Supplementary Table 2. Overview of observational studies on associations of NSAID exposure in the second and/or third trimester and other pregnancy outcomes

Country
Data source
Time period / Study design
Size / Exposure / Comparison group / Outcome
Main findings / Ref.
USA
Slone Epidemiology Center’s Birth Defects Study
(1998–2003) / CC
n = 1,213 / Any NSAID, n = 33
OTC NSAIDs included / No PPHN
(n = 836) / PPHN: NS / 1
USA
The ELGAN Study
Children < 28 weeks old in 11 institutions
(2002–2004) / CC
n = 877 / Any NSAID, n = 64
OTC NSAIDs included / Unexposed to NSAIDs
(n = 813) / Quadriparetic CP in children born < 28 weeks after LMP:
For any NSAID: aOR 2.4; 95% CI 1.04–5.8
Diaparetic CP in children born < 28 weeks after LMP:
For any NSAID: aOR 3.5; 95% CI 1.1–11.0 / 2
USA
The NICHD Neonatal Research Network’s Data Base Study
(1995–2000) / CH
n = 573 / Indomethacin, n = 85
No OTC NSAIDs / Unexposed to indomethacin
(n = 464) / Grade III or IV IVH in VLBW babies:
For indomethacin: aOR 2.7; 95% CI 1.2–6.4 / 3
USA
Hospital records, meconium analysis
(2001) / CC
n = 101 / Any NSAID, n = 50
Ibuprofen, n = 23
Naproxen, n = 19
Acetylsalicylic acid, n = 44
OTC NSAIDs included / No PPHN
(n = 61) / PPHN:
For any NSAID: aOR 21.5; 95% CI 7.1–64.7
For ibuprofen: aOR 12.9; 95% CI 3.9–42.3
For naproxen: aOR 3.3; 95% CI 1.2–9.3
For acetylsalicylic acid: aOR 8.1; 95% CI 3.3–20.0 / 4
Finland
Record analysis
(2001) / CC
n = 66 / Indomethacin, n = 31
No OTC NSAIDs / No renal damage at
< 33 gestational weeks
(n = 35) / Renal damage: NS / 5
Finland
Record analysis
(2001) / CH
n = 240 / Indomethacin, n = 82
No OTC NSAIDs / None / Grade I or II IVH:
For indomethacin dose > 150mg/day: aOR 3.9; 95% CI 1.4–10.7
For indomethacin therapy > 2 days: aOR 3.4; 95% CI 1.3–8.9
Severe NEC:
For indomethacin dose > 150mg/day: aOR 4.3; 95% CI 1.2–14.4, for indomethacin therapy > 2 days: aOR 4.4; 95% CI 1.1–17.4
Sepsis:
For indomethacin: aOR 9.3; 95% CI 2.3–36.9 / 6
USA
Record analysis
(1991–1995) / CH
n = 72 / Indomethacin, n = 72
No OTC NSAIDs / None / Premature closure of ductus arteriosus:
For indomethacin with advancing gestational age, p < 0.05. / 7
USA
Record analysis
(1986– 1991) / CC
n = 114 / Indomethacin, n = 57
No OTC NSAIDs / Unexposed to indomethacin at corresponding gestational age
(n = 57) / Increased risk of premature closure of ductus arteriosus:
For indomethacin: p < 0.05
NEC:
For indomethacin: p < 0.005
Grade II or IV IVH:
For indomethacin: p < 0.02
Oliguria:
For indomethacin: p < 0.003 / 8

Abbreviations: CH, cohort; CC, case–control; PPHN, persistent pulmonary hypertension of the newborn; NS, no excess risk (statistically not significant); ELGAN, Extremely Low Gestational Age Newborns;

CP, cerebral palsy; LMP, last menstrual period; aOR = adjusted OR; IVH = intraventricular haemorrhage; VLBW = very low birth weight (< 1500g); NEC = necrotizing enterocolitis.

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