# Risk factors for hemodynamically significant patent ductus arteriosus and ibuprofen treatment failure in premature twins: a retrospective case-control study

## TL;DR

This study identifies risk factors for a heart condition in premature twins and poor response to ibuprofen treatment, aiming to improve personalized care.

## Contribution

The study identifies sIUGR as a risk factor for heart condition and MCDA/PROMs as risk factors for ibuprofen treatment failure in preterm twins.

## Key findings

- sIUGR is an independent risk factor for hemodynamically significant patent ductus arteriosus in preterm twins.
- MCDA and PROMs > 18 hours are independent risk factors for ibuprofen treatment failure in preterm twins.
- Elevated NT-proBNP and Hs-cTn levels may contribute to heart condition development in preterm infants with sIUGR.

## Abstract

Premature twins face a dual challenge: a high incidence of hemodynamically significant patent ductus arteriosus (hsPDA) and a poor response to ibuprofen. Current management, derived from singleton data, fails to address this population's unique risks. Our study specifically investigates risk factors for hsPDA development and ibuprofen treatment failure in preterm twins to enable personalized prevention and therapy. Thus, the potential biomarkers for the occurrence of hsPDA and ibuprofen closure failure were examined.

A single-center, retrospective case-control study. 736 twin infants born at ≤34 weeks of gestation were included, of which 70 were exposed to hsPDA and 66 were exposed to ibuprofen. Clinical data were obtained from the Electronic Medical Record system. For the occurrence of hsPDA and failure of ibuprofen treatment, multivariate logistic regression was employed to identify the independent risk factor and the potential biomarkers were examined.

1. When compared to the non-hsPDA group, the hsPDA group demonstrated markedly higher incidences of low birth weight, lower gestational age, male gender, low 5 min Apgar scores, selective intrauterine growth restriction (sIUGR), use of pulmonary surfactant, respiratory distress syndrome (RDS), ≥grade III intraventricular hemorrhage, and early-onset sepsis (p < 0.05). The hsPDA group had a notably higher rate of sIUGR (28.6%) relative to the non-hsPDA group (15.2%, p = 0.004). Furthermore, in twins with sIUGR, the larger infant exhibited a higher hsPDA incidence than the non-hsPDA group (p < 0.05). 2. Univariate analysis revealed that vaginal delivery, birth weight, gestational age, male gender, 5 min Apgar score, early-onset sepsis, RDS, and sIUGR were associated with the occurrence of hsPDA (p < 0.05). Multivariate regression identified sIUGR [odds ratio (OR) = 3.337, 95% confidence interval (95% CI) 1.301–8.560] as an independent risk factor (IRF), while a higher birth weight (OR = 0.537, 95% CI 0.437–0.660) was noted to be a protective factor (p < 0.05). 3. Compared with the successful treatment group, the treatment failure group showed higher rates of premature rupture of membranes (PROMs) > 18 h, postnatal surfactant use, and monochorionic diamniotic (MCDA) twins (p < 0.0167, Bonferroni correction). The treatment failure group included 11 MCDA cases (73.3%), markedly more than the successful treatment group (33.3%, p = 0.006). 4. Univariate regression analysis identified gestational age, birth weight, MCDA, 5 min Apgar score, and PROMs > 18 h as factors associated with ibuprofen treatment failure (p < 0.05). Multivariate regression revealed MCDA (OR = 4.686, 95% CI 1.070–20.530) and PROMs > 18 h (OR = 15.198, 95% CI 2.377–97.178) as IRFs for ibuprofen treatment failure (p < 0.05). 5. In the pharmacological closure group, MCDA twins exhibited markedly lower closure rates after both the first and total two courses compared to dichorionic diamniotic twins (p < 0.05). MCDA twins required higher cumulative drug doses (40.21 ± 1.27 vs. 32.21 ± 0.53, p < 0.05), although no significant difference in the frequency of administration was detected. The MCDA group also had a higher rate of surgical interventions (39.29% vs. 10.53%, p < 0.05). 6. The NT-proBNP, Hs-cTn, PGE2, Cortisol, and TXA2 levels in the sIUGR group were markedly elevated versus those in the non-sIUGR group, with statistically significant differences (p < 0.05).

In preterm twins ≤34 weeks, sIUGR is an IRF for hsPDA. In addition, MCDA and PROMs > 18 h are IRFs for ibuprofen treatment failure. Meanwhile, elevated levels of NT-proBNP and Hs-cTn may play a role in the development of hsPDA in preterm infants with sIUGR.