Valproate (Epilepsy)

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)3.36 [2.79, 4.06]13%29 studies1,0175,201low ROB6.18 [5.02; .]
Major congenital malformations3.24 [2.56, 4.10]23%22 studies8334,753low ROB5.94 [4.56; .]
Congenital heart defects3.30 [2.11, 5.17]17%10 studies1443,902low ROB6.06 [3.64; .]
Limb defects3.76 [1.96, 7.23]0%6 studies2262,183not evaluable ROB6.99 [3.33; .]
Neural Tube Defects9.34 [4.08, 21.40]0%7 studies523,298not evaluable ROB18.17 [7.62; .]
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; .]
Microcephaly / Small head circumference for gestational age1.31 [0.63, 2.74]0%5 studies34199not evaluable ROB-
Polydactyly5.06 [0.71, 36.27]16%4 studies101,415not evaluable ROB-
Oro-facial clefts3.90 [1.68, 9.04]16%4 studies3292,989not evaluable ROB7.26 [2.75; .]
Urinary malformations1.16 [0.46, 2.92]18%3 studies261,985not evaluable ROB-
Digestive system anomalies1.31 [0.50, 3.46]0%2 studies161,561not evaluable ROB-
Minor congenital malformations5.11 [2.13, 12.25]0%3 studies4383not evaluable ROB9.69 [3.68; .]
Nervous system anomalies13.76 [4.97, 38.10]0%2 studies211372not evaluable ROB27.01 [9.41; .]
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-
Genital anomalies3.06 [0.98, 9.55]0%2 studies324298not evaluable ROB-
Hip dislocation and/or dysplasia15.00 [0.12, 1923.88]-1 study1not evaluable ROB-
Valproate syndrome--0 study-
Chromosomal abnormalities10.77 [0.44, 265.09]-1 study1263not evaluable ROB-
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-

Growth parameters and prematurity
Adverse outcome OR 95%CII2k No. casesNo. exposedpublication biasROBE-value
Preterm (< 37 weeks)1.19 [1.01, 1.41]0%13 studies252,1632,049low ROB1.67 [1.10; .]
Small for gestational age (weight)1.34 [0.97, 1.85]67%10 studies209,3683,888low ROB-
Low birth weight (< 2500g)1.35 [0.92, 2.00]46%4 studies91,6721,797not 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-
Preeclampsia1.41 [0.84, 2.37]0%4 studies53,64791not evaluable ROB-
Assisted deliveries (forceps, vacuum, ...)1.18 [0.73, 1.90]0%2 studies177220not evaluable ROB-
Gestational diabetes0.62 [0.13, 2.89]0%3 studies981not 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 study20,260not evaluable ROB-
Amniotic fluid problems (polyhydramnios and/or oligohydramnios)2.05 [0.04, 110.56]-1 study11not evaluable ROB-
Polyhydramnios0.11 [0.00, 14.76]-1 study5not evaluable ROB-
Maternal consequences (as a whole)2.86 [0.52, 15.77]-1 study812not 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-
Jaundice4.33 [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
Behavioral disorders0.93 [0.65, 1.34]0%5 studies1512,088not evaluable ROB-
Emotional disorders0.97 [0.77, 1.22]0%4 studies5912,069not evaluable ROB-
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)1.46 [1.01, 2.11]36%7 studies4683,144not evaluable ROB2.27 [1.08; .]
Early intrauterine death (< 22 weeks)1.04 [0.84, 1.29]0%5 studies3662,475not evaluable ROB-
Late intrauterine deaths (> 22 weeks)1.83 [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/delay3.02 [2.10, 4.36]55%14 studies72,2491,394critical ROB5.50 [3.62; .]
Cognitive developmental disorders/delay (> 6 years old)2.59 [1.90, 3.51]12%11 studies3082,266low ROB4.61 [3.22; .]
ASD (Autism spectrum disorder): Diagnosis/Risk2.71 [2.08, 3.52]16%8 studies4,7563,135not evaluable ROB4.85 [3.58; .]
Neuro-developmental disorders (as a whole)3.24 [2.20, 4.79]50%9 studies10,7853,173not evaluable ROB5.94 [3.82; .]
ADHD (Attention deficit hyperactivity disorder): Diagnosis/Risk1.48 [1.23, 1.78]0%9 studies6622,197not evaluable ROB2.33 [1.77; .]
ASD (Autism spectrum disorder): Diagnosis2.77 [2.19, 3.50]7%7 studies4,7263,108not evaluable ROB4.98 [3.81; .]
Psychomotor developmental disorders/delay2.72 [1.74, 4.24]18%9 studies82343not evaluable ROB4.88 [2.87; .]
Cognitive developmental disorders/delay (3-6 years old)6.12 [3.14, 11.91]43%6 studies3,4661,170not evaluable ROB11.71 [5.73; .]
ADHD (Attention deficit hyperactivity disorder): Diagnosis1.54 [1.27, 1.86]0%6 studies6532,119not evaluable ROB2.45 [1.86; .]
Cognitive developmental disorders/delay (< 3 years old)4.09 [1.87, 8.96]58%5 studies103190not evaluable ROB7.64 [3.14; .]
Severe cognitive developmental delay (Mental retardation) (> 6 years old)2.81 [2.06, 3.82]0%6 studies2892,071not evaluable ROB5.06 [3.55; .]
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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