Patent ductus arteriosus and the risk of bronchopulmonary dysplasia-associated pulmonary hypertension.

BACKGROUND: The aim of the study was to determine whether prolonged exposure to a moderate/large patent ductus arteriosus left-to-right shunt (PDA) increases the risk of late (beyond 36 weeks) pulmonary hypertension (BPD-PH) and pulmonary vascular disease (BPD-PVD) during the neonatal hospitalization in preterm infants (<28 weeks' gestation) with bronchopulmonary dysplasia (BPD). METHODS: All infants requiring respiratory support ≥36 weeks had systematic echocardiographic evaluations for BPD-PH at planned intervals. Infants were classified as having either flow-associated BPD-PH (BPD-flow-PH) or BPD-PVD. RESULTS: 256 infants survived ≥36 weeks: 105 had NO BPD (were off respiratory support by 36 weeks); 151 had BPD. 22/151 had BPD-PH (12/22 had BPD-flow-PH from a PDA that persisted beyond 36 weeks; 10/22 had BPD-PVD). Moderate/large PDA shunts that persisted beyond 36 weeks were significantly associated with an increased incidence of BPD-PH due to BPD-flow-PH. We found no association between the duration of PDA exposure and the incidence of BPD-PVD. CONCLUSIONS: Moderate/large PDA shunts increase the risk of flow-associated BPD-PH when present beyond 36 weeks. Although term infants with PDA-congenital heart disease can develop pulmonary vascular remodeling and PVD after months of PDA exposure, we found no echocardiographic evidence in preterm infants that prolonged PDA exposure increases the incidence of BPD-PVD during the neonatal hospitalization. IMPACT: In our study, preterm infants (<28 weeks' gestation) with bronchopulmonary dysplasia (BPD) had a 15% incidence of pulmonary hypertension (PH) beyond 36 weeks' postmenstrual age as a comorbidity. Moderate/large patent ductus arteriosus (PDA) shunts increased the risk of flow-associated PH when present beyond 36 weeks. Although months of prolonged PDA exposure can cause pulmonary vascular remodeling and pulmonary vascular disease (PVD) in term infants with PDA-congenital heart disease, we found no echocardiographic evidence for an association between the duration of PDA exposure and the incidence of late PVD during the neonatal hospitalization in preterm infants with BPD.

Interactions between PDA-associated polymorphisms and genetic ancestry alter ductus arteriosus gene expression.

BACKGROUND: DNA polymorphisms in PTGIS and TFAP2B have been identified as risk factors for patent ductus arteriosus (PDA) in a population composed of preterm infants with European genetic ancestry but not in more genetically diverse populations. GOAL: To determine if the effects of TFAP2B and PTGIS polymorphisms on ductus arteriosus (DA) gene expression differ based on genetic ancestry. METHODS: DA from 273 human second trimester fetuses were genotyped for TFAP2B and PTGIS polymorphisms and for polymorphisms distributing along genetic ancestry lines. RT-PCR was used to measure the RNA expression of 49 candidate genes involved with DA closure. RESULTS: Seventeen percent of the DA analyzed were of European ancestry. In multivariable regression analyses we found consistent associations between four PDA-related TFAP2B polymorphisms (rs2817399(A), rs987237(G), rs760900(C), and rs2817416(C)) and expression of the following genes: EPAS1, CACNB2, ECE1, KCNA2, ATP2A3, EDNRA, EDNRB, BMP9, and BMP10, and between the PTGIS haplotype rs493694(G)/rs693649(A) and PTGIS and NOS3. These changes only occurred in DA with European ancestry. No consistent positive or negative associations were found among DA samples unless an interaction between the polymorphisms and genetic ancestry was taken into account. CONCLUSION: PTGIS and TFAP2B polymorphisms were associated with consistent changes in DA gene expression when present in fetuses with European ancestry. IMPACT: DNA polymorphisms in PTGIS and TFAP2B have been identified as risk factors for patent ductus arteriosus (PDA) in a population composed primarily of preterm infants with European genetic ancestry but not in more genetically diverse populations. The same PTGIS and TFAP2B polymorphisms are associated with changes in ductus gene expression when present in ductus from fetuses with European genetic ancestry. No consistent associations with gene expression can be found unless an interaction between the polymorphisms and genetic ancestry is taken into account.

Patent ductus arteriosus, tracheal ventilation, and the risk of bronchopulmonary dysplasia.

BACKGROUND: An increased risk for bronchopulmonary dysplasia (BPD) exists when moderate-to-large patent ductus arteriosus shunts (hsPDA) persist beyond 14 days. GOAL: To examine the interaction between prolonged exposures to tracheal ventilation (≥10 days) and hsPDA on the incidence of BPD in infants <28 weeks gestation. STUDY DESIGN: Predefined definitions of prolonged ventilation (≥10 days), hsPDA (≥14 days), and BPD (room air challenge test at 36 weeks) were used to analyze deidentified data from the multicenter TRIOCAPI RCT in a secondary analysis of the trial. RESULTS: Among 307 infants who survived >14 days, 41 died before 36 weeks. Among survivors, 93/266 had BPD. The association between BPD and hsPDA depended on the length of intubation. In multivariable analyses, prolonged hsPDA shunts were associated with increased BPD (odds ratio (OR) (95% confidence interval (CI)) = 3.00 (1.58-5.71)) when infants required intubation for ≥10 days. In contrast, there was no significant association between hsPDA exposure and BPD when infants were intubated <10 days (OR (95% CI) = 1.49 (0.98-2.26)). A similar relationship between prolonged hsPDA and length of intubation was found for BPD/death (n = 307): infants intubated ≥10 days: OR (95% CI) = 2.41 (1.47-3.95)); infants intubated <10 days: OR (95% CI) = 1.37 (0.86-2.19)). CONCLUSIONS: Moderate-to-large PDAs were associated with increased risks of BPD and BPD/death-but only when infants required intubation ≥10 days. IMPACT: Infants with a moderate-to-large hsPDA that persist beyond 14 days are only at risk for developing BPD if they also receive prolonged tracheal ventilation for ≥10 days. Infants who receive less ventilatory support (intubation for <10 days) have the same incidence of BPD whether the ductus closes shortly after birth or whether it persists as a moderate-to-large shunt for several weeks. Early PDA closure may be unnecessary in infants who require short durations of intubation since the PDA does not seem to alter the incidence of BPD in infants who require intubation for <10 days.

Prolonged Tracheal Intubation and the Association Between Patent Ductus Arteriosus and Bronchopulmonary Dysplasia: A Secondary Analysis of the PDA-TOLERATE trial.

In the PDA-TOLERATE trial, persistent (even for several weeks) moderate to large patent ductus arteriosus (PDA) was not associated with an increased risk of BPD when the infant required <10 days of intubation. However, in infants requiring intubation for ≥10 days, prolonged PDA exposure (≥11 days) was associated with an increased risk of moderate/severe BPD.

Relationship between Duration of Infant Exposure to a Moderate-to-Large Patent Ductus Arteriosus Shunt and the Risk of Developing Bronchopulmonary Dysplasia or Death Before 36 Weeks.

OBJECTIVE: This study was aimed to examine the relationship between duration of infant exposure to a moderate-to-large patent ductus arteriosus (PDA) shunt and the risk of developing bronchopulmonary dysplasia (BPD) or death before 36 weeks (BPD/death). STUDY DESIGN: Infants <28 weeks' gestation who survived ≥7 days (n = 423) had echocardiograms performed on day 7 and at planned intervals. RESULTS: In multivariable regression models, BPD/death did not appear to be increased until infants had been exposed to a moderate-to-large PDA for at least 7-13 days: OR (95%CI) (referent = closed or small PDA): moderate-to-large PDA exposure for <7 days: 0.38 (range, 0.10-1.46); for 7 to 13 days = 2.12 (range, 1.04-4.32); for ≥14 days = 3.86 (range, 2.15-6.96). Once the threshold of 7 to 13 days had been reached, additional exposure (≥14 days) did not significantly add to the increased incidence of BPD/death: (referent exposure = 7-13 days) exposure for 14 to 27 days = 1.34 (range, 0.52-3.45); for 28 to 48 days = 2.34 (range, 0.88-6.19); for ≥49 days = 1.80 (range. 0.59-5.47). A similar relationship was found for the outcome of BPD-alone. CONCLUSION: Infants < 28 weeks' gestation required at least 7 to 13 days of exposure to a moderate-to-large PDA before a significant increase in the incidence of BPD/death was apparent. Once this threshold was reached additional exposure to a moderate-to-large PDA did not significantly add to the increased incidence of BPD/death.

Lack of Equipoise in the PDA-TOLERATE Trial: A Comparison of Eligible Infants Enrolled in the Trial and Those Treated Outside the Trial.

The PDA: TO LEave it alone or Respond And Treat Early trial compared the effects of 2 strategies for treatment of patent ductus arteriosus (PDA) in infants <280/7 weeks of gestation; however 137 potentially eligible infants were not recruited and received treatment of their PDA outside the PDA-TOLERATE trial due to "lack-of-physician-equipoise" (LPE). Despite being less mature and needing more respiratory support, infants with LPE had lower rates of mortality than enrolled infants. Infants with LPE treated before day 6 had lower rates of late respiratory morbidity than infants with LPE treated ≥day 6. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01958320.

PDA-TOLERATE Trial: An Exploratory Randomized Controlled Trial of Treatment of Moderate-to-Large Patent Ductus Arteriosus at 1 Week of Age.

OBJECTIVE: To compare early routine pharmacologic treatment of moderate-to-large patent ductus arteriosus (PDA) at the end of week 1 with a conservative approach that requires prespecified respiratory and hemodynamic criteria before treatment can be given. STUDY DESIGN: A total of 202 neonates of <28 weeks of gestation age (mean, 25.8 ± 1.1 weeks) with moderate-to-large PDA shunts were enrolled between age 6 and 14 days (mean, 8.1 ± 2.2 days) into an exploratory randomized controlled trial. RESULTS: At enrollment, 49% of the patients were intubated and 48% required nasal ventilation or continuous positive airway pressure. There were no differences between the groups in either our primary outcome of ligation or presence of a PDA at discharge (early routine treatment [ERT], 32%; conservative treatment [CT], 39%) or any of our prespecified secondary outcomes of necrotizing enterocolitis (ERT, 16%; CT, 19%), bronchopulmonary dysplasia (BPD) (ERT, 49%; CT, 53%), BPD/death (ERT, 58%; CT, 57%), death (ERT,19%; CT, 10%), and weekly need for respiratory support. Fewer infants in the ERT group met the rescue criteria (ERT, 31%; CT, 62%). In secondary exploratory analyses, infants receiving ERT had significantly less need for inotropic support (ERT, 13%; CT, 25%). However, among infants who were ≥26 weeks gestational age, those receiving ERT took significantly longer to achieve enteral feeding of 120 mL/kg/day (median: ERT, 14 days [range, 4.5-19 days]; CT, 6 days [range, 3-14 days]), and had significantly higher incidences of late-onset non-coagulase-negative Staphylococcus bacteremia (ERT, 24%; CT,6%) and death (ERT, 16%; CT, 2%). CONCLUSIONS: In preterm infants age <28 weeks with moderate-to-large PDAs who were receiving respiratory support after the first week, ERT did not reduce PDA ligations or the presence of a PDA at discharge and did not improve any of the prespecified secondary outcomes, but delayed full feeding and was associated with higher rates of late-onset sepsis and death in infants born at ≥26 weeks of gestation. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01958320.

Effects of antenatal betamethasone on preterm human and mouse ductus arteriosus: comparison with baboon data.

BACKGROUND: Although studies involving preterm infants ≤34 weeks gestation report a decreased incidence of patent ductus arteriosus after antenatal betamethasone, studies involving younger gestation infants report conflicting results. METHODS: We used preterm baboons, mice, and humans (≤276/7 weeks gestation) to examine betamethasone's effects on ductus gene expression and constriction both in vitro and in vivo. RESULTS: In mice, betamethasone increased the sensitivity of the premature ductus to the contractile effects of oxygen without altering the effects of other contractile or vasodilatory stimuli. Betamethasone's effects on oxygen sensitivity could be eliminated by inhibiting endogenous prostaglandin/nitric oxide signaling. In mice and baboons, betamethasone increased the expression of several developmentally regulated genes that mediate oxygen-induced constriction (K+ channels) and inhibit vasodilator signaling (phosphodiesterases). In human infants, betamethasone increased the rate of ductus constriction at all gestational ages. However, in infants born ≤256/7 weeks gestation, betamethasone's contractile effects were only apparent when prostaglandin signaling was inhibited, whereas at 26-27 weeks gestation, betamethasone's contractile effects were apparent even in the absence of prostaglandin inhibitors. CONCLUSIONS: We speculate that betamethasone's contractile effects may be mediated through genes that are developmentally regulated. This could explain why betamethasone's effects vary according to the infant's developmental age at birth.

Prophylactic Indomethacin Compared with Delayed Conservative Management of the Patent Ductus Arteriosus in Extremely Preterm Infants: Effects on Neonatal Outcomes.

OBJECTIVE: To determine whether prophylactic indomethacin (PINDO) has more or less morbidity than delayed conservative management of the moderate-to-large patent ductus arteriosus (PDA). STUDY DESIGN: We performed a prospective double cohort controlled study of infants delivered at ≤276/7 weeks gestation (n = 397). From January 2005 through April 2011, all infants were treated with PINDO (n = 247). From May 2011 through August 2016, no infant was treated with indomethacin until at least 8 postnatal days (conservative epoch, n = 150). Echocardiograms were performed on day 7 and at planned intervals until the PDA was small or closed. A single neonatologist prospectively collected all data. RESULTS: The incidence of moderate-to-large PDA on day 7 and duration of exposure to moderate-to-large PDA were significantly less in the PINDO epoch (incidence = 10%, median = 2 days) than the conservative epoch (incidence = 67%, median = 14 days). Ligation rates were low in both epochs (PINDO = 14%, conservative = 5%). In multivariate analyses, PINDO infants had a significantly lower incidence of bronchopulmonary dysplasia (BPD) (risk ratio = 0.68, CI: 0.46-0.89) and BPD or death (risk ratio= 0.78, CI: 0.62-0.95) than conservative infants. There were no differences between the epochs in death, intraventricular hemorrhage grades 3 and 4, necrotizing enterocolitis, or retinopathy of prematurity receiving treatment. The effects of PINDO on BPD and BPD or death were no longer significant when analyses were adjusted for presence of a moderate-to-large PDA on day 7. The significant effects of PINDO were independent of whether or not a ligation was performed. CONCLUSIONS: PINDO decreases BPD and BPD or death compared with delayed conservative PDA management. These effects are mediated by closure of the PDA.

Effects of Prophylactic Indomethacin on Vasopressor-Dependent Hypotension in Extremely Preterm Infants.

OBJECTIVE: To determine whether a moderate-to-large patent ductus arteriosus (PDA) is responsible for vasopressor-dependent hypotension, occurring at the end of the first postnatal week. STUDY DESIGN: We performed a retrospective, double cohort controlled study of infants delivered at ≤27+6 weeks' gestation (n = 313). From January 2004 through April 2011, all infants were treated with prophylactic indomethacin ([PINDO] epoch). From May 2011 through December 2015, no infant was treated with indomethacin until at least 8 postnatal days (conservative epoch). Echocardiograms were performed on postnatal days 6 or 7. Hypotension was managed by a predefined protocol. The primary outcome was the incidence of dopamine-dependent hypotension, defined as having received at least 6 µg/kg/min dopamine for at least 24 hours during postnatal days 4-7. RESULTS: As expected, the incidence of moderate-to-large PDA at the end of the first week differed significantly between epochs (PINDO = 8%; conservative = 64%). In multivariate analyses, infants in the PINDO epoch had a significantly lower incidence of vasopressor-dependent hypotension (11%) than infants in the conservative epoch (21%; OR = 0.40, 95% CI 0.20-0.82). Infants in the PINDO epoch also required less mean airway pressure, had a lower respiratory severity score, and lower mode of ventilation score than infants in the conservative epoch during postnatal days 4-7. The effects of PINDO on both the incidence of vasopressor-dependent hypotension and the need for respiratory support were no longer significant when analyses were adjusted for "presence or absence of a moderate-to-large PDA." CONCLUSION: PINDO decreases vasopressor-dependent hypotension and the need for respiratory support at the end of the first postnatal week. These effects are mediated by closure of the PDA.

Antenatal Betamethasone: A Prolonged Time Interval from Administration to Delivery Is Associated with an Increased Incidence of Severe Intraventricular Hemorrhage in Infants Born before 28 Weeks Gestation.

OBJECTIVE: To examine the effects of antenatal steroids on severe intraventricular hemorrhage (IVH) in infants born during the IVH vulnerable period (<28 weeks gestational age) and to evaluate rates of IVH correlated with the time interval between treatment or retreatment and birth. STUDY DESIGN: A total of 429 infants (<28 weeks gestation), who delivered ≥24 hours after the first betamethasone (BMZ) course (2 doses), were divided into groups based on the interval between the first course of BMZ and delivery: <10 days or ≥10 days. The primary outcome was severe IVH. Multiple regression analyses were performed to adjust for potential confounders. RESULTS: Three hundred ninety-two infants delivered after a single BMZ course (312 delivered <10 days; 80 ≥10 days). The incidence of severe IVH was 17% for infants delivered ≥10 days and 7% for those delivered <10 days after a single BMZ course (aOR 4.16; 95% CI 1.59-10.87, P = .004); 37 infants (born ≥10 days from the first BMZ course) received a second/rescue BMZ course. The incidence of severe IVH among infants receiving a second/rescue course was 8%, which was similar to the incidence among infants born <10 days (aOR 1.7; 95% CI 0.41-6.6, P = .48). CONCLUSIONS: In infants born before 28 weeks gestation, delivery ≥10 days from the first BMZ course is associated with a higher incidence of severe IVH; a second/rescue course may reverse this effect.

Microarray gene expression analysis in ovine ductus arteriosus during fetal development and birth transition.

BACKGROUND: Patent ductus arteriosus (PDA) in the newborn is the most common congenital heart anomaly and is significantly more common in preterm infants. Contemporary pharmacological treatment is effective in only 70-80% of the cases. Moreover, indomethacin or ibuprofen, which are used to close a PDA may be accompanied by serious side effects in premature infants. To explore the novel molecular pathways, which may be involved in the maturation and closure of the ductus arteriosus (DA), we used fetal and neonatal sheep to test the hypothesis that maturational development of DA is associated with significant alterations in specific mRNA expression. METHODS: We conducted oligonucleotide microarray experiments on the isolated mRNA from DA and ascending aorta from three study groups (premature fetus-97 ± 0 d, near-term fetus-136 ± 0.8 d, and newborn lamb-12 ± 0 h). We compared the alterations in mRNA expression in DA and aorta to identify genes specifically involved in DA maturation. RESULTS: Results demonstrate significant changes in wingless-integrin1, thrombospondin 1, receptor activator of nuclear factor-kappa B, nitric oxide synthase, and retinoic acid receptor activation signaling pathways. CONCLUSION: We conclude that these pathways may play an important role during both development and postnatal DA closure and warrant further investigation.

Predicting the Need for Home Oxygen Therapy in Preterm Infants Born Before 28 Weeks' Gestation.

OBJECTIVE: To discover a predictor, that could be used at least 3 to 4 weeks' before discharge, to identify infants who would need home oxygen therapy. We hypothesized that infants requiring a high level of respiratory support at 34 weeks' postmenstrual age (PMA) would require home oxygen. STUDY DESIGN: Single center retrospective study of 143 infants less than 28 weeks' gestation. We determined when infants weaned from each level of respiratory support (mechanical ventilation, nasal continuous airway pressure [nCPAP] or biphasic positive pressure, nasal cannula flow ≥ 2 L/min, nasal cannula flow < 2 L/min or no respiratory support). Our primary outcome was need for home oxygen. RESULT: Infants who required nCPAP at 34 weeks' PMA had a 100% positive predictive value for home oxygen therapy. CONCLUSION: Higher levels of respiratory support at 34 weeks' PMA can predict the need for home oxygen and is useful in preparing patients and families for discharge.

Effects of Advancing Gestation and Non-Caucasian Race on Ductus Arteriosus Gene Expression.

OBJECTIVE: To identify genes affected by advancing gestation and racial/ethnic origin in human ductus arteriosus (DA). STUDY DESIGN: We collected 3 sets of DA tissue (n = 93, n = 89, n = 91; total = 273 fetuses) from second trimester pregnancies. We examined four genes, with DNA polymorphisms that distribute along racial lines, to identify "Caucasian" and "non-Caucasian" DA. We used real time polymerase chain reaction to measure RNA expression of 48 candidate genes involved in functional closure of the DA, and used multivariable regression analyses to examine the relationships between advancing gestation, "non-Caucasian" race, and gene expression. RESULTS: Mature gestation and non-Caucasian race are significant predictors for identifying infants who will close their patent DA when treated with indomethacin. Advancing gestation consistently altered gene expression in pathways involved with oxygen-induced constriction (eg, calcium-channels, potassium-channels, and endothelin signaling), contractile protein maturation, tissue remodeling, and prostaglandin and nitric oxide signaling in all 3 tissue sets. None of the pathways involved with oxygen-induced constriction appeared to be altered in "non-Caucasian" DA. Two genes, SLCO2A1 and NOS3, (involved with prostaglandin reuptake/metabolism and nitric oxide production, respectively) were consistently decreased in "non-Caucasian" DA. CONCLUSIONS: Prostaglandins and nitric oxide are the most important vasodilators opposing DA closure. Indomethacin inhibits prostaglandin production, but not nitric oxide production. Because decreased SLCO2A1 and NOS3 expression can lead to increased prostaglandin and decreased nitric oxide concentrations, we speculate that prostaglandin-mediated vasodilation may play a more dominant role in maintaining the "non-Caucasian" patent DA, making it more likely to close when inhibited by indomethacin.

Hypotension following patent ductus arteriosus ligation: the role of adrenal hormones.

OBJECTIVE: To test the hypothesis that an impaired adrenal response to stress might play a role in the hypotension that follows patent ductus arteriosus (PDA) ligation. STUDY DESIGN: We performed a multicenter study of infants born at <32 weeks' gestation who were about to undergo PDA ligation. Serum adrenal steroids were measured 3 times: before and after a cosyntropin (1.0 µg/kg) stimulation test (performed before the ligation), and at 10-12 hours after the ligation. A standardized approach for diagnosis and treatment of postoperative hypotension was followed at each site. A modified inotrope score (1 × dopamine [µg/kg/min] + 1 × dobutamine) was used to monitor the catecholamine support an infant received. Infants were considered to have catecholamine-resistant hypotension if their greatest inotrope score was >15. RESULTS: Of 95 infants enrolled, 43 (45%) developed hypotension and 14 (15%) developed catecholamine-resistant hypotension. Low postoperative cortisol levels were not associated with the overall incidence of hypotension after ligation. However, low cortisol levels were associated with the refractoriness of the hypotension to catecholamine treatment. In a multivariate analysis: the OR for developing catecholamine-resistant hypotension was OR 36.6, 95% CI 2.8-476, P = .006. Low cortisol levels (in infants with catecholamine-resistant hypotension) were not attributable to adrenal immaturity or impairment; their cortisol precursor concentrations were either low or unchanged, and their response to cosyntropin was similar to infants without catecholamine-resistant hypotension. CONCLUSION: Infants with low cortisol concentrations after PDA ligation are likely to develop postoperative catecholamine-resistant hypotension. We speculate that decreased adrenal stimulation, rather than an impaired adrenal response to stimulation, may account for the decreased production.

Prophylactic indomethacin and the risk of serious pulmonary hemorrhages in preterm infants less than 28 weeks' gestation.

OBJECTIVE: To determine if prophylactic indomethacin (PINDO) decreases serious pulmonary hemorrhages in infants <28 weeks. STUDY DESIGN: Intention-to-treat analysis of 615 consecutively admitted infants during four alternating protocol-driven epochs of PINDO or expectant patent ductus arteriosus (PDA) management. RESULTS: 41/615 (6.7%) developed serious pulmonary hemorrhage at 2 (1, 3) days (median (IQR)). In unadjusted and adjusted multivariable models, infants born in a PINDO epoch had significantly lower incidences of pulmonary hemorrhage and pulmonary hemorrhage or death before 7 days. There were less moderate/large PDA during PINDO epochs. The associations between PINDO and pulmonary hemorrhage and pulmonary hemorrhage/death were no longer significant when presence of a PDA was included in the analyses. There was no apparent association between PINDO epochs and the incidence of serious intraventricular hemorrhages. CONCLUSION: Even though PINDO no longer appears to affect the incidence of sIVH it still is associated with a lower incidence of pulmonary hemorrhage.

Dopamine-resistant hypotension and severe retinopathy of prematurity.

OBJECTIVE: To examine the relationship between the cause or severity of hypotension and the development of severe ROP (sROP) (≥stage 3 or stage 2 with plus disease in zone I or II). STUDY DESIGN: Infants (<28 weeks' gestation, n = 242) were observed for hypotension and treated with a standardized hypotension-treatment protocol. Hypotension was classified as resulting from one of the following causes: (1) culture-positive infection and/or necrotizing enterocolitis; (2) patent ductus arteriosus ligation; or (3) "idiopathic" (no cause identified other than prematurity), and as being either dopamine responsive or dopamine resistant. Cortisol levels were measured for infants with dopamine-resistant hypotension. Eye examinations were performed until the retinopathy of prematurity resolved or the vasculature matured. Multivariable logistic regression analysis was performed to determine the relationship between the cause/severity of hypotension and sROP. RESULTS: Overall, 66% of infants developed hypotension (41% were dopamine responsive and 25% were dopamine resistant). sROP developed in 19% of infants. "Idiopathic" dopamine-resistant hypotension was the only cause significantly related to sROP. Of the infants with dopamine-resistant hypotension, 66% had low serum cortisol (≤10 µg/dL). Low cortisol, in the presence of dopamine-resistant hypotension, was significantly associated with sROP and accounted for the relationship between "idiopathic" hypotension and sROP. When low cortisol was included in statistical models, other known risk factors, such as immature gestation, were no longer significantly related to sROP. CONCLUSION: Low cortisol, in the presence of dopamine-resistant hypotension, has the greatest magnitude of association with sROP.