Importance

Patent ductus arteriosus (PDA) is associated with increased mortality and worsened respiratory outcomes, including bronchopulmonary dysplasia (BPD), in preterm infants. Nonsteroidal anti-inflammatory drugs (NSAIDs) are efficacious in closing PDA, but the effectiveness of NSAID-mediated PDA closure in improving mortality and preventing BPD is unclear.

Objective

To determine the effectiveness of NSAID treatment for PDA in reducing mortality and moderate/severe BPD at 36 weeks postmenstrual age.

Design, setting, and participants

This cohort study included 12 018 infants born at 28 gestational weeks or younger discharged between January 2006 and December 2013 from neonatal intensive care units in 25 US children's hospitals included in the Pediatric Health Information System. We performed an instrumental variable analysis that incorporated clinician preference-based, institutional variation in NSAID treatment frequency to determine the effect of NSAID treatment for PDA on mortality and BPD.

Exposures

Proportion of NSAID-treated infants born at each infant's institution within ±6 months of that infant's birth.

Main outcomes and measures

The primary composite outcome was death, moderate, or severe BPD at 36 weeks postmenstrual age.

Results

Of the 6370 male and 5648 female infants in this study, 4995 (42%) were white, 3176 (26%) were African American, 1823 (15%) were Hispanic, and 1555 (13%) were other races/ethnicities. The proportion of NSAID-treated infants at each infant's hospital within ±6 months of that infant's birth was associated with NSAID treatment and not associated with gestation, race/ethnicity, or sex. An infant's chances of receiving NSAID treatment increased by 0.84% (95% CI, 0.8-0.9; P < .001) for every 1% increase in the annual NSAID treatment percentage at a given hospital. An instrumental variable analysis demonstrated no association between NSAID treatment and the odds of mortality or BPD (odds ratio, 0.94; 95% CI, 0.70-1.25; P = .69), mortality (odds ratio, 0.73; 95% CI, 0.43-1.13; P = .18), or BPD (odds ratio, 1.01; 95% CI, 0.73-1.45; P = .94) in survivors.

Conclusions and relevance

When we incorporated clinician preference-based practice variation as an instrument to minimize the effect of unmeasured confounding, we detected no changes in the odds of mortality or moderate/severe BPD among similar preterm infants born at 28 weeks or younger following NSAID treatment for PDA initiated 2 to 28 days postnatally. Our findings agree with available randomized clinical trial evidence and support a conservative approach to PDA management.

Unlabelled

We surveyed neonatal leadership at 46 US children's hospitals via web-based survey to identify local preferences and concerns regarding indomethacin prophylaxis, nonsteroidal anti-inflammatory drug (NSAID) treatment, and patent ductus arteriosus (PDA) ligation. We received a 100 % survey response (N = 46). Practice guidelines for prophylactic indomethacin were reported at 28 % of NICUs, for NSAID treatment of PDA at 39 % and for surgical ligation at 27 %. Respondents noted intra-institutional practice variation for indomethacin prophylaxis (33 %), NSAID treatment (70 %), and PDA ligation (73 %). The majority of institutions did not prescribe indomethacin prophylaxis (72 %). For PDA treatment, indomethacin was preferred over ibuprofen (80 %). We validated our survey results via comparison with billing data as documented in the Pediatric Health Information System (PHIS) database, finding that survey responses directly correlated with local billing data (p < 0.0001). At institutions that did not typically administer NSAIDs for PDA closure or surgical PDA ligation, a lack of evidence for their effectiveness in improving long-term outcomes and the risk of treatment-associated adverse effects were the most often cited reasons.

Conclusion

No consensus exists among providers at US children's hospitals regarding prophylactic indomethacin, NSAID treatment, or PDA ligation. Lack of evidence and safety concerns play a prominent role.

What is known

• NSAIDs and surgical PDA ligation are efficacious in preventing intraventricular hemorrhage (IVH) and closing PDA in preterm infants, but have not been shown to improve long-term respiratory, neurodevelopmental, or mortality outcomes. What is New: • Practice preferences for indomethacin prophylaxis, NSAID, and surgical PDA treatment vary both among and within institutions. Lack of treatment effectiveness and the risk of adverse effects are major concerns.

Background

Previous epidemiological studies have found positive associations between maternal infections and childhood leukaemia; however, evidence from prospective cohort studies is scarce. We aimed to examine the associations using large-scale prospective data.

Methods

Data were pooled from six population-based birth cohorts in Australia, Denmark, Israel, Norway, the UK and the USA (recruitment 1950s-2000s). Primary outcomes were any childhood leukaemia and acute lymphoblastic leukaemia (ALL); secondary outcomes were acute myeloid leukaemia (AML) and any childhood cancer. Exposures included maternal self-reported infections [influenza-like illness, common cold, any respiratory tract infection, vaginal thrush, vaginal infections and urinary tract infection (including cystitis)] and infection-associated symptoms (fever and diarrhoea) during pregnancy. Covariate-adjusted hazard ratio (HR) and 95% confidence interval (CI) were estimated using multilevel Cox models.

Results

Among 312 879 children with a median follow-up of 13.6 years, 167 leukaemias, including 129 ALL and 33 AML, were identified. Maternal urinary tract infection was associated with increased risk of any leukaemia [HR (95% CI) 1.68 (1.10-2.58)] and subtypes ALL [1.49 (0.87-2.56)] and AML [2.70 ([0.93-7.86)], but not with any cancer [1.13 (0.85-1.51)]. Respiratory tract infection was associated with increased risk of any leukaemia [1.57 (1.06-2.34)], ALL [1.43 (0.94-2.19)], AML [2.37 (1.10-5.12)] and any cancer [1.33 (1.09-1.63)]; influenza-like illness showed a similar pattern but with less precise estimates. There was no evidence of a link between other infections and any outcomes.

Conclusions

Urinary tract and respiratory tract infections during pregnancy may be associated with childhood leukaemia, but the absolute risk is small given the rarity of the outcome.