Valproate (All indications)

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)3.16 [2.64, 3.78]38%33 studies198,7168,172critical ROB5.77 [4.72; .]
Major congenital malformations3.01 [2.46, 3.68]44%25 studies198,5287,694critical ROB5.46 [4.36; .]
Congenital heart defects2.74 [2.19, 3.44]13%15 studies18,3897,248low ROB4.93 [3.80; .]
Hypospadias5.88 [4.60, 7.51]1%10 studies9,5676,978low ROB11.24 [8.68; .]
Limb defects2.85 [1.79, 4.55]0%7 studies1,3342,695not evaluable ROB5.15 [2.98; .]
Neural Tube Defects9.34 [4.08, 21.40]0%7 studies523,298not evaluable ROB18.17 [7.62; .]
Spina bifida13.80 [7.20, 26.46]0%6 studies6401,764not evaluable ROB27.10 [13.88; .]
Oro-facial clefts3.67 [2.51, 5.38]0%7 studies5,6186,898not evaluable ROB6.81 [4.46; .]
Microcephaly / Small head circumference for gestational age1.36 [0.67, 2.78]0%6 studies4721,112not evaluable ROB-
Polydactyly2.55 [0.48, 13.67]30%5 studies3,0952,112not evaluable ROB-
Nervous system anomalies3.08 [1.88, 5.03]0%4 studies3742,919not evaluable ROB5.61 [3.18; .]
Club foot / Talipes equinovarus4.97 [3.12, 7.91]17%3 studies3,8103,641not evaluable ROB9.41 [5.70; .]
Urinary malformations1.18 [0.56, 2.49]0%4 studies292,318not evaluable ROB-
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; .]
Digestive system anomalies1.46 [0.65, 3.30]0%3 studies231,894not evaluable ROB-
Genital anomalies3.25 [1.54, 6.89]0%3 studies1,045810not evaluable ROB5.96 [2.44; .]
Cleft palate4.85 [1.37, 17.12]0%2 studies1,181941not evaluable ROB9.16 [2.08; .]
Minor congenital malformations5.11 [2.13, 12.25]0%3 studies4383not evaluable ROB9.69 [3.68; .]
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; .]
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-
Hypoplastic left heart (HLH/HLHS)19.60 [3.59, 107.13]-1 study218913not evaluable ROB38.69 [6.63; .]
Pulmonary valve atresia27.80 [4.99, 154.94]-1 study154913not evaluable ROB55.10 [9.45; .]
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; .]
15 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)1.08 [0.99, 1.17]0%15 studies252,9784,796low ROB-
Small for gestational age (weight)1.32 [1.00, 1.74]74%12 studies210,1166,632low ROB-
Low birth weight (< 2500g)1.49 [1.23, 1.82]15%6 studies94,9122,363not evaluable ROB2.35 [1.76; .]
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-
4 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-
Preeclampsia0.95 [0.78, 1.15]0%4 studies53,7602,489not evaluable ROB-
Assisted deliveries (forceps, vacuum, ...)1.18 [0.73, 1.90]0%2 studies177220not evaluable ROB-
Gestational diabetes1.60 [0.23, 10.91]48%4 studies14110not evaluable ROB-
Postpartum hemorrhage1.44 [1.01, 2.06]-1 study319215not evaluable ROB2.23 [1.08; .]
Maternal consequences (as a whole)1.35 [1.03, 1.77]0%2 studies12,260238not evaluable ROB2.03 [1.19; .]
3 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)1.76 [1.06, 2.91]0%7 studies1371,026not evaluable ROB2.91 [1.33; .]
Neonatal medical care1.98 [1.52, 2.59]0%6 studies2,098777not evaluable ROB3.38 [2.41; .]
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; .]
Neonatal intracranial hemorrhage15.00 [1.09, 206.94]0%2 studies33not evaluable ROB29.49 [1.40; .]
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
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; .]
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)1.46 [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-
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/delay2.87 [2.05, 4.02]52%15 studies72,2491,423critical ROB5.19 [3.52; .]
ADHD (Attention deficit hyperactivity disorder): Diagnosis/Risk1.52 [1.28, 1.81]0%11 studies12,5132,387low ROB2.42 [1.88; .]
Cognitive developmental disorders/delay (> 6 years old)2.99 [2.00, 4.48]38%11 studies2462,735low ROB5.44 [3.42; .]
Neuro-developmental disorders (as a whole)4.09 [3.54, 4.73]0%10 studies10,8263,740low ROB7.64 [6.53; .]
ASD (Autism spectrum disorder): Diagnosis/Risk2.86 [2.28, 3.58]8%8 studies4,6893,604not evaluable ROB5.16 [4.00; .]
Psychomotor developmental disorders/delay3.03 [1.99, 4.64]23%10 studies82373low ROB5.52 [3.39; .]
ASD (Autism spectrum disorder): Diagnosis2.91 [2.40, 3.53]0%7 studies4,6593,577not evaluable ROB5.28 [4.24; .]
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): Diagnosis1.54 [1.27, 1.86]0%6 studies6532,119not evaluable ROB2.45 [1.86; .]
ADHD (Attention deficit hyperactivity disorder): Risk1.51 [0.99, 2.32]16%7 studies11,883339not evaluable ROB-
Severe cognitive developmental delay (Mental retardation) (> 6 years old)4.15 [3.12, 5.51]0%6 studies2272,540not evaluable ROB7.76 [5.70; .]
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) (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-
Fonctions exécutives (A CONSOLIDER)2.76 [1.64, 4.67]0%2 studies77not evaluable ROB4.97 [2.66; .]
Childhood autism (F84.0)4.90 [2.32, 10.37]-1 study2,065388not evaluable ROB9.27 [4.06; .]
Fonctions mnésiques (A CONSOLIDER)3.94 [2.00, 7.76]-1 study49not evaluable ROB7.34 [3.42; .]
Learning disorders 1.27 [1.00, 1.61]-1 study232not evaluable ROB1.86 [1.07; .]
2 non statistically significant endpoints reported in only one study

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