Valproate (All indications) updated on 12-01-2025

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)3.06 [2.60, 3.61]28%36 studies149,2798,567low ROB5.58 [4.65; .]
Major congenital malformations2.91 [2.43, 3.49]34%28 studies149,0918,089low ROB5.28 [4.30; .]
Congenital heart defects2.63 [2.04, 3.38]21%15 studies2,2217,175low ROB4.69 [3.50; .]
Hypospadias5.88 [4.60, 7.51]1%10 studies9,5676,978low ROB11.24 [8.68; .]
Limb defects2.43 [1.77, 3.33]0%8 studies1,3343,319not evaluable ROB4.29 [2.94; .]
Spina bifida13.22 [7.24, 24.13]0%7 studies7691,776not evaluable ROB25.93 [13.97; .]
Microcephaly / Small head circumference for gestational age1.18 [0.95, 1.46]0%8 studies134,5924,605not evaluable ROB-
Neural Tube Defects9.34 [4.08, 21.40]0%7 studies523,298not evaluable ROB18.17 [7.62; .]
Oro-facial clefts3.57 [2.43, 5.25]0%7 studies2,8576,825not evaluable ROB6.61 [4.30; .]
Nervous system anomalies3.21 [2.06, 4.98]0%5 studies3743,543not evaluable ROB5.87 [3.54; .]
Polydactyly2.55 [0.48, 13.67]30%5 studies3,0952,112not evaluable ROB-
Urinary malformations1.35 [0.72, 2.52]0%5 studies292,942not evaluable ROB-
Club foot / Talipes equinovarus4.97 [3.12, 7.91]17%3 studies3,8103,641not evaluable ROB9.41 [5.70; .]
Digestive system anomalies1.49 [0.85, 2.60]0%4 studies232,518not evaluable ROB-
Genital anomalies4.68 [3.21, 6.82]0%4 studies1,0451,434not evaluable ROB8.83 [5.87; .]
Minor congenital malformations4.84 [2.06, 11.36]0%4 studies43106not evaluable ROB9.14 [3.54; .]
Cardiac septal defects2.67 [1.74, 4.10]0%2 studies16,5781,030not evaluable ROB4.78 [2.87; .]
Cleft lip with or without cleft palate5.08 [1.87, 13.82]0%3 studies1,6471,204not evaluable ROB9.64 [3.15; .]
Craniosynostosis6.12 [1.26, 29.85]0%2 studies768914not evaluable ROB11.72 [1.82; .]
Cleft palate4.85 [1.37, 17.12]0%2 studies1,181941not evaluable ROB9.16 [2.08; .]
Ano-rectal atresia and stenosis11.70 [3.09, 44.30]-1 study547913not evaluable ROB22.89 [5.63; .]
Atrial septal defect9.00 [5.40, 15.00]-1 study3,283913not evaluable ROB17.49 [10.27; .]
Atrioventricular septal defect1.94 [0.12, 31.09]-1 study529913not evaluable ROB-
Bilateral renal agenesis including Potter syndrome13.61 [0.84, 219.81]-1 study75913not evaluable ROB-
Bladder exstrophy and/or epispadia12.46 [0.77, 201.01]-1 study82913not evaluable ROB-
Chromosomal abnormalities2.66 [0.64, 11.11]0%2 studies1887not evaluable ROB-
Coarctation of aorta1.32 [0.08, 21.11]-1 study779913not evaluable ROB-
Diaphragmatic hernia2.71 [0.17, 43.52]-1 study378913not evaluable ROB-
Down syndrom / Trisomy 2115.00 [0.12, 1923.88]-1 study1not evaluable ROB-
Ebstein's anomaly20.35 [1.25, 330.13]-1 study50913not evaluable ROB40.20 [1.82; .]
Eye defects0.45 [0.12, 1.72]0%2 studies10309not evaluable ROB-
Eye, ear, face and neck malformations1.13 [0.47, 2.70]0%2 studies2957not evaluable ROB-
Gastroschisis4.22 [0.26, 67.72]-1 study243913not evaluable ROB-
Hip dislocation and/or dysplasia15.00 [0.12, 1923.88]-1 study1not evaluable ROB-
Hypoplastic left heart (HLH/HLHS)19.60 [3.59, 107.13]-1 study218913not evaluable ROB38.69 [6.63; .]
Hypoplastic right heart (HRH/HRHS)15.46 [0.96, 249.87]-1 study66913not evaluable ROB-
Oesophageal atresia with or without tracheo-oesophageal fistula2.62 [0.16, 41.96]-1 study392913not evaluable ROB-
Omphalocele3.86 [0.24, 61.86]-1 study266913not evaluable ROB-
Pulmonary valve atresia27.80 [4.99, 154.94]-1 study154913not evaluable ROB55.10 [9.45; .]
Respiratory system anomalies2.45 [0.40, 14.80]43%2 studies2957not evaluable ROB-
Tetralogy of Fallot7.20 [1.33, 38.92]-1 study586913not evaluable ROB13.88 [2.00; .]
Valproate syndrome--0 study-
Ventricular septal defect4.00 [2.08, 7.71]-1 study4,652913not evaluable ROB7.46 [3.57; .]
Ear, face and neck anomalies0.71 [0.03, 14.91]-1 study2263not evaluable ROB-

Growth parameters and prematurity
Adverse outcome OR 95%CII2k No. casesNo. exposedpublication biasROBE-value
Preterm (< 37 weeks)1.08 [1.00, 1.17]0%19 studies289,8506,325low ROB1.39 [1.05; .]
Small for gestational age (weight)1.43 [1.10, 1.86]75%12 studies656,1737,528low ROB2.21 [1.43; .]
Low birth weight (< 2500g)1.41 [1.04, 1.91]70%6 studies267,0344,304not evaluable ROB2.16 [1.23; .]
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-
Very preterm (28 to 32 weeks)1.21 [0.54, 2.70]-1 study8,590991not evaluable ROB-
Extremely preterm (< 28 weeks)0.85 [0.12, 6.01]-1 study2,042991not evaluable ROB-
Large head circumference for gestational age0.79 [0.01, 44.65]-1 study10not evaluable ROB-
Very low birth weight (< 1500g)0.63 [0.09, 4.51]-1 study309226not evaluable ROB-

Maternal consequences
Adverse outcome OR 95%CII2k No. casesNo. exposedpublication biasROBE-value
Caesarean0.94 [0.79, 1.12]0%4 studies187,2441,241not evaluable ROB-
Assisted deliveries (forceps, vacuum, ...)1.18 [0.73, 1.90]0%2 studies177220not evaluable ROB-
Preeclampsia0.94 [0.77, 1.15]0%3 studies53,7512,428not evaluable ROB-
Postpartum hemorrhage0.99 [0.47, 2.06]88%2 studies203,631530not evaluable ROB-
Maternal consequences (as a whole)1.49 [1.23, 1.82]0%3 studies12,9942,133not evaluable ROB2.35 [1.75; .]
Abruptio placentae (retroplacental hematoma)1.25 [0.94, 1.66]-1 study20,3222,398not evaluable ROB-
Amniotic fluid problems (polyhydramnios and/or oligohydramnios)2.05 [0.04, 110.56]-1 study11not evaluable ROB-
Gestational diabetes0.65 [0.02, 17.40]-1 study111not evaluable ROB-
Polyhydramnios0.11 [0.00, 14.76]-1 study5not evaluable ROB-

Neonatal disorders
Adverse outcome OR 95%CII2k No. casesNo. exposedpublication biasROBE-value
Low Apgar score (< 7) (at 5 min)1.77 [1.20, 2.62]0%8 studies16,4991,341not evaluable ROB2.94 [1.68; .]
Neonatal medical care1.98 [1.58, 2.47]0%7 studies46,9091,092not evaluable ROB3.36 [2.54; .]
Low Apgar score (< 7) (at 1 min)2.39 [0.84, 6.81]50%4 studies134673not evaluable ROB-
Neonatal disorders (as a whole)1.05 [0.76, 1.44]35%3 studies225,7531,218not evaluable ROB-
Withdrawal syndrome / Neonatal abstinence syndrome / Poor neonatal adaptation189.00 [2.70, 13229.55]-1 study12not evaluable ROB377.50 [4.84; .]
Feeding difficulty24.38 [1.49, 397.73]0%2 studies23not evaluable ROB48.26 [2.35; .]
Fetal distress0.09 [0.00, 1.83]-1 study416not evaluable ROB-
Neonatal intracranial hemorrhage15.00 [1.09, 206.94]0%2 studies33not evaluable ROB29.49 [1.40; .]
Jaundice / Icterus4.33 [0.06, 320.42]-1 study11not evaluable ROB-
Neonatal hypotonia15.00 [0.12, 1923.88]-1 study1not evaluable ROB-
Neonatal infections15.00 [0.12, 1923.88]-1 study1not evaluable ROB-
Neonatal tachypnea15.00 [0.12, 1923.88]-1 study1not evaluable ROB-
Very low Apgar score (< 5) (at 1 min)--0 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; .]
Child/Infant growth abnormalities (> 1 year)0.24 [0.03, 2.07]-1 study744not evaluable ROB-
Child/Infant head circumference abnormalities (> 1 year)1.39 [0.03, 71.26]-1 study42not evaluable ROB-
Child/Infant lenght abnormalities (> 1 year)2.55 [0.69, 9.43]-1 study1063not evaluable ROB-
Child/Infant weight abnormalities (> 1 year)1.16 [0.35, 3.82]-1 study1263not evaluable ROB-

Intrauterine deaths
Adverse outcome OR 95%CII2k No. casesNo. exposedpublication biasROBE-value
Intrauterine deaths (as a whole or unspecified)1.42 [0.99, 2.03]33%7 studies4623,046not evaluable ROB-
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-
Therapeutic terminations of pregnancy0.64 [0.01, 40.08]-1 study6not evaluable ROB-
Ectopic pregnancy1.70 [0.03, 85.94]-1 study1,290not evaluable ROB-

Neuro-developmental disorders
Adverse outcome OR 95%CII2k No. casesNo. exposedpublication biasROBE-value
Cognitive developmental disorders/delay (> 6 years old)2.69 [1.99, 3.62]40%14 studies24,6334,361low ROB4.81 [3.40; .]
Language disorders/delay2.81 [2.05, 3.83]48%16 studies72,2491,448critical ROB5.06 [3.53; .]
ADHD (Attention deficit hyperactivity disorder): Diagnosis/Risk1.28 [1.13, 1.44]0%12 studies165,0893,988low ROB1.87 [1.50; .]
ASD (Autism spectrum disorder): Diagnosis/Risk2.44 [1.82, 3.27]57%10 studies81,3855,766low ROB4.31 [3.04; .]
ASD (Autism spectrum disorder): Diagnosis2.53 [1.87, 3.42]60%9 studies81,3555,739not evaluable ROB4.49 [3.14; .]
ADHD (Attention deficit hyperactivity disorder): Diagnosis1.26 [1.10, 1.43]0%7 studies153,2293,720not evaluable ROB1.83 [1.44; .]
Neuro-developmental disorders (as a whole)4.09 [3.54, 4.73]0%10 studies10,7773,740low ROB7.64 [6.53; .]
Severe cognitive developmental delay (Mental retardation) (> 6 years old)3.20 [2.45, 4.18]15%8 studies24,6144,141not evaluable ROB5.85 [4.33; .]
Psychomotor developmental disorders/delay2.94 [2.01, 4.29]26%10 studies46513probable ROB5.32 [3.43; .]
Cognitive developmental disorders/delay (3-6 years old)5.06 [2.73, 9.37]52%7 studies3,4661,199not evaluable ROB9.58 [4.90; .]
ADHD (Attention deficit hyperactivity disorder): Risk1.51 [0.99, 2.32]16%7 studies11,883339not evaluable ROB-
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)5.02 [3.12, 8.08]0%4 studies3,4261,101not evaluable ROB9.52 [5.70; .]
ASD (Autism spectrum disorder): Risk1.28 [0.48, 3.42]0%3 studies3779not evaluable ROB-
Childhood autism (F84.0)4.90 [2.32, 10.37]-1 study2,065388not evaluable ROB9.27 [4.06; .]
Learning disorders 1.27 [1.00, 1.61]-1 study232not evaluable ROB1.86 [1.07; .]
Severe cognitive developmental delay (Mental retardation) (< 3 years old)3.29 [1.00, 10.85]-1 study1329not evaluable ROB-

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