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Supplementary A. Search strategy
Electronic search from database
In PubMed, we used “MeSH” term and keywords to build search strategy. In Embase, we used
“Emtree” term and keywords to build strategy. In Web of Science, we only used keywords in search.
In PubMed, the search strategy was:
("Heart Defects, Congenital"[Mesh] OR "Congenital Heart Defect"[tw] OR "Congenital Heart
Defects"[tw] OR heart Abnormalit*[tw] OR aortic Coarctation*[tw] OR "Coarctation of the
Aorta"[tw] OR "Coarctation of Aorta"[tw] OR "ARVD-C"[tw] OR "Arrhythmogenic Right
Ventricular Cardiomyopathy"[tw] OR "Arrhythmogenic Right Ventricular Dysplasia-
Cardiomyopathy"[tw] OR "Barth Syndrome"[tw] OR "Cor Triatriatum"[tw] OR "Subdivided Left
Atrium"[tw] OR "Subdivided Left Atriums" OR triatrial Heart*[tw] OR "Cor Triatriatum
Sinistrum"[tw] OR "Coronary Vessel Anomalies"[tw] OR "Coronary Vessel Anomaly"[tw] OR
crisscross Heart*[tw] OR "Criss cross Heart"[tw] OR "Criss cross Hearts"[tw] OR
Dextrocardia*[tw] OR "Patent Ductus Arteriosus"[tw] OR "Patency of the Ductus Arteriosus"[tw]
OR epstein Anomal*[tw] OR ebstein's Malformation*[tw] OR epstein Malformation*[tw] OR
ebstein s Malformation*[tw] OR ebstein's Anomal*[tw] OR ebstein s Anomal*[tw] OR "Ectopia
Cordis"[tw] OR "Eisenmenger's Complex"[tw] OR "Eisenmenger Complex"[tw] OR
eisenmenger's Syndrome*[tw] OR eisenmenger Syndrome*[tw] OR eisenmenger Syndrome*[tw]
OR "Heart Septal Defect"[tw] OR "Heart Septal Defects"[tw] OR atrial Isomerism*[tw] OR
"Hypoplastic Left Heart Syndrome"[tw] OR "Isolated Noncompaction of the Ventricular
Myocardium"[tw] OR leopard Syndrome*[tw] OR "Cardio Cutaneous Syndrome"[tw] OR
lentigines Syndrome*[tw] OR "Levocardia"[tw] OR marfan Syndrome*[tw] OR marfan's
Syndrome*[tw] OR noonan Syndrome*[tw] OR "Tetralogy of Fallot"[tw] OR "Fallot's
Tetralogy"[tw] OR "Fallot Tetralogy"[tw] OR "Fallots Tetralogy"[tw] OR "Transposition of Great
Vessels"[tw] OR "Great Vessels Transposition"[tw] OR "Transposition of Great Arteries"[tw] OR
"Great Arteries Transposition"[tw] OR "Dextro-Looped Transposition of the Great Arteries"[tw]
OR "Dextro Looped Transposition of the Great Arteries"[tw] OR "Double-Outlet Right
Ventricle"[tw] OR "Taussig-Bing Anomaly"[tw] OR tricuspid Atresia*[tw] OR "Tricuspid Valve
Atresia"[tw] OR "Tricuspid Valve Atresias"[tw] OR "Absent Right Atrioventricular
Connection"[tw] OR "Trilogy of Fallot"[tw] OR "Fallot Trilogy"[tw] OR "Fallot's Trilogy"[tw]
OR turner Syndrome*[tw] OR turner's Syndrome*[tw] OR turners Syndrome*[tw] OR "Bonnevie
Ullrich"[tw] OR "Congenital Heart Disease"[tw] OR "Congenital Heart Diseases"[tw] OR
"Congenital Cardiac Defect"[tw] OR "Congenital Cardiac Defects"[tw] OR naxos disease*[tw]
OR "Holt Oram syndrome"[tw] OR "heart hand syndrome"[tw] OR "congenital heart block"[tw])
AND ("Smoking"[Mesh] OR Smok*[tw] OR Tobacco*[tw] OR Nicotiana*[tw] OR cigar*[tw] OR
cannab*[tw]) AND ("Pregnancy"[Mesh] OR Pregnan*[tw] OR Gestat*[tw] OR Gravidit*[tw] OR
"child bearing"[tw] OR "childbearing"[tw])
In Embase, the strategy was:
((“congenital heart disease”/exp OR “congenital heart disease” OR “congenital heart diseases” OR
“congenital cardiac disease” OR “congenital cardiac diseases” OR “congenital cardiac distress”
OR “congenital cardiac distresses” OR “congenital heart distress” OR “congenital heart distresses”
OR “congenital heart failure” OR “congenital heart failures” OR “heart congenital disease” OR
“heart congenital diseases” OR “neonatal cardiopathy” OR “persistent truncus arteriosus” OR
“congenital heart block” OR “congenital cardiac block” OR “congenital cardial block” OR
“congenital heart malformation” OR “congenital heart malformations” OR “congenital heart
anomaly” OR “congenital heart anomalies” OR “congenital heart defect” OR “congenital heart
defects” OR “heart right ventricle dysplasia” OR “arrhythmogenic heart right ventricle dysplasia”
OR “arrhythmogenic right ventricular cardiomyopathy” OR “arrhythmogenic right ventricular
dysplasia” OR “cardiomyopathy, arrhythmogenic right ventricular” OR “Naxos disease” OR
“Naxos diseases” OR “right ventricular cardiomyopathy” OR “right ventricular dysplasia” OR
“Holt Oram syndrome” OR “atriodigital syndrome” OR “heart hand syndrome” OR “LEOPARD
syndrome” OR “cardiocutaneous syndrome” OR “cardiomyopathic lentiginosis” OR “lentiginosis
profuse” OR “lentigines syndrome” OR “cardiomyopathic lentiginosis” OR “McKusick Kaufman
syndrome” OR “congenital heart block” OR “congenital cardiac block” OR “congenital cardial
block”) AND (“smoking”/exp OR smok* OR Tobacco* OR Nicotiana* OR cigar* OR cannab*)
AND (“pregnancy”/exp OR pregnan* OR “child bearing” OR “childbearing” OR gestat* OR
gravidit*))
In Web of Science, the strategy was:
((“Congenital Heart Defect” OR “Congenital Heart Defects” OR “Heart Abnormality” OR “Heart
Abnormalities” OR “Aortic Coarctation” OR “Aortic CoarctationS” OR “Coarctation of the Aorta”
OR “Coarctation of Aorta” OR “ARVD-C” OR “Arrhythmogenic Right Ventricular
Cardiomyopathy” OR “Arrhythmogenic Right Ventricular Dysplasia-Cardiomyopathy” OR
“Barth Syndrome” OR “Cor Triatriatum” OR “Subdivided Left Atrium” OR “Subdivided Left
Atriums” OR “Triatrial Heart” OR “Triatrial Hearts” OR “Cor Triatriatum Sinistrum” OR
“Coronary Vessel Anomalies” OR “Coronary Vessel Anomaly” OR “Crisscross Heart” OR “Criss
cross Heart” OR “Criss cross Hearts” OR “Dextrocardia” OR “Patent Ductus Arteriosus” OR
“Patency of the Ductus Arteriosus" OR “Ebstein Anomaly” OR “Ebstein Anomalies” OR
“Ebstein's Malformation” OR “Ebstein's Malformations” OR “Ebsteins Malformation” OR
“Ebsteins Malformations” OR “Ebstein's Anomaly” OR “Ebstein's Anomalies” OR “Ebsteins
Anomaly” OR “Ebsteins Anomalies” OR “Ectopia Cordis” OR “Eisenmenger's Complex” OR
“Eisenmenger Complex” OR “Eisenmenger's Syndrome” OR “Eisenmengers Syndrome” OR
“Eisenmenger Syndrome” OR “Heart Septal Defect” OR “Heart Septal Defects” OR “Atrial
Isomerism” OR “Atrial Isomerism” OR “Hypoplastic Left Heart Syndrome” OR “Isolated
Noncompaction of the Ventricular Myocardium” OR “LEOPARD Syndrome” OR “Cardio
Cutaneous Syndrome” OR “Lentigines Syndrome” OR “Levocardia” OR “Marfan Syndrome” OR
“Marfan's Syndrome” OR “Noonan Syndrome” OR “Tetralogy of Fallot” OR “Fallot's Tetralogy”
OR “Fallot Tetralogy” OR “Fallots Tetralogy” OR “Transposition of Great Vessels” OR “Great
Vessels Transposition” OR “Transposition of Great Arteries” OR “Great Arteries Transposition”
OR “Dextro-Looped Transposition of the Great Arteries” OR “Dextro Looped Transposition of the
Great Arteries” OR “Double-Outlet Right Ventricle” OR “Taussig-Bing Anomaly” OR “Tricuspid
Atresia” OR “Tricuspid Valve Atresia” OR “Tricuspid Valve Atresias” OR “Absent Right
Atrioventricular Connection” OR “Trilogy of Fallot” OR “Fallot Trilogy” OR “Fallot's Trilogy”
OR “Turner Syndrome” OR “Turner's Syndrome” OR “Turners Syndrome” OR “Bonnevie Ullrich”
OR “Congenital Heart Disease” OR “Congenital Heart Diseases” OR “Congenital Cardiac Defect”
OR “Congenital Cardiac Defects” OR “Naxos disease” OR “Holt Oram syndrome” OR
“atriodigital syndrome” OR “heart hand syndrome” OR “congenital heart block” OR “congenital
cardiac block” OR “congenital cardial block”) AND (Smok* OR Tobacco* OR Nicotiana* OR
cigar* OR cannab*) AND (Pregnan* OR Gestat* OR Gravidit* OR “child bearing” OR
“childbearing”))
Supplementary B. Summary for ORs for ordinal smoking data
Study Subtype Smoking RR and 95%CI
Alverson et al. 2011
[25]
Any CHD
1-10 cig/d 1.11 (0.96-1.28)
11-20 cig/d 1.13 (0.95-1.36)
≥21 cig/d 1.07 (0.80-1.45)
ASD
1-10 cig/d 1.41 (0.95-2.11)
11-20 cig/d 1.59 (0.98-2.58)
≥21 cig/d 1.64 (0.74-3.62)
AVSD
1-10 cig/d 1.44 (0.70-2.97)
11-20 cig/d 1.57 (0.68-3.59)
≥21 cig/d 2.00 (0.60-6.71)
CTD
1-10 cig/d 0.83 (0.60-1.15)
11-20 cig/d 1.15 (0.80-1.64)
≥21 cig/d 0.91 (0.48-1.72)
LVOTO
1-10 cig/d 1.42 (1.01-1.99)
11-20 cig/d 0.60 (0.34-1.06)
≥21 cig/d 1.00 (0.48-2.11)
SPD 1-10 cig/d 1.14 (0.93-1.41)
11-20 cig/d 1.19 (0.92-1.54)
≥21 cig/d 1.07 (0.68-1.67)
TGA
1-10 cig/d 0.82 (0.51-1.30)
11-20 cig/d 0.81 (0.46-1.43)
≥21 cig/d 1.12 (0.51-2.47)
TOF
1-10 cig/d 0.84 (0.52-1.35)
11-20 cig/d 1.17 (0.69-1.98)
≥21 cig/d 0.21 (0.03-1.49)
VSD
1-10 cig/d 1.24 (0.96-1.60)
11-20 cig/d 1.13 (0.81-1.58)
≥21 cig/d 1.15 (0.66-2.00)
Cedergren et al. 2006
[59] Any CHD
1-10 cig/d 0.96 (0.88-1.04)
≥11 cig/d 1.00 (0.90-1.12)
Grewal et al. 2008
[32]
CTD ≤5 cig/d 1.0 (0.5-2.0)
>5 cig/d 0.5 (0.2-1.2)
TGA ≤5 cig/d 0.3 (0.1-1.4)
>5 cig/d 0.4 (0.1-1.7)
TOF ≤5 cig/d 1.6 (0.8-3.2)
>5 cig/d 0.5 (0.2-1.7)
Kuciene et al. 2010
[37] SPD
<10 cig/d 2.06 (1.46-2.90)
10-20 cig/d 3.24 (1.67-6.27)
Lupo et al. 2012 [40] Any CHD
< 15 cig/d 1.12 (0.95-1.31)
15-24 cig/d 0.98 (0.75-1.27)
≥25 cig/d 1.81 (1.13-2.89)
Malik et al. 2008 [41]
ASD
< 15 cig/d 2.02 (1.47-2.77)
15-24 cig/d 1.78 (1.05-3.01)
≥25 cig/d 2.35 (0.92-6.00)
AVSD < 15 cig/d 1.02 (0.53-1.97)
15-24 cig/d 2.18 (1.04-4.55)
≥25 cig/d 2.01 (0.44-9.12)
CTD
< 15 cig/d 1.06 (0.82-1.35)
15-24 cig/d 0.84 (0.56-1.27)
≥25 cig/d 0.97 (0.44-2.12)
LVOTO
< 15 cig/d 0.99 (0.74-1.32)
15-24 cig/d 0.89 (0.57-1.38)
≥25 cig/d 0.93 (0.38-2.26)
RVOTO < 15 cig/d 1.25 (0.95-1.65)
15-24 cig/d 0.93 (0.59-1.49)
≥25 cig/d 2.35 (1.21-4.53)
SPD < 15 cig/d 1.44 (1.18-1.76)
15-24 cig/d 1.50 (1.11-2.03)
≥25 cig/d 2.06 (1.20-3.54)
TGA < 15 cig/d 1.08 (0.73-1.58)
15-24 cig/d 0.79 (0.42-1.48)
≥25 cig/d 1.19 (0.41-3.49)
TOF < 15 cig/d 1.03 (0.71-1.48)
15-24 cig/d 0.62 (0.31-1.26)
≥25 cig/d 1.01 (0.30-3.38)
VSD
< 15 cig/d 1.30 (1.00-1.69)
15-24 cig/d 1.33 (0.89-2.00)
≥25 cig/d 1.68 (0.82-3.47)
Patel et al. 2012 [43] AVSD
< 14 cig/d 1.5 (0.9-2.5)
14-24 cig/d 1.2 (0.5-2.7)
≥25 cig/d 4.4 (1.5-12.8)
Tikkanen et al. 1991
[50] VSD
1-14 cig/d 1.18 (0.77-1.83)
15-29 cig/d 1.59 (0.62-4.04)
Tikkanen et al. 1991
[51] Any CHD
1-14 cig/d 0.90 (0.69-1.18)
15-29 cig/d 1.64 (0.93-2.87)
Tikkanen et al. 1992
[52] CTD
1-14 cig/d 1.07 (0.62-1.85)
15-29 cig/d 0.85 (0.19-3.70)
Tikkanen et al. 1992
[53] ASD
1-14 cig/d 0.7 (.03-1.6)
15-29 cig/d 0.8 (0.1-5.7)
Wasserman et al.
1996 [8]
CTD 1-19 cig/d 1.3 (0.84-2.0)
≥20 cig/d 1.4 (0.65-3.0)
TGA 1-19 cig/d 1.4 (0.74-2.6)
≥20 cig/d 2.1 (0.79-5.6)
TOF 1-19 cig/d 1.3 (0.72-2.4)
≥20 cig/d 0.52 (0.08-2.4)
Williams et al. 2004
[57] VSD
1-14 cig/d 1.37 (0.85-2.21)
15-24 cig/d 1.15 (0.66-1.99)
≥25 cig/d 0.90 (0.23-2.45)
ASD: atrial septal defect AVSD: atrioventricular septal defect CHD: congenital heart defect CTD: conotruncal heart defect LVOTO: left ventricular outflow tract obstruction RVOTO: right ventricular outflow tract obstruction SPD: septal defect TGA: transposition of the great arteries TOF: tetralogy of Fallot VSD: ventricular septal defect
Supplementary C. Summary of risk of bias
Red: high risk of bias
Green: low risk of bias
Yellow: unclear
Supplementary D. Linaer dose-response curve (solid line is the fitted line, and dash line is the 95%CI)
any CHD
0.5
1.0
1.5
2.0
2.5
RR
0 5 10 15 20 25smoking (cig/d)
SPD
1.0
1.2
1.4
1.6
1.8
2.0
RR
0 5 10 15 20smoking (cig/d)
TGA
0.6
0.8
1.0
1.2
1.4
1.6
1.8R
R
0 5 10 15 20smoking (cig/d)
TOF
0.0
100.0
200.0
300.0
400.0
500.0
600.0
RR
0 5 10 15 20smoking (cig/d)
CTD
0.8
1.0
1.2
1.4
1.6R
R
0 5 10 15 20 25smoking (cig/d)
ASD
1.0
1.5
2.0
2.5
3.0
RR
0 5 10 15 20 25smoking (cig/d)
VSD
0.8
1.0
1.2
1.4
1.6
1.8R
R
0 5 10 15 20 25smoking (cig/d)
Supplementary E. Quadratic dose-response curve (solid line is the fitted line, and dash line is the 95%CI)
any CHD
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
RR
0 5 10 15 20 25smoking (cig/d)
SPD
0.8
1.0
1.2
1.4
1.6
1.8
RR
0 5 10 15 20smoking (cig/d)
TGA
0.5
1.0
1.5
2.0
2.5R
R
0 5 10 15 20smoking (cig/d)
TOF
0.0
500.0
1000.0
1500.0
2000.0
2500.0
3000.0
RR
0 5 10 15 20smoking (cig/d)
CTD
0.8
1.0
1.2
1.4
1.6
1.8
2.0R
R
0 5 10 15 20 25smoking (cig/d)
ASD
0.5
1.0
1.5
2.0
2.5
3.0
RR
0 5 10 15 20 25smoking (cig/d)
VSD
0.6
0.8
1.0
1.2
1.4
1.6R
R
0 5 10 15 20 25smoking (cig/d)
Supplementary file F. Funnel Plots (1) Any CHD
(2) ASD
0.2
.4.6
.8
SE
of lo
gR
R
-2 -1 0 1 2log RR
Funnel plot with pseudo 95% confidence limits0
.2.4
.6.8
SE
of lo
gR
R
-1 0 1 2log RR
Funnel plot with pseudo 95% confidence limits
(3) AVSD
(4) CTD
0.1
.2.3
SE
of lo
gR
R
-.5 0 .5 1log RR
Funnel plot with pseudo 95% confidence limits
0.1
.2.3
.4
SE
of lo
gR
R
-1 -.5 0 .5 1log RR
Funnel plot with pseudo 95% confidence limits
(5) LVOTO
(6) RVOTO
0.1
.2.3
.4
SE
of lo
gR
R
-1 -.5 0 .5log RR
Funnel plot with pseudo 95% confidence limits0
.1.2
.3.4
SE
of lo
gR
R
-1 -.5 0 .5 1log RR
Funnel plot with pseudo 95% confidence limits
(7) TGA
(8) TOF
0.5
1
SE
of lo
gR
R
-2 -1 0 1 2log RR
Funnel plot with pseudo 95% confidence limits0
.05
.1.1
5.2
SE
of lo
gR
R
-.4 -.2 0 .2 .4log RR
Funnel plot with pseudo 95% confidence limits
(9) SPD
(10) VSD
0.1
.2.3
.4
SE
of lo
gR
R
-.5 0 .5 1log RR
Funnel plot with pseudo 95% confidence limits
0.1
.2.3
.4
SE
of lo
gR
R
-1 -.5 0 .5 1log RR
Funnel plot with pseudo 95% confidence limits