Valproate (Epilepsy) updated on 04-22-2025

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)3.15 [2.67, 3.72]12%32 studies1,0746,035low ROB5.75 [4.77; .]
Major congenital malformations3.00 [2.46, 3.66]19%25 studies8905,587low ROB5.46 [4.36; .]
Congenital heart defects2.88 [1.91, 4.33]30%11 studies1444,526low ROB5.21 [3.24; .]
Limb defects2.52 [1.76, 3.61]0%7 studies2262,807not evaluable ROB4.48 [2.92; .]
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; .]
Craniosynostosis15.00 [0.12, 1923.88]-1 study1not evaluable ROB-
Down syndrom / Trisomy 2115.00 [0.12, 1923.88]-1 study1not evaluable ROB-
Eye defects0.45 [0.12, 1.72]0%2 studies10309not evaluable ROB-
Hip dislocation and/or dysplasia15.00 [0.12, 1923.88]-1 study1not evaluable ROB-
Valproate syndrome--0 study-
Cleft palate1.87 [0.04, 96.99]-1 study28not evaluable ROB-
Ear, face and neck anomalies0.71 [0.03, 14.91]-1 study2263not evaluable ROB-
Eye, ear, face and neck malformations1.03 [0.41, 2.59]-1 study624not evaluable ROB-
Respiratory system anomalies4.16 [1.88, 9.20]-1 study624not evaluable ROB7.79 [3.17; .]

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-
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-

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; .]
Abruptio placentae (retroplacental hematoma)0.63 [0.19, 2.09]-1 studynot 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-
Maternal consequences (as a whole)1.69 [1.28, 2.25]0%2 studies7421,907not evaluable ROB2.78 [1.88; .]
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)1.78 [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; .]
Fetal distress0.09 [0.00, 1.83]-1 study416not evaluable ROB-
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
Language disorders/delay2.94 [2.10, 4.11]52%15 studies72,2491,419critical ROB5.32 [3.62; .]
ASD (Autism spectrum disorder): Diagnosis/Risk2.48 [1.95, 3.15]33%10 studies5,4784,842low ROB4.39 [3.31; .]
Cognitive developmental disorders/delay (> 6 years old)2.58 [2.13, 3.12]1%14 studies5533,437low ROB4.60 [3.68; .]
ASD (Autism spectrum disorder): Diagnosis2.54 [2.00, 3.23]34%9 studies5,4484,815not evaluable ROB4.52 [3.42; .]
ADHD (Attention deficit hyperactivity disorder): Diagnosis/Risk1.28 [1.10, 1.48]0%10 studies1,7503,343low ROB1.88 [1.44; .]
Neuro-developmental disorders (as a whole)3.24 [2.20, 4.79]50%9 studies10,7363,173not evaluable ROB5.94 [3.82; .]
ADHD (Attention deficit hyperactivity disorder): Diagnosis1.30 [1.12, 1.51]0%7 studies1,7413,265not evaluable ROB1.92 [1.48; .]
Psychomotor developmental disorders/delay2.61 [1.80, 3.79]17%9 studies46483not evaluable ROB4.66 [3.00; .]
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 (3-6 years old)6.12 [3.14, 11.91]43%6 studies3,4661,170not evaluable ROB11.71 [5.73; .]
Cognitive developmental disorders/delay (< 3 years old)4.09 [2.17, 7.69]53%5 studies64330not evaluable ROB7.65 [3.77; .]
ADHD (Attention deficit hyperactivity disorder): Risk1.15 [0.68, 1.96]0%5 studies32149not evaluable ROB-
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-
Learning disorders 1.34 [0.99, 1.81]-1 study172not evaluable ROB-
Severe cognitive developmental delay (Mental retardation) (< 3 years old)3.29 [1.00, 10.85]-1 study1329not evaluable ROB-

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