SupplementaryTable 1. Overview of observational studies on associations of NSAID exposure in the first trimester and miscarriage and congenital malformations

Country
Data source
Time period / Study design
Size / Exposure / Comparison group / Outcome
Main findings / Ref.
Israel
OB–GYN database, hospitalisation database, medication dispensing database
(2003–2009) / CH
n = 65,457 / Any NSAID, n = 4,495
Non-selective COX-2 inhibitors, n = 4,424
Selective COX-2 inhibitors, n = 71
OTC NSAIDs included / Unexposed to NSAIDs
(n = 60,962) / Miscarriage: NS
For indomethacin: adjusted HR 2.8, 95% CI 1.70–4.69; no dose–response effect / 1
Norway
Norwegian Mother and Child Cohort Study database, medical birth registry
(1999–2008) / CH
n = 90,417 / Any NSAID, n = 3,529
Ibuprofen, n = 3,034
Diclofenac, n = 192
Naproxen, n = 168
OTC NSAIDs included / Unexposed to NSAIDs
(n = 83,906) / Congenital malformations: NS
Cardiac malformations detected 18 months postpartum: NS / 2
Israel
Maternal and infant hospitalisation database, medication dispensing database (1998–2009) / CH
n = 110,783 / Any NSAID, n = 5,267
Conventional NSAIDs,
n = 5,153
Selective COX-2 inhibitors, n = 114 / 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 / 3
USA
Right from the Start Study – community based study
(2004–2010) / CH
n = 2,780 / Any NSAID, n = 1,185
OTC NSAIDs included / Unexposed to NSAIDs
(n = 1,595) / Miscarriage: NS / 4
USA
National Birth Defects Prevention Study
(1997–2004) / CC
n = 19,741 / Any NSAID, n = 4,625
OTC NSAIDs included / No congenital malformations
(n = 5,546) / 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 / 5
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) / Selected congenital malformations (neural tube, cardiac, oesophageal, anorectal, abdominal wall malformations, diaphragmatic hernia, and amniotic bands): NS / 6
Canada
Quebec Pregnancy Registry
(1997 onwards) / 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 / 7
Italy
TIS database
(1988–2008) / CH
n = 917 / Diclofenac, n = 145
OTC NSAIDs included / Exposed to non-teratogens
(n = 501) / Congenital malformations: NS
Miscarriage: NS / 8
Canada
Quebec Pregnancy Registry
(1997 to 2003) / CH
n = 36,387 / Any NSAID, n = 1,056
No OTC NSAIDs / Unexposed to NSAIDs
(n = 35,331) / 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 / 9
Denmark
Hospital discharge registry, medical birth registry, prescription database
(1998–2002) / CC
n = 17,589 / Any NSAID, n = 1,554
No OTC NSAIDs / Children of corresponding gestational age
(n = 15,990) / Miscarriage: NS / 10
USA
National Birth Defects Prevention Study
(1997–1998) / CC
n = 858 / Any NSAID, n = 30
OTC NSAIDs included / No congenital malformations
(n = 690) / VSD: NS / 11
USA
Prenatal interview
(1996–1998) / CH
n = 1,055 / Any NSAID, n = 53
OTC NSAIDs included / Unexposed to NSAIDs
(n = 980) / 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 / 12
Sweden
Medical birth registry, Swedish Register of Congenital Malformations, Swedish Child Cardiology Register
(1995–1998) / CH
n = 72,142 / Any NSAID, n = 2,557
OTC NSAIDs included / Rest of population / 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 / 13
Denmark
Hospital discharge registry, medical birth registry, prescription database
(1991–1998) / 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 / 14

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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