What impact does early/prophylactic indomethacin have on intraventricular hemorrhage (IVH) in extremely low birth weight (ELBW) infants? Does it have an impact on other outcomes including long term neurological development and complications of premature birth? What screening is recommended prior to or during treatment?

Comment by InpharmD Researcher

Prophylactic intravenous indomethacin in preterm infants, particularly very low birth weight (VLBW) and extremely low birth weight (ELBW) infants, reduces the incidence of symptomatic patent ductus arteriosus (PDA) and severe intraventricular hemorrhage (IVH) but may not improve survival or long-term neurodevelopmental outcomes. While it decreases the need for surgical PDA ligation, some studies suggest an association with transient renal side effects, such as oliguria or anuria, but without increasing risks of necrotizing enterocolitis or significant bleeding. Prolonged courses of indomethacin for PDA treatment do not appear to offer additional benefits over shorter regimens and may increase the risk of adverse effects. Therefore, short-term benefits may be seen, but there is a lack of evidence for improving survival or neurodevelopmental outcomes in preterm infants. Despite the general safe profile, consider screening the infants for risk of developing these adverse events, along with other precautions and contraindications outlined in the prescribing label.

Background

A 2010 Cochrane systematic review and meta-analysis examined the impact of prophylactic intravenous indomethacin on mortality and morbidity in preterm infants. The analysis included data from 19 randomized controlled trials involving 2,872 infants, most of whom were very low birth weight (VLBW). The largest individual study within the meta-analysis enrolled 1,202 extremely low birth weight (ELBW) infants. The intervention involved administering indomethacin within the first 24 hours of life, with dosing regimens varying across studies. Meta-analyses demonstrated that prophylactic indomethacin significantly reduced the incidence of symptomatic patent ductus arteriosus (PDA), the need for PDA surgical ligation, and the occurrence of severe intraventricular hemorrhage (IVH). However, no statistically significant effect was observed on mortality before hospital discharge (RR 0.82, 95% CI 0.65 to 1.03) or at the latest follow-up (RR 0.96, 95% CI 0.81 to 1.12). Additionally, long-term neurodevelopmental assessments, including cognitive and educational outcomes, revealed no protective benefit. Safety analyses showed an increased incidence of transient oliguria or anuria, but no significant risk of necrotizing enterocolitis, gastrointestinal perforation, or clinically significant bleeding. Given these findings, prophylactic indomethacin offers short-term benefits in reducing PDA and severe IVH but does not improve survival or long-term neurodevelopmental outcomes. [1]

A 2007 Cochrane systematic review analyzed five randomized controlled trials involving 431 preterm infants to determine the efficacy and safety of a prolonged versus short course of indomethacin for the treatment of PDA. Eligibility criteria included preterm infants diagnosed with PDA through clinical and/or echocardiographic assessment, and treatment regimens varied between four or more doses for the prolonged course and three or fewer doses for the short course. The primary outcome assessed was failure of PDA closure after completion of treatment, while secondary outcomes included the incidence of IVH. The results found no statistically significant difference between prolonged and short courses in terms of PDA closure failure (RR 0.82, 95% CI 0.51–1.33). The incidence of severe IVH did not differ significantly (RR 0.64; 95% CI 0.36 to 1.12). Given the increased risk of NEC without a clear benefit in PDA closure rates or long-term respiratory outcomes, the review concluded that a prolonged indomethacin regimen cannot be recommended for routine PDA management in preterm infants. [2]

Relevant Prescribing Information

Information from the prescribing label to consider when screening for or during treatment: [3]
Monitor for signs of hepatic reactions. Indomethacin for Injection may need to be discontinued.
Indomethacin for Injection may inhibit platelet aggregation
Monitor neonates for blood in stool due to gastrointestinal effects
Monitor neonates for intraventricular hemorrhage as indomethacin may inhibit platelet aggregation.
Monitor renal function and serum electrolytes.
Indomethacin is contraindicated in neonates with proven or suspected infection that is untreated, active bleeding, thrombocytopenia or coagulation defects, suspected of having necrotizing enterocolitis, significant renal function impairment, congenital heart disease in whom patency of the ductus arteriosus is necessary for satisfactory pulmonary or systemic blood flow.

Literature Review

A search of the published medical literature revealed 6 studies investigating the researchable question:

Level of evidence

B - One high-quality study or multiple studies with limitations Read more→

Please see Tables 1-6 for your response.

Effect of Prophylactic Indomethacin in Extremely Low Birth Weight Infants Based on Predicted Risk of Severe Intraventricular Hemorrhage
Design	Post-hoc analysis of the Trial of Indomethacin Prophylaxis in Preterms (TIPP) N= 1202
Objective	To determine if the relative treatment effects of prophylactic indomethacin on severe IVH and the composite outcome of death or NDI vary based on risk of severe IVH
Study Groups	Indomethacin group (n= 601) Placebo group (n= 601)
Inclusion Criteria	Preterm infants with birth weight between 500 and 999 grams
Exclusion Criteria	Infants with missing 5-minute Apgar score
Methods	Post-hoc analysis of TIPP trial data. Developed a predictive model for severe IVH risk using gestational age, birth weight, antenatal steroids, delivery mode, outborn status, sex, and 5-minute Apgar score. Participants divided into risk quartiles. Logistic regression used to determine adjusted Odds Ratios (aOR) for severe IVH and death or NDI based on indomethacin treatment for each quartile. While 1202 infants were included in the TIPP study, only 910 had adequate data for analysis. But this post-hoc analysis included all 1202 infants for analysis.
Duration	Not specified
Outcome Measures	Primary: Severe IVH Secondary: Composite outcome of death or NDI
Baseline Characteristics	Characteristic	Infants (n= 910)
	Birth weight, g (standard deviation [SD])	793 (127)
	Gestational age, weeks (SD)	26.2 (1.8)
	Female	456 (50%)
	Singleton birth	679 (75%)
Results	Outcome	Quartile 1	Quartile 2	Quartile 3	Quartile 4
	Severe IVH, aOR (95% CI)	0.68 (0.19 to 2.37)	0.61 (0.27 to 1.42)	0.63 (0.31 to 1.31)	0.58 (0.32 to 1.05)
	Death or NDI, aOR (95% CI)	Not significant	Not significant	Not significant	Not significant
Adverse Events	Not specified
Study Author Conclusions	These findings do not support selective prophylactic indomethacin treatment to improve long-term outcomes of ELBW infants at high risk for severe IVH.
Critique	The study provides valuable insights into the treatment effects of prophylactic indomethacin based on predicted risk of severe IVH. However, the post-hoc nature and lack of external validation for the predictive model may limit the generalizability of the findings. Additionally, the TIPP trial's age may affect its applicability to current clinical practices.

References:

[1] Foglia EE, Roberts RS, Stoller JZ, et al. Effect of Prophylactic Indomethacin in Extremely Low Birth Weight Infants Based on the Predicted Risk of Severe Intraventricular Hemorrhage. Neonatology. 2018;113(2):183-186. doi:10.1159/000485172
[2] Schmidt B, Asztalos EV, Roberts RS, et al. Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms. JAMA. 2003;289(9):1124-1129. doi:10.1001/jama.289.9.1124

Long-Term Effects of Indomethacin Prophylaxis in Extremely-Low-Birth-Weight Infants
Design	Randomized, double-blind, placebo-controlled trial N= 1202
Objective	To determine whether the prophylactic administration of indomethacin improves survival without neurosensory impairment in extremely-low-birth-weight infants
Study Groups	Indomethacin group (n= 601) Placebo group (n= 601)
Inclusion Criteria	Infants with birth weights of 500 to 999 g, at least two hours old
Exclusion Criteria	Unable to administer study drug within 6 hr of birth, structural heart disease or renal disease, dysmorphic features or congenital abnormalities, maternal tocolytic therapy with indomethacin within 72 hr before delivery, overt clinical bleeding, platelet count <50,000/mm3, hydrops, not considered viable, unlikely to be available for follow-up
Methods	Infants received either indomethacin (0.1 mg/kg) or placebo intravenously once daily for three days. The primary outcome was a composite of death, cerebral palsy, cognitive delay, deafness, and blindness at a corrected age of 18 months. Secondary outcomes included hydrocephalus, seizure disorder, microcephaly, patent ductus arteriosus, pulmonary hemorrhage, chronic lung disease, intracranial abnormalities, necrotizing enterocolitis, and retinopathy.
Duration	January 1996 to October 1997 (enrollment); follow-up at 18 months corrected age
Outcome Measures	Primary: Death or survival with neurosensory impairment at 18 months Secondary: Patent ductus arteriosus, incidence of intraventricular hemorrhage (IVH)
Baseline Characteristics	Characteristic	Indomethacin Group (n= 601)	Placebo Group (n= 601)
	Mothers' age, years	29 ± 7	29 ± 7
	Racial or ethnic background White Black Asian Other or unknown	414 (69%) 81 (13%) 31 (5%) 75 (12%)	404 (67%) 85 (14%) 42 (7%) 70 (12%)
	Birth weight, g	782 ± 131	783 ± 130
	Gestational age, weeks	25.9 ± 1.8	26.0 ± 1.9
	Female sex	292 (49%)	295 (49%)
Results	Outcome	Indomethacin Group	Placebo Group	p-value
	Death or impairment	271/574 (47%)	261/569 (46%)	0.61
	Patent ductus arteriosus	142/601 (24%)	301/601 (50%)	<0.001
	Severe periventricular or intraventricular hemorrhage	52/569 (9%)	75/567 (13%)	0.02
Adverse Events	No serious adverse effects on outcomes such as necrotizing enterocolitis or retinopathy were reported
Study Author Conclusions	Prophylaxis with indomethacin does not improve survival without neurosensory impairment at 18 months in extremely-low-birth-weight infants, despite reducing the frequency of patent ductus arteriosus and severe hemorrhage.
Critique	The study was well-designed with a large sample size and rigorous methodology, ensuring reliable results. However, the lack of long-term benefits despite short-term improvements raises questions about the clinical significance of indomethacin prophylaxis. The study's generalizability is enhanced by its broad inclusion criteria, but the findings may not apply to all settings due to variations in clinical practices and patient populations.

References:

Schmidt B, Davis P, Moddemann D, et al. Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants. N Engl J Med. 2001;344(26):1966-1972. doi:10.1056/NEJM200106283442602

Low-dose indomethacin therapy and extension of intraventricular hemorrhage: A multicenter randomized trial
Design	Prospective, randomized, placebo-controlled trial N= 61
Objective	To test the hypothesis that indomethacin would prevent extension of intraventricular hemorrhage in very low birth weight infants
Study Groups	Indomethacin (n= 27) Placebo (n= 34)
Inclusion Criteria	Neonates of 600 to 1250 gm birth weight with evidence of low-grade intraventricular hemorrhage at 6 to 11 hours of age
Exclusion Criteria	Not specified
Methods	Indomethacin (0.1 mg/kg) given intravenously at 6 to 12 postnatal hours and every 24 hours for two more doses. Saline placebo was administered to the control group. Cranial ultrasonography was used to define initial IVH status.
Duration	September 5, 1989, to August 31, 1992
Outcome Measures	Primary: Extension of intraventricular hemorrhage (IV) Secondary: Closure of patent ductus arteriosus, adverse events
Baseline Characteristics	Characteristic	Indomethacin (n= 27)	Placebo (n= 34)
	Birth weight, gm	600 to 1250	600 to 1250
Results	Outcome	Indomethacin (n= 27)	Placebo (n= 34)	p-value
	Extension of IVH	9	12	1.00
	Closure of PDA by day 5	2/24	14/30	0.003
Adverse Events	No significant differences in adverse events attributed to indomethacin treatment between the two groups, including abnormal creatinine, platelet, and urine output. Excessive bleeding occurred in 2 patients in the indomethacin group. There was no incidence of necrotizing enterocolitis.
Study Author Conclusions	Low-dose intravenous indomethacin therapy at 6 to 12 hours of age does not prevent extension of existing IVH in very low birth weight infants but promotes closure of the patent ductus arteriosus without significant adverse events
Critique	The sample size was relatively small, and the study did not specify exclusion criteria. Additionally, the study did not provide detailed baseline characteristics such as gestational age and sex, which are important for understanding the comparability of the study groups.

References:

Ment LR, Oh W, Ehrenkranz RA, et al. Low-dose indomethacin therapy and extension of intraventricular hemorrhage: a multicenter randomized trial. J Pediatr. 1994;124(6):951-955. doi:10.1016/s0022-3476(05)83191-9

Randomized Trial to Compare Renal Function and Ductal Response between Indomethacin and Ibuprofen Treatment in Extremely Low Birth Weight Infants
Design	Double-blind randomized control trial N= 144
Objective	To compare renal function and ductal response between indomethacin and ibuprofen in extremely low birth weight (ELBW) infants
Study Groups	Indomethacin (n= 73) Ibuprofen (n= 71)
Inclusion Criteria	Preterm infants with a birth weight <1,000 g; radiographic figure of respiratory distress syndrome; requirement for mechanical ventilation; echocardiography proven and clinically significant PDA
Exclusion Criteria	Evidence of infection or sepsis; lethal congenital anomalies; oliguria (<1 ml/kg/h) and/or serum creatinine >2.0 mg/dl; low platelet count (<50,000/mm3) or bleeding tendency
Methods	Infants were randomly assigned to receive indomethacin (0.2, 0.1, and 0.1 mg/kg IV every 24 h for 3 doses) or ibuprofen lysine (10, 5, and 5 mg/kg IV every 24 h for 3 doses). Renal function and ductal response were assessed using urine output, serum creatinine, and echocardiographic evaluations.
Duration	Not explicitly stated
Outcome Measures	Primary: Significant decrease in urine output Secondary: Intraventricular hemorrhage grade 2 or higher, ductal outcomes, bronchopulmonary dysplasia, necrotizing enterocolitis, retinopathy of prematurity
Baseline Characteristics	Characteristic	Indomethacin (n= 73)	Ibuprofen (n= 71)
	Birth weight, g	812 ± 160	801 ± 156
	Gestational age, weeks	26.3 ± 1.6	26.2 ± 1.7
	Sex (male/female)	38/35	35/36
	SGA/AGA	13/60	16/55
	Prenatal steroid	57 (78%)	53 (75%)
	Chorioamnionitis (clinical)	5 (7.5%)	7 (9.8%)
	Rupture of membrane (>24 h)	8 (10.7%)	7 (9.8%)
	Cesarean delivery	40 (55%)	36 (50.7%)
Results	Outcome	Indomethacin (n= 73)	Ibuprofen (n= 71)	Odds ratio (95% confidence interval [CI])	p-value
	Significant decrease in urine output	30 (41%)	15 (21%)	2.39 (1.15 to 4.95)	0.02
	Intraventricular hemorrhage	15 (21%)	16 (23%)	0.89 (0.40 to 1.97)	0.98
	Ductal response Complete closure Reduction in lumen size	55 (75%) 48 (66%) 7 (9%)	46 (65%) 41 (58%) 5 (7%)	1.77 (0.86 to 3.62) 1.41 (0.72 to 2.76) 1.4 (0.42 to 4.63)	0.15 0.39 0.76
	Bronchopulmonary dysplasia Mild Moderate Severe	51 (69%) 12 28 11	45 (63%) 14 21 10	0.75 (0.37 to 1.49)	0.48
	Necrotizing enterocolitis stage 2 or higher	3 (4.1%)	4 (5.6%)	0.72 (0.55 to 3.23)	0.72
	Retinopathy of prematurity I II III IV	27 (37%) 10 11 4 2	22 (31%) 8 9 4 1	1.31 (0.65 to 2.61)	0.48
Adverse Events	Significant decreases in urine output were more common in the indomethacin group (41% vs. 21%; p = 0.02). Indomethacin was associated with lower GFR and higher serum creatinine on days 1, 2, and 7
Study Author Conclusions	With the current dosage, ibuprofen had fewer renal side effects but was associated with a lower rate of persistent ductal closure in ELBW infants. The precise role of prostaglandin on renal tubular function in ELBW infants remains to be further investigated.
Critique	The study's limitations include the lack of an untreated control group and the potential need for dosage adjustments to optimize outcomes. Additionally, the study does not explore the long-term effects of these treatments on renal function.

References:

Lin YJ, Chen CM, Rehan VK, et al. Randomized Trial to Compare Renal Function and Ductal Response between Indomethacin and Ibuprofen Treatment in Extremely Low Birth Weight Infants. Neonatology. 2017;111(3):195-202. doi:10.1159/000450822

Oral indomethacin versus oral ibuprofen for treatment of patent ductus arteriosus: a randomised controlled study in very low-birthweight infants
Design	Randomized controlled study N= 32
Objective	To evaluate the efficacy of oral indomethacin (IDC) and ibuprofen (IB) for closing patent ductus arteriosus (PDA) in very-low birth weight (VLBW) infants with a gestational age of 24–32 weeks
Study Groups	Oral IDC (n= 17) Oral IB (n= 15)
Inclusion Criteria	Birth weight 500–1500 g, gestational age 24–32 weeks, postnatal age 1–30 days, hsPDA confirmed by echocardiography
Exclusion Criteria	Major congenital anomalies, life-threatening infection, hydrops fetalis, severe IVH, severe bleeding, urine output < 1.0 ml/kg/hr, impaired renal function, previous course of IDC or IB for PDA
Methods	Infants received three oral doses of either IDC or IB. IDC dose: 0.2 mg/kg, followed by two doses 12 and 24 hours later. IB dose: 10 mg/kg, followed by two doses at 24 and 48 hours of 5 mg/kg. Echocardiography was performed before and after treatment.
Duration	15 December 2013 to 31 May 2015
Outcome Measures	Primary: Complete closure of PDA Secondary: Incidence of intraventricular hemorrhage (IVH), underwent surgery for PDA ligation, moderate-to-severe bronchopulmonary dysplasia (BPD), underwent surgery for retinopathy of prematurity (ROP), periventricular leukomalacia
Baseline Characteristics	Characteristic	Oral IDC (n= 17)	Oral IB (n= 15)
	Median gestational age, wks (range)	28 (25-30)	29 (24-32)
	Median birthweight, g (range)	930 (510-1370)	950 (520-1360)
	Birthweight <1000 g (%)	9 (53)	8 (53)
	Small for gestational age (%)	1 (6)	4 (27)
	Gestational age <28 weeks (%)	4 (24)	3 (20)
	Male (%)	7 (41)	8 (53)
	Received dexamethasone in utero (%)	14 (82)	12 (80)
	Received MgSO4 in utero (%)	3 (18)	1 (7)
	Chorioamnionitis (%)	1 (6)	4 (27)
	Apgar score <7 at 5 min (%)	6 (35)	6 (40)
	Respiratory distress syndrome (%)	12 (71)	9 (60)
	Surfactant replacement (%)	8 (47)	9 (60)
	Median age, hrs, at first dose study treatment (range)	60 (23-504)	64 (24-332)
	Median size, mm, pre-treatment PDA (range)	2.7 (2-4)	2.6 (2-4)
	Median ratio left atrium: aorta (range)	1.50 (1.2-2.0)	1.45 (0.9-1.9)
Results	Endpoint	Oral IDC (n= 17)	Oral IB (n= 15)	p-value
	PDA closed/treated	11/17 (65)	4/15 (27)	0.03
	IVH grade 3 or higher	1 (6%)	2 (13%)	0.43
	Underwent surgery for PDA lication	3 (18%)	7 (47%)	0.08
	Moderate-to-severe bronchopulmonary dysplasia (BPD)	5 (29%)	7 (47%)	0.07
	Underwent surgery for retinopathy of prematurity (ROP)	4 (24%)	1 (7%)	0.74
	Periventricular leukomalacia	2 (12%)	2 (13%)	0.84
Adverse Events	No significant difference between the drugs in clinical and laboratory measures of adverse effects, nor of other clinical outcomes
Study Author Conclusions	Oral IDC was more effective than oral IB for closing PDA in VLBW infants, without significant differences in side-effects or short-term outcomes.
Critique	The study was limited by its small sample size and early termination due to the introduction of IV IDC. The findings may not be generalizable to all VLBW infants due to the specific inclusion criteria and the small number of participants.

References:

Khuwuthyakorn V, Jatuwattana C, Silvilairat S, Tantiprapha W. Oral indomethacin versus oral ibuprofen for treatment of patent ductus arteriosus: a randomised controlled study in very low-birthweight infants. Paediatr Int Child Health. 2018;38(3):187-192. doi:10.1080/20469047.2018.1483566

Effects of Prophylactic Indomethacin in Extremely Low Birth Weight Infants With and Without Adequate Exposure to Antenatal Steroids
Design	Post-hoc analysis of the Trial of Indomethacin Prophylaxis in Preterms (TIPP) N= 1136
Objective	To examine if antenatal steroids modify the immediate and long-term effects of prophylactic indomethacin in extremely low birth weight infants (ELBW)
Study Groups	Adequate Antenatal Steroids (n= 635) Inadequate Antenatal Steroids (n= 501)
Inclusion Criteria	Infants with birth weights of 500 to 999 g
Exclusion Criteria	Strong suspicion or diagnosis of renal or structural heart disease, maternal tocolytic therapy with indomethacin or other prostaglandin inhibitor within 72 hours of delivery, overt bleeding at more than one site, hydrops
Methods	In the original study, eligible patients were randomized to receive either intravenous indomethacin 0.1 mg or normal saline every 24 hours for three doses or normal saline. Data on antenatal steroid exposure were collected from the participants. In the present post-hoc analysis, participants from the parent study were stratified based on adequate or inadequate exposure to antenatal steroids. Adequate exposure was defined as any exposure to antenatal steroids that occurred at least 24 hours before delivery.
Duration	January 1996 to March 1998
Outcome Measures	Primary: composite outcome at 18 months of death, cerebral palsy, cognitive delay, deafness, and blindness Secondary: patent ductus arteriosus (PDA), surgical closure of a PDA, and severe (grades 3 and 4) periventricular and intraventricular hemorrhages (PIVH)
Baseline Characteristics		Adequate (n= 635)	Inadequate (n= 501)
	Infants
	Gestational Age, weeks	26.1 (1.9)	25.7 (1.8)
	Female	319 (50.2%)	237 (47.3%)
	Birth weight, grams	785 (131)	773 (130)
	Birth weight <10th percentile	151 (23.8%)	86 (17.2%)
	Inborn	632 (99.5%)	464 (92.6%)
	Apgar score at 5 min, median (IQR)	8 (7–9)	7 (6–8)
	Mothers
	Age, years	29.0 (6.8)	28.7 (7.1)
	White	462 (73.0%)	318 (64.6%)
	Preeclampsia or Eclampsia	112 (17.6%)	64 (12.8%)
	Tocolysis	142 (22.4%)	70 (14.0%)
	IQR= Interquartile range
Results	Endpoint	Antenatal Steroid Exposure	Indomethacin	Placebo	OR (95% CI)	p-value
	Death or impairment	Adequate	145 (45.5%)	127 (40.2%)	1.24 (0.90-1.70)	0.13
	Death or impairment	Inadequate	123 (49.2%)	133 (53%)	0.86 (0.61-1.22)	-
	Death	Adequate	60 (18.1%)	45 (13.6%)	1.40 (0.92-2.14)	0.22
	Death	Inadequate	64 (24.8%)	66 (25.3%)	0.97 (0.66-1.45)	-
	Cerebral Palsy	Adequate	37 (13.7%)	31 (11.0%)	1.28 (0.77-2.13)	0.23
	Cerebral Palsy	Inadequate	19 (9.8%)	24 (12.4%)	0.77 (0.41-1.46)	-
	Cognitive Delay	Adequate	68 (26.5%)	62 (23.0%)	1.20 (0.81-1.78)	0.34
	Cognitive Delay	Inadequate	49 (26.8%)	54 (29.0%)	0.89 (0.57-1.41)	-
	Severe PIVH	Adequate	21 (6.5%)	28 (8.7%)	0.73 (0.41-1.32)	0.62
	Severe PIVH	Inadequate	31 (12.7%)	47 (19.3%)	0.60 (0.37-0.99)	-
	PDA	Adequate	72 (21.5%)	157 (46.9%)	0.31 (0.22-0.43)	0.89
	PDA	Inadequate	69 (26.4%)	144 (54.5%)	0.30 (0.21-0.43)	-
	Surgical closure of PDA	Adequate	21 (6.3%)	40 (11.9%)	0.49 (0.28-0.86)	0.97
	Surgical closure of PDA	Inadequate	18 (6.9%)	34 (12.9%)	0.50 (0.28-0.91)	-
	OR= Odds Ratio, CI= Confidence Interval
Adverse Events	Not disclosed
Study Author Conclusions	There is little evidence that the effects of prophylactic indomethacin vary in ELBW infants with and without adequate exposure to antenatal steroids.
InpharmD Researcher Critique	Patients with inadequate exposure to antenatal steroids had a statistically significantly lower risk of severe PIVH with prophylactic indomethacin. However, the results are limited by the post-hoc nature of this analysis. Future studies are needed to determine if prophylactic indomethacin provides more benefit in patients with inadequate exposure to antenatal steroids.

References:

Schmidt B, Seshia M, Shankaran S, et al. Effects of prophylactic indomethacin in extremely low-birth-weight infants with and without adequate exposure to antenatal corticosteroids. Arch Pediatr Adolesc Med. 2011;165(7):642-646. doi:10.1001/archpediatrics.2011.95