low ROB5.35 [4.33; .]
Congenital heart defects2.80 [1.96, 4.01]23%12 studies1444,526low ROB5.05 [3.32; .]
Limb defects2.47 [1.74, 3.51]0%8 studies2262,807not evaluable ROB4.37 [2.87; .]
Neural Tube Defects9.34 [4.08, 21.40]0%7 studies523,298not evaluable ROB18.17 [7.62; .]
Microcephaly / Small head circumference for gestational age1.09 [0.82, 1.46]0%6 studies8002,152not evaluable ROB-
Hypospadias4.64 [2.00, 10.77]36%5 studies642,933not evaluable ROB8.76 [3.42; .]
Spina bifida9.14 [2.63, 31.73]0%4 studies14518not evaluable ROB17.76 [4.71; .]
Minor congenital malformations4.84 [2.06, 11.36]0%4 studies43106not evaluable ROB9.14 [3.54; .]
Oro-facial clefts3.44 [1.86, 6.36]0%5 studies3293,613not evaluable ROB6.34 [3.12; .]
Polydactyly5.06 [0.71, 36.27]16%4 studies101,415not evaluable ROB-
Urinary malformations1.36 [0.71, 2.59]0%4 studies262,609not evaluable ROB-
Digestive system anomalies1.44 [0.79, 2.62]0%3 studies162,185not evaluable ROB-
Nervous system anomalies7.35 [2.65, 20.39]40%3 studies211996not evaluable ROB14.17 [4.73; .]
Genital anomalies4.93 [3.28, 7.41]0%3 studies324922not evaluable ROB9.33 [6.01; .]
Chromosomal abnormalities2.66 [0.64, 11.11]0%2 studies1887not evaluable ROB-
Cleft lip with or without cleft palate7.19 [1.57, 32.82]0%2 studies7291not evaluable ROB13.86 [2.52; .]
Eye defects0.45 [0.12, 1.72]0%2 studies10309not evaluable ROB-
Valproate syndrome--0 study-
Respiratory system anomalies4.16 [1.88, 9.20]-1 study624not evaluable ROB7.79 [3.17; .]
6 non statistically significant endpoints reported in only one study

Growth parameters and prematurity
Adverse outcome OR 95%CII2k No. casesNo. exposedpublication biasROBE-value
Preterm (< 37 weeks)1.21 [1.02, 1.42]0%14 studies91,5682,056low ROB1.70 [1.16; .]
Small for gestational age (weight)1.47 [1.04, 2.06]68%9 studies170,3153,195not evaluable ROB2.29 [1.25; .]
Low birth weight (< 2500g)1.35 [0.95, 1.93]62%4 studies92,6773,047not evaluable ROB-
Large for gestational age (weight)1.21 [0.74, 1.98]22%3 studies158845not evaluable ROB-
Macrosomia (> 4000g)0.91 [0.55, 1.51]28%3 studies577,4071,059not evaluable ROB-
3 non statistically significant endpoints reported in only one study

Maternal consequences
Adverse outcome OR 95%CII2k No. casesNo. exposedpublication biasROBE-value
Caesarean0.93 [0.76, 1.14]0%3 studies831926not evaluable ROB-
Preeclampsia1.43 [0.81, 2.51]0%3 studies1330not evaluable ROB-
Assisted deliveries (forceps, vacuum, ...)1.18 [0.73, 1.90]0%2 studies177220not evaluable ROB-
Postpartum hemorrhage1.44 [1.01, 2.06]-1 study319215not evaluable ROB2.23 [1.08; .]
Maternal consequences (as a whole)1.69 [1.28, 2.25]0%2 studies7421,907not evaluable ROB2.78 [1.88; .]
4 non statistically significant endpoints reported in only one study

Neonatal disorders
Adverse outcome OR 95%CII2k No. casesNo. exposedpublication biasROBE-value
Low Apgar score (< 7) (at 5 min)1.78 [0.92, 3.45]0%5 studies63683not evaluable ROB-
Neonatal medical care2.01 [1.54, 2.62]0%5 studies2,092771not evaluable ROB3.43 [2.44; .]
Low Apgar score (< 7) (at 1 min)2.54 [0.71, 9.05]66%3 studies132667not evaluable ROB-
Feeding difficulty24.38 [1.49, 397.73]0%2 studies23not evaluable ROB48.26 [2.35; .]
Neonatal disorders (as a whole)0.92 [0.76, 1.11]0%2 studies222,323992not evaluable ROB-
Neonatal intracranial hemorrhage15.00 [1.09, 206.94]0%2 studies33not evaluable ROB29.49 [1.40; .]
Withdrawal syndrome / Neonatal abstinence syndrome / Poor neonatal adaptation189.00 [2.70, 13229.55]-1 study12not evaluable ROB377.50 [4.84; .]
Very low Apgar score (< 5) (at 1 min)--0 study-
5 non statistically significant endpoints reported in only one study

Long term consequences
Adverse outcome OR 95%CII2k No. casesNo. exposedpublication biasROBE-value
Child/Infant death (> 28 days of life)3.01 [1.62, 5.60]0%2 studies4,7141,694not evaluable ROB5.47 [2.62; .]
4 non statistically significant endpoints reported in only one study

Intrauterine deaths
Adverse outcome OR 95%CII2k No. casesNo. exposedpublication biasROBE-value
Intrauterine deaths (as a whole or unspecified)1.64 [1.14, 2.35]50%8 studies7973,167not evaluable ROB2.66 [1.54; .]
Early intrauterine deaths (< 22 weeks) / Spontaneous abortions1.04 [0.84, 1.29]0%6 studies3692,499not evaluable ROB-
Late intrauterine deaths (> 22 weeks) / Stillbirths1.83 [1.01, 3.31]0%5 studies422,475not evaluable ROB3.07 [1.14; .]
Elective/induced termination of pregnancy1.83 [0.80, 4.17]0%3 studies211,304not evaluable ROB-
Perinatal death2.16 [0.95, 4.89]0%3 studies271,833not evaluable ROB-
2 non statistically significant endpoints reported in only one study

Neuro-developmental disorders
Adverse outcome OR 95%CII2k No. casesNo. exposedpublication biasROBE-value
Language disorders/delay2.88 [2.12, 3.90]61%17 studies72,7842,234critical ROB5.20 [3.67; .]
ASD (Autism spectrum disorder): Diagnosis/Risk2.44 [1.96, 3.03]25%11 studies5,4925,085low ROB4.31 [3.33; .]
Cognitive developmental disorders/delay (> 6 years old)2.62 [2.12, 3.24]8%15 studies5533,456low ROB4.68 [3.66; .]
ASD (Autism spectrum disorder): Diagnosis2.49 [2.00, 3.09]25%10 studies5,4625,058low ROB4.41 [3.42; .]
ADHD (Attention deficit hyperactivity disorder): Diagnosis/Risk1.25 [1.10, 1.42]0%11 studies2,1864,139low ROB1.80 [1.42; .]
Psychomotor developmental disorders/delay2.81 [1.89, 4.16]37%11 studies1501,298probable ROB5.06 [3.19; .]
ADHD (Attention deficit hyperactivity disorder): Diagnosis1.26 [1.11, 1.44]0%8 studies2,1774,061not evaluable ROB1.83 [1.45; .]
Neuro-developmental disorders (as a whole)3.24 [2.20, 4.79]50%9 studies10,7363,173not evaluable ROB5.94 [3.82; .]
Cognitive developmental disorders/delay (3-6 years old)4.66 [2.20, 9.87]67%7 studies3,4661,966not evaluable ROB8.78 [3.82; .]
Severe cognitive developmental delay (Mental retardation) (> 6 years old)2.77 [2.23, 3.44]0%8 studies5343,217not evaluable ROB4.98 [3.88; .]
Cognitive developmental disorders/delay (< 3 years old)4.09 [2.17, 7.69]53%5 studies64330not evaluable ROB7.65 [3.77; .]
Severe cognitive developmental delay (Mental retardation) (3-6 years old)3.21 [1.34, 7.71]54%5 studies3,4261,897not evaluable ROB5.88 [2.01; .]
ADHD (Attention deficit hyperactivity disorder): Risk1.15 [0.68, 1.96]0%5 studies32149not evaluable ROB-
ASD (Autism spectrum disorder): Risk1.28 [0.48, 3.42]0%3 studies3779not evaluable ROB-
Learning disorders 2.46 [0.81, 7.48]85%3 studies54984not evaluable ROB-
1 non statistically significant endpoints reported in only one study

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