Supplementary Table 1. Overview of observational studies on associations of NSAID exposure in the first trimester and miscarriage and congenital malformations
Country
Data source
Time period
Israel
OB–GYN database,
hospitalisation database,
medication dispensing database
(2003–2009)
Study design
Size
Exposure
Comparison group
Outcome
Main findings
CH
n = 65,457
Unexposed to NSAIDs
(n = 60,962)
Miscarriage: NS
For indomethacin: adjusted HR 2.8, 95% CI 1.70–4.69; no
dose–response effect
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Norway
Norwegian Mother and Child
Cohort Study database, medical
birth registry
(1999–2008)
Israel
Maternal and infant
hospitalisation database,
medication dispensing database
(1998–2009)
USA
Right from the Start Study –
community based study
(2004–2010)
USA
National Birth Defects Prevention
Study
(1997–2004)
CH
n = 90,417
Unexposed to NSAIDs
(n = 83,906)
Congenital malformations: NS
Cardiac malformations detected 18 months postpartum: NS
2
Unexposed to NSAIDs
(n = 105,537)
Congenital malformations: NS
Musculoskeletal malformations:
For selective COX-2 inhibitors: aOR 3.39; 95% CI 1.37–8.34
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CH
n = 2,780
Any NSAID, n = 4,495
Non-selective COX-2
inhibitors, n = 4,424
Selective COX-2
inhibitors, n = 71
OTC NSAIDs included
Any NSAID, n = 3,529
Ibuprofen, n = 3,034
Diclofenac, n = 192
Naproxen, n = 168
OTC NSAIDs included
Any NSAID, n = 5,267
Conventional NSAIDs,
n = 5,153
Selective COX-2
inhibitors, n = 114
Any NSAID, n = 1,185
OTC NSAIDs included
Unexposed to NSAIDs
(n = 1,595)
Miscarriage: NS
4
CC
n = 19,741
Any NSAID, n = 4,625
OTC NSAIDs included
No congenital
malformations
(n = 5,546)
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Norway
Norwegian Mother and Child
Cohort Study database, medical
birth registry
(1999–2006)
CH
n = 67,891
Any NSAID, n = 3,023
OTC NSAIDs included
Unexposed to NSAIDs
(n = 64,074)
Anophthalmia/micropthalmia:
For any NSAID: aOR 2.1; 95% CI 1.3–3.5
Cleft lip +/- palate:
For ibuprofen: aOR 1.3; 95% CI 1.1–1.6
For naproxen: aOR 1.7; 95% CI 1.1–2.5
Amniotic bands:
For ibuprofen: aOR 2.2; 95% CI 1.4–3.5
For acetylsalicylic acid: aOR 2.5; 95% CI 1.1–5.6
Pulmonary valve stenosis in term infants:
For naproxen: aOR 2.4; 95% CI 1.3–4.5
Selected congenital malformations (neural tube, cardiac,
oesophageal, anorectal, abdominal wall malformations,
diaphragmatic hernia, and amniotic bands): NS
CH
n = 110,783
Ref.
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Canada
Quebec Pregnancy Registry
(1997 onwards)
Italy
TIS database
(1988–2008)
Canada
Quebec Pregnancy Registry
(1997 to 2003)
CC
n = 51,755
Any NSAID, n = 352
No OTC NSAIDs
No miscarriage
(n = 47,050)
Miscarriage:
For any NSAID: aOR 2.4; 95% CI 2.1–2.8
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CH
n = 917
Diclofenac, n = 145
OTC NSAIDs included
Congenital malformations: NS
Miscarriage: NS
8
CH
n = 36,387
Any NSAID, n = 1,056
No OTC NSAIDs
Exposed to nonteratogens
(n = 501)
Unexposed to NSAIDs
(n = 35,331)
9
Denmark
Hospital discharge registry,
medical birth registry,
prescription database
(1998–2002)
USA
National Birth Defects Prevention
Study
(1997–1998)
USA
Prenatal interview
(1996–1998)
CC
n = 17,589
Any NSAID, n = 1,554
No OTC NSAIDs
Children of
corresponding
gestational age
(n = 15,990)
Congenital malformations:
For any NSAID: aOR 2.2; 95% CI 1.7–2.8
Cardiac septal malformations:
For any NSAID: aOR 3.3; 95% CI 1.9–6.0
Respiratory system malformations:
For any NSAID: aOR 9.5; 95% CI 3.1–29.6
Miscarriage: NS
CC
n = 858
Any NSAID, n = 30
OTC NSAIDs included
No congenital
malformations
(n = 690)
VSD: NS
11
CH
n = 1,055
Any NSAID, n = 53
OTC NSAIDs included
Unexposed to NSAIDs
(n = 980)
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Sweden
Medical birth registry, Swedish
Register of Congenital
Malformations, Swedish Child
Cardiology Register
(1995–1998)
Denmark
Hospital discharge registry,
medical birth registry,
prescription database
(1991–1998)
CH
n = 72,142
Any NSAID, n = 2,557
OTC NSAIDs included
Rest of population
Miscarriage:
For any NSAID: adjusted HR 1.8; 95% CI 1.0–3.2
For NSAIDs used around conception: adjusted HR 5.6; 95% CI
2.3–13.7
For NSAIDs used > 1 week: adjusted HR 8.1; 95% CI 2.8–23.4
Congenital malformations: NS
Cardiac malformations:
For any NSAID: aOR 1.86; 95% CI 1.32–2.62
Orofacial clefts:
For any NSAID aOR 2.61, 95% CI 1.01–6.78
CH* and CC**
n* = 18,721
n** = 34,018
Any NSAID, n* = 1,257
Any NSAID, n** = 63
No OTC NSAIDs
Unexposed to any
drugs*
(n = 17,259)
No miscarriage**
(n = 29 750)
Congenital malformations*: NS
Miscarriage**:
For NSAID exposure in gestational weeks 0 to 1: aOR 7.0;
95% CI 2.7–17.7, weeks 2 to 3: aOR 3.0; 95% CI 1.2–7.4,
weeks 4 to 6: aOR 4.4; 95% CI 2.7–7.2, weeks 7 to 9: aOR
2.7; 95% CI 1.8–4.0
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Abbreviations: aOR, adjusted OR; CH, cohort; CC, case–control; NS, no excess risk (statistically not significant); OB–GYN, obstetrics and gynaecology; OTC, over-the-counter; TIS, Teratology Information Services
database; VSD, ventricular septal defects.
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