Valproate (All indications)

Table   Graphic  
individual studies
OutcomeTE95% CIn casesn exposedkPub. bias Congenital malformations All congenital malformations (majors, minors, majors and minors, or unspecified) Jäger-Roman (Valproate), 1986 Robert (Valproate), 1986 D'Souza (Valproate) (Controls unexposed, sick), 1991 Kaneko (Valproate), 1999 Samrén (Valproate), 1999 Canger (Valproate), 1999 Hvas (Valproate) (Controls unexposed, sick), 2000 Dean (Valproate), 2002 Kaaja (Valproate), 2003 Endo (Valproate) (Controls unexposed, sick), 2004 Artama (Valproate), 2005 Viinikainen (Valproate) (Controls unexposed, sick) a, 2006 Diav-Citrin (Valproate) (Mixed indications), 2008 Mawer (Valproate) (Controls unexposed, sick), 2010 Bànhidy (Valproate), 2011 Charlton (Valproate) (Controls unexposed, sick), 2011 Arteaga-Vázquez (Valproate), 2012 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 Cassina (Valproate) (Controls unexposed, disease free) (Mixed indications), 2013 Veiby (Valproate) (Controls unexposed, sick) (Mixed indications), 2014 Campbell (Valproate) (Controls unexposed, sick), 2014 Vanya (Valproate) (Controls unexposed, sick), 2015 Petersen (Valproate) (Controls unexposed, sick), 2017 Tomson (Valproate), 2018 Huber-Mollema (Valproate), 2019 Vajda (Valproate) (Controls unexposed, sick), 2019 Putignano (Valproate), 2019 Aydin (Valproate) (Controls unexposed, sick), 2020 Thomas (Valproate) (Controls unexposed, sick), 2021 Hosny (Valproate) (Controls unexposed, sick), 2021 The NAAED (Controls unexposed, disease free) (Indications NOS), 2022 Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 333.16[2.64; 3.78]198,7168,172critical Major congenital malformations Robert (Valproate), 1986 Jäger-Roman (Valproate), 1986 Samrén (Valproate), 1999 Canger (Valproate), 1999 Hvas (Valproate) (Controls unexposed, sick), 2000 Dean (Valproate), 2002 Kaaja (Valproate), 2003 Viinikainen (Valproate) (Controls unexposed, sick) a, 2006 Diav-Citrin (Valproate) (Mixed indications), 2008 Mawer (Valproate) (Controls unexposed, sick), 2010 Charlton (Valproate) (Controls unexposed, sick), 2011 Bànhidy (Valproate), 2011 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 Cassina (Valproate) (Controls unexposed, disease free) (Mixed indications), 2013 Veiby (Valproate) (Controls unexposed, sick) (Mixed indications), 2014 Campbell (Valproate) (Controls unexposed, sick), 2014 Vanya (Valproate) (Controls unexposed, sick), 2015 Petersen (Valproate) (Controls unexposed, sick), 2017 Tomson (Valproate), 2018 Vajda (Valproate) (Controls unexposed, sick), 2019 Huber-Mollema (Valproate), 2019 Thomas (Valproate) (Controls unexposed, sick), 2021 Hosny (Valproate) (Controls unexposed, sick), 2021 The NAAED (Controls unexposed, disease free) (Indications NOS), 2022 Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 253.01[2.46; 3.68]198,5287,694critical Congenital heart defects D'Souza (Valproate) (Controls unexposed, sick), 1991 Canger (Valproate), 1999 Artama (Valproate), 2005 Diav-Citrin (Valproate) (Mixed indications), 2008 Mawer (Valproate) (Controls unexposed, sick), 2010 Bànhidy (Valproate), 2011 Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012 Vajda (Valproate) (Controls unexposed, sick), 2013 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Ban (Valproate) (Mixed indications) (Controls unexposed NOS), 2015 Tomson (Valproate), 2018 Thomas (Valproate) (Controls unexposed, sick), 2021 Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 152.74[2.19; 3.44]18,3897,248low Hypospadias D'Souza (Valproate) (Controls unexposed, sick), 1991 Diav-Citrin (Valproate) (Mixed indications), 2008 Bànhidy (Valproate), 2011 Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Veiby (Valproate) (Controls unexposed, disease free) (Mixed indications), 2014 Tomson (Valproate), 2018 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 105.88[4.60; 7.51]9,5676,978low Limb defects Artama (Valproate), 2005 Mawer (Valproate) (Controls unexposed, sick), 2010 Vajda (Valproate) (Controls unexposed, sick), 2013 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Ban (Valproate) (Mixed indications) (Controls unexposed NOS), 2015 Thomas (Valproate) (Controls unexposed, sick), 2021 72.85[1.79; 4.55]1,3342,695not evaluable Neural Tube Defects Canger (Valproate), 1999 Mawer (Valproate) (Controls unexposed, sick), 2010 Bànhidy (Valproate), 2011 Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012 Vajda (Valproate) (Controls unexposed, sick), 2013 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Tomson (Valproate), 2018 79.34[4.08; 21.40]523,298not evaluable Spina bifida Czeizel (Valproate), 1992 Artama (Valproate), 2005 Viinikainen (Valproate) (Controls unexposed, sick) a, 2006 Charlton (Valproate) (Controls unexposed, sick), 2011 Veiby (Valproate) (Controls unexposed, sick) (Mixed indications), 2014 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 613.80[7.20; 26.46]6401,764not evaluable Oro-facial clefts Hernández-Díaz (Valproate) (Controls exposed to Lamotrigine, sick), 2012 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Tomson (Valproate), 2018 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 73.67[2.51; 5.38]5,6186,898not evaluable Microcephaly / Small head circumference for gestational age Dravet (Valproate), 1992 Battino (Valproate), 1999 Díaz-Romero (Valproate), 1999 Kini (Valproate) (Controls unexposed, sick), 2006 Pennell (Valproate), 2012 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 61.36[0.67; 2.78]4721,112not evaluable Polydactyly D'Souza (Valproate) (Controls unexposed, sick), 1991 Viinikainen (Valproate) (Controls unexposed, sick) a, 2006 Bànhidy (Valproate), 2011 Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 Tomson (Valproate), 2018 52.41[0.43; 13.52]3,0952,112not evaluable Nervous system anomalies Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Ban (Valproate) (Mixed indications) (Controls unexposed NOS), 2015 Thomas (Valproate) (Controls unexposed, sick), 2021 Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 43.08[1.88; 5.03]3742,919not evaluable Club foot / Talipes equinovarus Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 Cohen (Valproate) (Mixed indications) (Controls unexposed, NOS), 2023 34.97[3.12; 7.91]3,8103,641not evaluable Urinary malformations Artama (Valproate), 2005 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Tomson (Valproate), 2018 Thomas (Valproate) (Controls unexposed, sick), 2021 41.18[0.56; 2.49]292,318not evaluable Cardiac septal defects Källén (Valproate) (Controls unexposed, NOS) (Indications NOS), 2013 Veiby (Valproate) (Controls unexposed, disease free) (Mixed indications), 2014 22.67[1.74; 4.10]16,5781,030not evaluable Cleft lip with or without cleft palate Artama (Valproate), 2005 Viinikainen (Valproate) (Controls unexposed, sick) a, 2006 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 35.08[1.87; 13.82]1,6471,204not evaluable Craniosynostosis D'Souza (Valproate) (Controls unexposed, sick), 1991 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 26.12[1.26; 29.85]768914not evaluable Digestive system anomalies Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Thomas (Valproate) (Controls unexposed, sick), 2021 31.46[0.65; 3.30]231,894not evaluable Genital anomalies Artama (Valproate), 2005 Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 Ban (Valproate) (Mixed indications) (Controls unexposed NOS), 2015 33.25[1.54; 6.89]1,045810not evaluable Cleft palate Viinikainen (Valproate) (Controls unexposed, sick) a, 2006 Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 24.85[1.37; 17.12]1,181941not evaluable Minor congenital malformations Robert (Valproate), 1986 Battino (Valproate), 1992 Dean (Valproate), 2002 35.11[2.13; 12.25]4383not evaluable Ano-rectal atresia and stenosis Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 111.70[3.09; 44.30]547913not evaluable Atrial septal defect Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 19.00[5.40; 15.00]3,283913not evaluable Atrioventricular septal defect Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 11.94[0.12; 31.09]529913not evaluable Bilateral renal agenesis including Potter syndrome Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 113.61[0.84; 219.81]75913not evaluable Bladder exstrophy and/or epispadia Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 112.46[0.77; 201.01]82913not evaluable Coarctation of aorta Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 11.32[0.08; 21.11]779913not evaluable Diaphragmatic hernia Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 12.71[0.17; 43.52]378913not evaluable Down syndrom / Trisomy 21 D'Souza (Valproate) (Controls unexposed, sick), 1991 115.00[0.12; 1923.88]-1not evaluable Ebstein's anomaly Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 120.35[1.25; 330.13]50913not evaluable Eye defects Dean (Valproate), 2002 Artama (Valproate), 2005 20.45[0.12; 1.72]10309not evaluable Gastroschisis Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 14.22[0.26; 67.72]243913not evaluable Hip dislocation and/or dysplasia D'Souza (Valproate) (Controls unexposed, sick), 1991 115.00[0.12; 1923.88]-1not evaluable Hypoplastic left heart (HLH/HLHS) Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 119.60[3.59; 107.13]218913not evaluable Hypoplastic right heart (HRH/HRHS) Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 115.46[0.96; 249.87]66913not evaluable Oesophageal atresia with or without tracheo-oesophageal fistula Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 12.62[0.16; 41.96]392913not evaluable Omphalocele Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 13.86[0.24; 61.86]266913not evaluable Pulmonary valve atresia Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 127.80[4.99; 154.94]154913not evaluable Tetralogy of Fallot Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 17.20[1.33; 38.92]586913not evaluable Valproate syndrome 0----- Ventricular septal defect Blotière (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 14.00[2.08; 7.71]4,652913not evaluable Chromosomal abnormalities Artama (Valproate), 2005 110.77[0.44; 265.09]1263not evaluable Ear, face and neck anomalies Artama (Valproate), 2005 10.71[0.03; 14.91]2263not evaluable Eye, ear, face and neck malformations Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 12.51[0.16; 40.18]2333not evaluable Respiratory system anomalies Veiby (Valproate) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014 10.50[0.02; 10.43]2333not evaluable Growth parameters and prematurity Preterm (< 37 weeks) Jäger-Roman (Valproate), 1986 Endo (Valproate) (Controls unexposed, sick), 2004 McVearry (Valproate), 2009 Nadebaum (Valproate), 2011 Cummings (Valproate) (Controls unexposed, disease free), 2011 Pennell (Valproate), 2012 Veiby (Valproate) (Controls unexposed, sick) b, 2013 Artama (Valproate) (Controls unexposed, sick), 2013 Kilic (Valproate) (Controls unexposed, sick) (Mixed indications), 2014 Arkilo (Valproate), 2015 Bank (Valproate) (Mixed indications), 2017 Cohen (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 Putignano (Valproate), 2019 Coste (Valproate) (Controls unexposed, NOS), 2020 Aydin (Valproate) (Controls unexposed, sick), 2020 151.08[0.99; 1.17]252,9784,796low Small for gestational age (weight) Endo (Valproate) (Controls unexposed, sick), 2004 Burja (Valproate) (Controls unexposed, sick), 2006 Pennell (Valproate), 2012 Artama (Valproate) (Controls unexposed, sick), 2013 Veiby (Valproate) (Controls unexposed, sick) b, 2013 Kilic (Valproate) (Controls unexposed, sick) (Mixed indications), 2014 Bank (Valproate) (Mixed indications), 2017 Cohen (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 Putignano (Valproate), 2019 Coste (Valproate) (Controls unexposed, NOS), 2020 Aydin (Valproate) (Controls unexposed, sick), 2020 Dreier (Valproate), 2021 121.32[1.00; 1.74]210,1166,632low Low birth weight (< 2500g) Kini (Valproate) (Controls unexposed, sick), 2006 Veiby (Valproate) (Controls unexposed, sick) b, 2013 Artama (Valproate) (Controls unexposed, sick), 2013 Kilic (Valproate) (Controls unexposed, sick) (Mixed indications), 2014 Wen (Valproate) (Mixed indications), 2017 Coste (Valproate) (Controls unexposed, NOS), 2020 61.49[1.23; 1.82]94,9122,363not evaluable Large for gestational age (weight) Artama (Valproate) (Controls unexposed, sick), 2013 Putignano (Valproate), 2019 Aydin (Valproate) (Controls unexposed, sick), 2020 31.21[0.74; 1.98]158845not evaluable Macrosomia (> 4000g) Endo (Valproate) (Controls unexposed, sick), 2004 Kini (Valproate) (Controls unexposed, sick), 2006 Coste (Valproate) (Controls unexposed, NOS), 2020 30.91[0.55; 1.51]577,4071,059not evaluable Very preterm (28 to 32 weeks) Coste (Valproate) (Controls unexposed, NOS), 2020 11.21[0.54; 2.70]8,590991not evaluable Extremely preterm (< 28 weeks) Coste (Valproate) (Controls unexposed, NOS), 2020 10.85[0.12; 6.01]2,042991not evaluable Large head circumference for gestational age Díaz-Romero (Valproate), 1999 10.79[0.01; 44.65]-10not evaluable Very low birth weight (< 1500g) Wen (Valproate) (Mixed indications), 2017 10.63[0.09; 4.51]309226not evaluable Maternal consequences Caesarean Endo (Valproate) (Controls unexposed, sick), 2004 Borthen (Valproate) (Controls unexposed, sick), 2010 Artama (Valproate) (Controls unexposed, sick), 2013 30.93[0.76; 1.14]831926not evaluable Preeclampsia Borthen (Valproate) (Controls unexposed, sick), 2011 Pennell (Valproate), 2012 Cohen (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 Aydin (Valproate) (Controls unexposed, sick), 2020 40.95[0.78; 1.15]53,7602,489not evaluable Assisted deliveries (forceps, vacuum, ...) Endo (Valproate) (Controls unexposed, sick), 2004 Borthen (Valproate) (Controls unexposed, sick), 2010 21.18[0.73; 1.90]177220not evaluable Gestational diabetes McVearry (Valproate), 2009 Pennell (Valproate), 2012 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Aydin (Valproate) (Controls unexposed, sick), 2020 41.60[0.23; 10.91]14110not evaluable Postpartum hemorrhage Borthen (Valproate) (Controls unexposed, sick), 2010 11.44[1.01; 2.06]319215not evaluable Abruptio placentae (retroplacental hematoma) Cohen (Valproate) (Controls unexposed NOS) (Mixed indications), 2019 11.25[0.94; 1.66]20,3222,398not evaluable Amniotic fluid problems (polyhydramnios and/or oligohydramnios) Aydin (Valproate) (Controls unexposed, sick), 2020 12.05[0.04; 110.56]-11not evaluable Maternal consequences (as a whole) Wen (Valproate) (Mixed indications), 2017 Alsfouk (Valproate), 2022 21.35[1.03; 1.77]12,260238not evaluable Polyhydramnios Endo (Valproate) (Controls unexposed, sick), 2004 10.11[0.00; 14.76]-5not evaluable Neonatal disorders Low Apgar score (< 7) (at 5 min) Borthen (Valproate) (Controls unexposed, sick), 2010 Pennell (Valproate), 2012 Veiby (Valproate) (Controls unexposed, sick) b, 2013 Artama (Valproate) (Controls unexposed, sick), 2013 Christensen (Valproate) (Controls unexposed, sick) (Mixed indications), 2015 Bank (Valproate) (Mixed indications), 2017 Putignano (Valproate), 2019 71.76[1.06; 2.91]1371,026not evaluable Neonatal medical care D'Souza (Valproate) (Controls unexposed, sick), 1991 Viinikainen (Valproate) (Controls unexposed, disease free) a, 2006 Artama (Valproate) (Controls unexposed, sick), 2013 Bank (Valproate) (Mixed indications), 2017 Putignano (Valproate), 2019 Aydin (Valproate) (Controls unexposed, sick), 2020 61.98[1.52; 2.59]2,098777not evaluable Low Apgar score (< 7) (at 1 min) Endo (Valproate) (Controls unexposed, sick), 2004 Pennell (Valproate), 2012 Artama (Valproate) (Controls unexposed, sick), 2013 Bank (Valproate) (Mixed indications), 2017 42.39[0.84; 6.81]134673not evaluable Neonatal disorders (as a whole) D'Souza (Valproate) (Controls unexposed, sick), 1991 Wen (Valproate) (Mixed indications), 2017 Coste (Valproate) (Controls unexposed, NOS), 2020 31.05[0.76; 1.44]225,7531,218not evaluable Withdrawal syndrome / Neonatal abstinence syndrome / Poor neonatal adaptation Burja (Valproate) (Controls unexposed, sick), 2006 1Out of scale189.00[2.70; 13229.55]12not evaluable Feeding difficulty D'Souza (Valproate) (Controls unexposed, sick), 1991 Burja (Valproate) (Controls unexposed, sick), 2006 224.38[1.49; 397.73]23not evaluable Fetal distress McVearry (Valproate), 2009 10.09[0.00; 1.83]416not evaluable Neonatal intracranial hemorrhage D'Souza (Valproate) (Controls unexposed, sick), 1991 Burja (Valproate) (Controls unexposed, sick), 2006 215.00[1.09; 206.94]33not evaluable Jaundice / Icterus D'Souza (Valproate) (Controls unexposed, sick), 1991 14.33[0.06; 320.42]11not evaluable Neonatal hypotonia D'Souza (Valproate) (Controls unexposed, sick), 1991 115.00[0.12; 1923.88]-1not evaluable Neonatal infections D'Souza (Valproate) (Controls unexposed, sick), 1991 115.00[0.12; 1923.88]-1not evaluable Neonatal tachypnea D'Souza (Valproate) (Controls unexposed, sick), 1991 115.00[0.12; 1923.88]-1not evaluable Very low Apgar score (< 5) (at 1 min) 0----- Long term consequences Behavioral disorders Veiby (Valproate) (Controls unexposed, sick) b, 2013 Cohen (Valproate), 2013 Bromley (Valproate), 2016 Huber-Mollema (Valproate), 2019 Dreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 50.93[0.65; 1.34]1512,088not evaluable Emotional disorders Cohen (Valproate), 2013 Bromley (Valproate), 2016 Huber-Mollema (Valproate), 2019 Dreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 40.97[0.77; 1.22]5912,069not evaluable Child/Infant death (> 28 days of life) Artama (Valproate) (Controls unexposed, sick), 2013 Coste (Valproate) (Controls unexposed, NOS), 2020 23.01[1.62; 5.60]4,7141,694not evaluable Child/Infant growth abnormalities (> 1 year) Pennell (Valproate), 2012 10.24[0.03; 2.07]744not evaluable Child/Infant head circumference abnormalities (> 1 year) Pennell (Valproate), 2012 11.39[0.03; 71.26]-42not evaluable Child/Infant lenght abnormalities (> 1 year) Kini (Valproate) (Controls unexposed, sick), 2006 12.55[0.69; 9.43]1063not evaluable Child/Infant weight abnormalities (> 1 year) Kini (Valproate) (Controls unexposed, sick), 2006 11.16[0.35; 3.82]1263not evaluable Intrauterine deaths Intrauterine deaths (as a whole or unspecified) Meador (Valproate), 2006 Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Tomson (Valproate), 2015 Arkilo (Valproate), 2015 Miškov (Valproate) (Controls unexposed, sick), 2016 Trivedi (Valproate) (Controls unexposed, sick), 2018 Vajda (Valproate) (Controls unexposed, sick), 2018 71.46[1.01; 2.11]4683,144not evaluable Early intrauterine death (< 22 weeks) Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Babic (Valproate), 2014 Tomson (Valproate), 2015 Arkilo (Valproate), 2015 Miškov (Valproate) (Controls unexposed, sick), 2016 51.04[0.84; 1.29]3662,475not evaluable Late intrauterine deaths (> 22 weeks) Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Tomson (Valproate), 2015 Arkilo (Valproate), 2015 AlSheikh (Valproate) (Controls unexposed, sick), 2020 Aydin (Valproate) (Controls unexposed, sick), 2020 51.83[1.01; 3.31]422,475not evaluable Elective/induced termination of pregnancy Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 Miškov (Valproate) (Controls unexposed, sick), 2016 Hosny (Valproate) (Controls unexposed, sick), 2021 31.83[0.80; 4.17]211,304not evaluable Perinatal death Canger (Valproate), 1999 Artama (Valproate) (Controls unexposed, sick), 2013 Tomson (Valproate), 2015 32.16[0.95; 4.89]271,833not evaluable Therapeutic terminations of pregnancy Miškov (Valproate) (Controls unexposed, sick), 2016 10.64[0.01; 40.08]-6not evaluable Ectopic pregnancy Campbell (Valproate) (Controls exposed to Lamotrigine, sick), 2014 11.70[0.03; 85.94]-1,290not evaluable Neuro-developmental disorders Language disorders/delay Gaily (Valproate) (Controls unexposed, sick), 2004 Adab (Valproate), 2004 Eriksson (Valproate), 2005 Shallcross (Valproate), 2011 Nadebaum (Valproate), 2011 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Meador (Valproate), 2013 Baker (Valproate) (Controls unexposed, sick), 2015 Deshmukh (Valproate), 2016 Videman (Valproate) (Controls unexposed, disease free), 2016 Bromley (Valproate), 2016 Kasradze (Valproate) (Controls unexposed, disease free), 2017 Coste (Valproate) (Controls unexposed, NOS), 2020 Husebye (Valproate) (Controls unexposed, sick), 2020 Thomas (Valproate), 2022 152.87[2.05; 4.02]72,2491,423critical ADHD (Attention deficit hyperactivity disorder): Diagnosis/Risk Adab (Valproate), 2004 Viinikainen (Valproate) b, 2006 Cohen (Valproate), 2013 Veiby (Valproate) (Controls unexposed, sick) b, 2013 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Bromley (Valproate) (Controls unexposed, sick), 2013 Bromley (Valproate), 2016 Huber-Mollema (Valproate), 2019 Richards (Valproate) (Controls unexposed, NOS) (Indications NOS), 2019 Wiggs (Valproate), 2020 Dreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 111.52[1.28; 1.81]12,5132,387low Cognitive developmental disorders/delay (> 6 years old) Gaily (Valproate) (Controls unexposed, sick), 2004 Adab (Valproate), 2004 Vinten (Valproate), 2005 Viinikainen (Valproate) b, 2006 Titze (Valproate) (Controls unexposed, sick), 2008 Nadebaum (Valproate), 2011 Meador (Valproate), 2013 Baker (Valproate) (Controls unexposed, sick), 2015 Bromley (Valproate), 2016 Bjørk (Valproate) (Controls unexposed, sick) (Mixed indications), 2022 Thomas (Valproate), 2022 112.99[2.00; 4.48]2462,735low Neuro-developmental disorders (as a whole) Katz (Valproate), 2001 Adab (Valproate), 2004 Viinikainen (Valproate) b, 2006 Dean (Valproate) (Controls unexposed, sick), 2007 Bromley (Valproate) (Controls unexposed, sick), 2013 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Arkilo (Valproate), 2015 Charlton (Valproate), 2017 Coste (Valproate) (Controls unexposed, NOS), 2020 Bjørk (Valproate) (Controls unexposed, sick) (Mixed indications), 2022 104.09[3.54; 4.73]10,8263,740low ASD (Autism spectrum disorder): Diagnosis/Risk Adab (Valproate), 2004 Bromley (Valproate) (Controls unexposed, sick), 2013 Wood (Valproate), 2015 Bjørk (Valproate) (Controls exposed to Lamotrigine, sick), 2018 Bjørk (Valproate) (Controls unexposed, sick), 2018 Huber-Mollema (Valproate), 2019 Wiggs (Valproate), 2020 Coste (Valproate) (Controls unexposed, NOS), 2020 Bjørk (Valproate) (Controls unexposed NOS) (Mixed indications), 2022 Bjørk (Valproate) (Controls unexposed, sick) (Mixed indications), 2022 102.86[2.23; 3.67]43,2246,052low Psychomotor developmental disorders/delay Koch (Valproate), 1996 Adab (Valproate), 2004 Viinikainen (Valproate) b, 2006 Thomas b (Valproate), 2008 Shallcross (Valproate), 2011 Cohen (Valproate), 2011 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Bromley (Valproate) (Controls unexposed, sick), 2013 Deshmukh (Valproate), 2016 Videman (Valproate) (Controls unexposed, disease free), 2016 103.03[1.99; 4.64]82373low ASD (Autism spectrum disorder): Diagnosis Adab (Valproate), 2004 Bromley (Valproate) (Controls unexposed, sick), 2013 Wood (Valproate), 2015 Huber-Mollema (Valproate), 2019 Wiggs (Valproate), 2020 Coste (Valproate) (Controls unexposed, NOS), 2020 Bjørk (Valproate) (Controls unexposed, sick) (Mixed indications), 2022 72.91[2.40; 3.53]4,6593,577not evaluable Cognitive developmental disorders/delay (3-6 years old) Gaily (Valproate) (Controls unexposed, sick), 2004 Cummings (Valproate) (Controls unexposed, disease free), 2011 Meador (Valproate), 2013 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Deshmukh (Valproate), 2016 Kasradze (Valproate) (Controls unexposed, disease free), 2017 Coste (Valproate) (Controls unexposed, NOS), 2020 75.06[2.73; 9.37]3,4661,199not evaluable ADHD (Attention deficit hyperactivity disorder): Diagnosis Adab (Valproate), 2004 Bromley (Valproate) (Controls unexposed, sick), 2013 Cohen (Valproate), 2013 Huber-Mollema (Valproate), 2019 Wiggs (Valproate), 2020 Dreier (Valproate) (Epilepsy) (Controls unexposed, sick), 2023 61.54[1.27; 1.86]6532,119not evaluable ADHD (Attention deficit hyperactivity disorder): Risk Viinikainen (Valproate) b, 2006 Veiby (Valproate) (Controls unexposed, sick) b, 2013 Rihtman (Valproate) (Controls unexposed, NOS) (Mixed indications), 2013 Cohen (Valproate), 2013 Bromley (Valproate), 2016 Richards (Valproate) (Controls unexposed, NOS) (Indications NOS), 2019 Huber-Mollema (Valproate), 2019 71.51[0.99; 2.32]11,883339not evaluable Severe cognitive developmental delay (Mental retardation) (> 6 years old) Gaily (Valproate) (Controls unexposed, disease free), 2004 Vinten (Valproate), 2005 Viinikainen (Valproate) b, 2006 Titze (Valproate) (Controls unexposed, sick), 2008 Meador (Valproate), 2013 Bjørk (Valproate) (Controls unexposed, sick) (Mixed indications), 2022 64.15[3.12; 5.51]2272,540not evaluable Cognitive developmental disorders/delay (< 3 years old) Thomas b (Valproate), 2008 Bromley (Valproate) (Controls unexposed, sick), 2010 Shallcross (Valproate), 2011 Meador (Valproate), 2013 Videman (Valproate) (Controls unexposed, disease free), 2016 54.09[1.87; 8.96]103190not evaluable Severe cognitive developmental delay (Mental retardation) (3-6 years old) Gaily (Valproate) (Controls unexposed, sick), 2004 Cummings (Valproate) (Controls unexposed, disease free), 2011 Meador (Valproate), 2013 Coste (Valproate) (Controls unexposed, NOS), 2020 45.02[3.12; 8.08]3,4261,101not evaluable ASD (Autism spectrum disorder): Risk Wood (Valproate), 2015 Bjørk (Valproate) (Controls unexposed, sick), 2018 Huber-Mollema (Valproate), 2019 31.28[0.48; 3.42]3779not evaluable Childhood autism (F84.0) Christensen (Valproate) (Controls unexposed NOS) (Mixed indications), 2013 14.90[2.32; 10.37]2,065388not evaluable Learning disorders Ren (Valproate) (Mixed indications), 2023 11.27[1.00; 1.61]-232not evaluable Severe cognitive developmental delay (Mental retardation) (< 3 years old) Meador (Valproate), 2013 13.29[1.00; 10.85]1329not evaluable0.0100.01.0