Valproate (Epilepsy)

Preterm (< 37 weeks)

R analysis

id	Study	Lib. in paper	Exposition period	Study type All studies Case control excluded Only case control	Control type	Tags	OR 95%CI	x1/n1 x0/n0	no cases	no exposed	ROB	Ref.
S8087 R24741	Aydin (Valproate) (Controls exposed to Lamotrigine, sick), 2020	Preterm delivery (before 37 weeks of gestation)	throughout pregnancy	retrospective cohort	exposed to other treatment, sick excluded	Adjustment: No	0.62 [0.01;35.19] ^C excluded (control group)	0/11 0/7	0	11		ref
S7922 R24603	Aydin (Valproate) (Controls unexposed, sick), 2020	Preterm delivery (before 37 weeks of gestation)	throughout pregnancy	retrospective cohort	unexposed, sick	Adjustment: No	0.37 [0.02;8.48] ^C	0/11 2/22	2	11		ref
S10070 R36641	Coste (Valproate) (Controls exposed to Lamotrigine, sick), 2020	Gestational age at birth (< 37 WA)	during pregnancy (anytime or not specified)	retrospective cohort (claims database)	exposed to other treatment, sick excluded	Adjustment: No	1.16 [0.86;1.57] ^C excluded (control group)	71/991 131/2,108	202	991		ref
S7799 R23024	Coste (Valproate) (Controls unexposed, NOS), 2020	Gestational age at birth (< 37 WA)	during pregnancy (anytime or not specified)	retrospective cohort (claims database)	unexposed (general population or NOS)	Adjustment: No	1.37 [1.08;1.74] ^C	71/991 91,255/1,710,441	91,326	991		ref
S8143 R25028	Cohen (Valproate) (Controls exposed to Lamotrigine, sick), 2019	Preterm birth (ICD-9 644.2, 774.2, 776.6, 362.20, 362.22, 362.27, 765 excluding 765.20, 765.29)	early pregnancy	retrospective cohort (claims database)	exposed to other treatment, sick excluded	Adjustment: Yes	1.15 [0.69;1.91] excluded (control group)	-/- -/-	-	-		ref
S8139 R25000	Cohen (Valproate) (Controls unexposed NOS), 2019	Preterm birth (ICD-9 644.2, 774.2, 776.6, 362.20, 362.22, 362.27, 765 excluding 765.20, 765.29)	early pregnancy	retrospective cohort (claims database)	unexposed (general population or NOS)	Adjustment: Yes	0.96 [0.68;1.35]	-/- 160,604/1,440,631	-	-		ref
S7460 R25126	Putignano (Valproate), 2019	Preterm birth (<37 weeks)	during pregnancy (anytime or not specified)	retrospective cohort	unexposed (general population or NOS)	Adjustment: No Matched	1.18 [0.54;2.55]	8/131 48/917	56	131		ref
S6255 R16666	Arkilo (Valproate), 2015	Premature delivery	during pregnancy (anytime or not specified)	retrospective cohort	exposed to other treatment, sick	Adjustment: No	1.95 [0.07;58.24] ^C	0/2 3/24	3	2		ref
S5931 R15131	Artama (Valproate) (Controls exposed to Lamotrigine, sick), 2013	Preterm birth (<37 gestational weeks)	during pregnancy (anytime or not specified)	population based cohort retrospective	exposed to other treatment, sick excluded	Adjustment: No	1.24 [0.57;2.71] ^C excluded (control group)	40/703 8/173	48	703		ref
S5911 R14910	Artama (Valproate) (Controls unexposed, disease free), 2013	Preterm birth (<37 gestational weeks)	during pregnancy (anytime or not specified)	population based cohort retrospective	unexposed, disease free excluded	Adjustment: Yes	1.24 [0.90;1.71] excluded (control group)	40/703 30,027/719,509	30,067	703		ref
S5919 R15006	Artama (Valproate) (Controls unexposed, sick), 2013	Preterm birth (<37 gestational weeks)	during pregnancy (anytime or not specified)	population based cohort retrospective	unexposed, sick	Adjustment: Yes	1.11 [0.74;1.65]	40/703 85/1,793	125	703		ref
S6353 R17321	Veiby (Valproate) (Controls exposed to Lamotrigine, sick) b, 2013	Preterm delivery (< 37 weeks)	during pregnancy (anytime or not specified)	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No	1.11 [0.27;4.53] ^C excluded (control group)	3/40 7/103	10	40		ref
S5506 R17325	Veiby (Valproate) (Controls unexposed, disease free) b, 2013	Preterm delivery (< 37 weeks)	during pregnancy (anytime or not specified)	prospective cohort	unexposed, disease free excluded	Adjustment: No	0.70 [0.20;3.00] excluded (control group)	3/40 7,269/106,899	7,272	40		ref
S6350 R17329	Veiby (Valproate) (Controls unexposed, sick) b, 2013	Preterm delivery (< 37 weeks)	during pregnancy (anytime or not specified)	prospective cohort	unexposed, sick	Adjustment: No	0.96 [0.28;3.31] ^C	3/40 30/386	33	40		ref
S6416 R17612	Pennell (Valproate), 2012	Preterm Birth (< 37 weeks GA)	during pregnancy (anytime or not specified)	prospective cohort	exposed to other treatment, sick	Adjustment: No	1.35 [0.39;4.61] ^C	5/62 6/98	11	62		ref
S6942 R19602	Cummings (Valproate) (Controls exposed to Lamotrigine, sick), 2011	Preterm (35-37 weeks)	throughout pregnancy	retrospective cohort (registry)	exposed to other treatment, sick excluded	Adjustment: No	0.33 [0.07;1.47] ^C excluded (control group)	3/58 5/35	8	58		ref
S5479 R19594	Cummings (Valproate) (Controls unexposed, disease free), 2011	Preterm (35-37 weeks)	throughout pregnancy	retrospective cohort (registry)	unexposed, disease free	Adjustment: No	5.59 [0.28;111.10] ^C	3/58 0/44	3	58		ref
S7168 R20066	Nadebaum (Valproate), 2011	Born premature (<37 wk)	during pregnancy (anytime or not specified)	prospective cohort	exposed to other treatment, sick	Adjustment: No	1.19 [0.04;32.08] ^C	1/23 0/9	1	23		ref
S7231 R20844	McVearry (Valproate), 2009	Premature birth	during pregnancy (anytime or not specified)	prospective cohort	exposed to other treatment, sick	Adjustment: No	1.94 [0.04;106.66] ^C	0/9 0/17	0	9		ref
S8221 R25741	Endo (Valproate) (Controls unexposed, disease free), 2004	Preterm delivery (< week 37)	at least 1st trimester	retrospective cohort	unexposed, disease free excluded	Adjustment: No	1.33 [0.15;11.99] ^C excluded (control group)	1/5 104/656	105	5		ref
S8311 R26298	Endo (Valproate) (Controls unexposed, sick), 2004	Preterm delivery (< week 37)	throughout pregnancy	retrospective cohort	unexposed, sick	Adjustment: No	0.43 [0.01;33.60] ^C	1/5 0/1	1	5		ref
S5495 R16630	Jäger-Roman (Valproate), 1986	Prematurity	at least 1st trimester	prospective cohort	unexposed (general population or NOS)	Adjustment: No	0.54 [0.03;9.92] ^C	0/14 7/116	7	14		ref
					Total	13 studies	1.19 [1.01;1.41]		91,568	2,049
x1: number of endpoints among exposed, n1: number of exposed; x0: number of endpoints among non exposed, n0: number of non exposed; ^C: calculated odds ratio from numbers of events and effectives

Forest plot

1: Valproate) (Controls unexposed, sick; 2: Valproate) (Controls unexposed, NOS; 3: Valproate) (Controls unexposed NOS; 4: Valproate; 5: Valproate; 6: Valproate) (Controls unexposed, sick; 7: Valproate) (Controls unexposed, sick) ; 8: Valproate; 9: Valproate) (Controls unexposed, disease free; 10: Valproate; 11: Valproate; 12: Valproate) (Controls unexposed, sick; 13: Valproate;

Sensitivity analysis

Publication bias and p-hacking diagnosis

funnel plot

Asymetry test p-value = 0.6598 (by Egger's regression)

slope=0.1999 (0.0798); intercept=-0.1169 (0.2584); t=0.4524; p=0.6598

p values plot

Sub-groups analysis using all included studies

excluded 8221, 6942, 5931, 5911, 6353, 5506, 8143, 8087, 10070

S8087 R24741	Aydin (Valproate) (Controls exposed to Lamotrigine, sick), 2020	Preterm delivery (before 37 weeks of gestation) (90)	throughout pregnancy	exposed to other treatment, sick	0.62 [0.01;35.19]	0/11 0/7
S7922 R24603	Aydin (Valproate) (Controls unexposed, sick), 2020	Preterm delivery (before 37 weeks of gestation) (90)	throughout pregnancy	unexposed, sick	0.37 [0.02;8.48]	0/11 2/22
S10070 R36641	Coste (Valproate) (Controls exposed to Lamotrigine, sick), 2020	Gestational age at birth (< 37 WA) (90)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	1.16 [0.86;1.57]	71/991 131/2108
S7799 R23024	Coste (Valproate) (Controls unexposed, NOS), 2020	Gestational age at birth (< 37 WA) (90)	during pregnancy (anytime or not specified)	unexposed (general population or NOS)	1.37 [1.08;1.74]	71/991 91255/1710441
S8143 R25028	Cohen (Valproate) (Controls exposed to Lamotrigine, sick), 2019	Preterm birth (ICD-9 644.2, 774.2, 776.6, 362.20, 362.22, 362.27, 765 excluding 765.20, 765.29) (90)	early pregnancy	exposed to other treatment, sick	1.15 [0.69;1.91]	-9/-9 -9/-9
S8139 R25000	Cohen (Valproate) (Controls unexposed NOS), 2019	Preterm birth (ICD-9 644.2, 774.2, 776.6, 362.20, 362.22, 362.27, 765 excluding 765.20, 765.29) (90)	early pregnancy	unexposed (general population or NOS)	0.96 [0.68;1.35]	-9/-9 160604/1440631
S7460 R25126	Putignano (Valproate), 2019	Preterm birth (<37 weeks) (90)	during pregnancy (anytime or not specified)	unexposed (general population or NOS)	1.18 [0.54;2.55]	8/131 48/917
S6255 R16666	Arkilo (Valproate), 2015	Premature delivery (90)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	1.95 [0.07;58.24]	0/2 3/24
S5931 R15131	Artama (Valproate) (Controls exposed to Lamotrigine, sick), 2013	Preterm birth (<37 gestational weeks) (90)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	1.24 [0.57;2.71]	40/703 8/173
S5911 R14910	Artama (Valproate) (Controls unexposed, disease free), 2013	Preterm birth (<37 gestational weeks) (90)	during pregnancy (anytime or not specified)	unexposed, disease free	1.24 [0.90;1.71]	40/703 30027/719509
S5919 R15006	Artama (Valproate) (Controls unexposed, sick), 2013	Preterm birth (<37 gestational weeks) (90)	during pregnancy (anytime or not specified)	unexposed, sick	1.11 [0.74;1.65]	40/703 85/1793
S6353 R17321	Veiby (Valproate) (Controls exposed to Lamotrigine, sick) b, 2013	Preterm delivery (< 37 weeks) (90)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	1.11 [0.27;4.53]	3/40 7/103
S5506 R17325	Veiby (Valproate) (Controls unexposed, disease free) b, 2013	Preterm delivery (< 37 weeks) (90)	during pregnancy (anytime or not specified)	unexposed, disease free	0.70 [0.20;3.00]	3/40 7269/106899
S6350 R17329	Veiby (Valproate) (Controls unexposed, sick) b, 2013	Preterm delivery (< 37 weeks) (90)	during pregnancy (anytime or not specified)	unexposed, sick	0.96 [0.28;3.31]	3/40 30/386
S6416 R17612	Pennell (Valproate), 2012	Preterm Birth (< 37 weeks GA) (90)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	1.35 [0.39;4.61]	5/62 6/98
S6942 R19602	Cummings (Valproate) (Controls exposed to Lamotrigine, sick), 2011	Preterm (35-37 weeks) (90)	throughout pregnancy	exposed to other treatment, sick	0.33 [0.07;1.47]	3/58 5/35
S5479 R19594	Cummings (Valproate) (Controls unexposed, disease free), 2011	Preterm (35-37 weeks) (90)	throughout pregnancy	unexposed, disease free	5.59 [0.28;111.10]	3/58 0/44
S7168 R20066	Nadebaum (Valproate), 2011	Born premature (<37 wk) (90)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	1.19 [0.04;32.08]	1/23 0/9
S7231 R20844	McVearry (Valproate), 2009	Premature birth (90)	during pregnancy (anytime or not specified)	exposed to other treatment, sick	1.94 [0.04;106.66]	0/9 0/17
S8221 R25741	Endo (Valproate) (Controls unexposed, disease free), 2004	Preterm delivery (< week 37) (90)	at least 1st trimester	unexposed, disease free	1.33 [0.15;11.99]	1/5 104/656
S8311 R26298	Endo (Valproate) (Controls unexposed, sick), 2004	Preterm delivery (< week 37) (90)	throughout pregnancy	unexposed, sick	0.43 [0.01;33.60]	1/5 0/1
S5495 R16630	Jäger-Roman (Valproate), 1986	Prematurity (90)	at least 1st trimester	unexposed (general population or NOS)	0.54 [0.03;9.92]	0/14 7/116