What evidence supports use of caffeine therapy beyond term-equivalent age in preterm infants who remain hospitalized in the NICU?

Is there any data to support late caffeine use in the NICU past term corrected?

Comment by InpharmD Researcher

There is very limited literature evaluating outcomes of late caffeine administration past term-corrected age, as much of the literature evaluates prematurity in terms of gestational age. In critically ill preterm neonates, published literature has indicated that early caffeine administration (within the first 2 days of life) is associated with reduced morbidity due to apnea of prematurity, especially with significantly lower rates of respiratory outcomes like bronchopulmonary dysplasia. However, early caffeine administration has also been associated with higher mortality rates vs late caffeine administration (after the third day of life). As a result, applicability of these findings specifically past term-corrected age is uncertain, and evidence with larger sample sizes are required to substantiate these claims.

A literature review identified 1 tertiary and 4 primary studies relevant to this inquiry.

Background

A 2024 systematic review and meta-analysis examined the effects of early versus late caffeine administration on preterm neonates. This analysis incorporated data from 11 studies, including 2 randomized controlled trials, encompassing a total of 122,579 preterm infants. This study aimed to determine the optimal timing for caffeine therapy by comparing outcomes when caffeine was introduced within the first 2 days of life (early administration) versus after 3 days (late administration). Among the included preterm infants, 63.9% received early caffeine and 36.1% received late caffeine. The outcomes assessed included mortality, bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), patent ductus arteriosus (PDA), late-onset sepsis, and length of hospital stay. Early caffeine administration was associated with significantly lower odds of developing BPD (OR 0.70, 95% CI 0.60 to 0.81), IVH (OR 0.86, 95% CI 0.82 to 0.90), ROP (OR 0.80, 95% CI 0.74 to 0.86), PDA (OR 0.60, 95% CI 0.47 to 0.78), and late-onset sepsis (OR 0.84, 95% CI 0.79 to 0.89), with all p-values indicating strong statistical significance. However, early caffeine therapy was linked to a higher mortality rate, with an odds ratio of 1.20, raising considerations about potential survival bias in observational studies. Despite this, early caffeine usage correlated with a reduced length of hospital stay by approximately 11.2 days. The authors concluded that while early caffeine administration offers several neonatal benefits, further randomized trials are warranted to address the increased mortality risk and determine the most effective strategy for caffeine initiation in preterm infants. [1]

Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

Is there any data to support late caffeine use in the NICU past term corrected?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-4 for your response.

Effectiveness and safety of early versus late caffeine therapy in managing apnoea of prematurity among preterm infants: a retrospective cohort study
Design	Retrospective, multicenter, matched cohort study at 2 level III neonatal intensive care units (NICUs) in Malaysia N= 190
Objective	To compare the effectiveness and safety of early versus late caffeine therapy on preterm infants’ clinical outcomes
Study Groups	Early caffeine therapy (n= 95) Late caffeine therapy (n= 95)
Inclusion Criteria	Preterm infants born at less than 37 weeks gestational age and admitted to an NICU within 24 hours of life
Exclusion Criteria	Infants with major congenital malformations, treated with an inappropriate caffeine dosing regimen, and with missing data while on caffeine therapy
Methods	Data were collected from electronic medical records of 2 tertiary care hospital NICUs. Infants were divided into early caffeine therapy (initiation within 2 days of life) and late caffeine therapy (initiation ≥ 3 days of life). Outcomes measured included bronchopulmonary dysplasia (BPD), ventilation days, length of hospital stay, average weight gain, osteopenia of prematurity, death, duration to reach full enteral feeding, and necrotizing enterocolitis. Data was extracted until death or NICU discharge. Propensity score matching (1:1) based on gestational age was used to minimize the impact of baseline characteristic differences between groups on outcomes.
Duration	January 2016 to December 2018
Outcome Measures	Primary: Duration of non-invasive mechanical ventilation, length of hospital stay, duration to achieve full enteral feeding, frequency of BPD Secondary: Risk of osteopenia of prematurity, mortality risk
Baseline Characteristics		Early caffeine (n= 95)	Late caffeine (n= 95)
	Mean gestational age, weeks	31.23 ± 2.30	30.61 ± 2.14
	Mean birth weight, g	1.53 ± 0.40	1.33 ± 0.38
	Gender - Male, n (%)	52 (54.7%)	45 (47.4%)
	Mean Apgar score - 1 min	7.200 ± 2.31	7.096 ± 2.47
	Mean Apgar score - 5 min	10 (8–10)	10 (9–10)
	Mode of delivery - Spontaneous vaginal delivery, n (%)	26 (27.4%)	36 (37.9%)
	Mode of delivery - Caesarean section, n (%)	69 (72.6%)	59 (62.1%)
	Small for gestational age, n (%)	10 (10.5%)	10 (10.5%)
	Antenatal steroid therapy, n (%)	94 (98.9%)	61 (64.2%)
	Intubation on day 1 of life, n (%)	61 (64.2%)	67 (70.5%)
	Surfactant therapy, n (%)*	42 (44.2%)	57 (60.0%)
	Median postnatal age when caffeine initiated, days*	1 (0)	13 (10–16)
	Median duration of caffeine therapy, days	13 (8–24)	16 (7–28)
	Median caffeine cumulative dose, mg/kg*	85 (55–172.5)	160 (70–280)
	Total parenteral nutrition (TPN) therapy, n (%)*	30 (31.6%)	62 (65.3%)
	Median TPN duration, days	10 (13.3)	11 (9–15)
	*p<0.05 at baseline
Results		Early caffeine (n= 89)	Late caffeine (n= 93)	p-value
	Median duration of non-invasive mechanical ventilation, days	5 (3–11.7)	12 (6.5–43)	<0.001
	Median length of hospital stay, days	26 (17–41.5)	44 (35–78.5)	<0.001
	Median duration to full enteral feeding, days	5 (3–7)	11 (9–14)	<0.001
	Frequency of BPD, n (%)	4 (4.5%)	12 (12.9%)	0.045
	Risk of osteopenia of prematurity, n (%)	7 (7.9%)	27 (29%)	<0.001
	Mortality risk, n (%)	6 (6.3%)	2 (2.1%)	0.279
Adverse Events	Preterm infants treated with late caffeine therapy were more likely to be diagnosed with osteopenia of prematurity (29% vs. 7.9%, p<0.001). The proportions of necrotizing enterocolitis and tachycardia secondary to caffeine use between groups were identical (p= 1).
Study Author Conclusions	Early oral caffeine therapy can potentially improve respiratory outcomes among infants with apnea of prematurity. However, an increase in mortality associated with early caffeine therapy requires further investigation.
Critique	The study provided valuable insights into the potential benefits of early caffeine therapy in improving respiratory outcomes and reducing hospital stay duration. However, the retrospective design and lack of randomization may introduce bias. The study did not account for all potential confounding factors, such as infants' comorbidities, significantly different factors at baseline, and concurrent drug therapies (including surfactant therapy), which could affect the outcomes observed. Further randomized controlled trials are needed to confirm the safety and efficacy of early caffeine therapy in preterm infants with apnea of prematurity.

References:
[1] [1] Yun WZ, Kassab YW, Yao LM, Khairuddin N, Ming LC, Hadi MA. Effectiveness and safety of early versus late caffeine therapy in managing apnoea of prematurity among preterm infants: a retrospective cohort study. Int J Clin Pharm. 2022;44(5):1140-1148. doi:10.1007/s11096-022-01437-0

Early Vs Late Caffeine Therapy in Preterm Infants: Analysis of Clinical Outcome
Design	Prospective, single-center, comparative study in a neonatal intensive care unit (NICU) in Pakistan N= 40
Objective	To study clinical outcome of early versus late caffeine therapy in preterm infants
Study Groups	Early caffeine group (n= 20) Late caffeine group (n= 20)
Inclusion Criteria	Preterm infants with gestational age <32 weeks and birth weight <1500 grams
Exclusion Criteria	Infants with major congenital anomalies or requiring emergent endotracheal intubation immediately after birth
Methods	Infants were randomly assigned 1:1 to receive either early caffeine (initiated before 3rd day of life) or late caffeine (initiated after 3rd day of life). Early caffeine regimen: loading dose of 20mg/kg intravenously on the first or second day of life, maintenance dose of 5mg/kg intravenously once daily thereafter. Late caffeine regimen: same dosage initiated between 3rd and 7th day of life. Caffeine therapy was continued for 34 weeks.
Duration	January 2018 to July 2018
Outcome Measures	Primary: Duration of NICU stay Secondary: Need of mechanical ventilation, development of Respiratory Distress Syndrome (RDS)
Baseline Characteristics		Early Caffeine Group (n=20)	Late Caffeine Group (n=20)	p-value
	Mean gestational age, weeks	29.84 ± 1.16	29.96 ± 1.23	0.735
	Male sex, n (%)	11 (55%)	13 (65%)	0.748
	Mean birth weight, grams	1149.35 ± 373.84	1181.25 ± 259.75	0.756
	Mode of Delivery - Vaginal Delivery, n (%)	11 (55%)	9 (45%)	0.752
	Mode of Delivery - Cesarean Section, n (%)	9 (45%)	11 (55%)	0.752
	Surfactant, n (%)	13 (65%)	16 (80%)	0.480
Results		Early Caffeine Group (n=20)	Late Caffeine Group (n=20)	p-value
	Mean hospital stay, days	22.25 ± 12.64	35.95 ± 22.06	0.021
	Mechanical ventilation, n (%)	14 (70%)	16 (80%)	0.716
	RDS, n (%)	14 (70%)	16 (80%)	0.716
Adverse Events	No specific adverse events reported.
Study Author Conclusions	Early caffeine therapy in preterm infants is associated with decreased duration of NICU stay. Further work is needed to establish its efficacy and safety.
Critique	The study was limited by its small sample size and single-center design, which may affect the generalizability of the findings. The lack of significant differences in some outcomes could be due to the small sample size. Future studies should include larger, multi-center trials to better assess the efficacy and safety of early caffeine therapy in preterm infants.

References:
[1] Niaz H, Jalil J, Adil M, et al. Early vs Late Caffeine Therapy in Preterm Infants: Analysis of Clinical Outcome. Pak Armed Forces Med J. 2021;71(2):503-06.

Early Caffeine Administration and Neurodevelopmental Outcomes in Preterm Infants
Design	Retrospective observational, multicenter, cohort study in Canada N= 2,108
Objective	To determine the association between early (within 2 days of birth) versus late caffeine exposure and neurodevelopmental outcomes in preterm infants
Study Groups	Early-caffeine group (n= 1,545) Late-caffeine group (n= 563)
Inclusion Criteria	Infants of <29 weeks’ gestation born between April 2009 and September 2011, admitted to Canadian Neonatal Network units, and assessed at Canadian Neonatal Follow-up Network centers
Exclusion Criteria	Infants who were moribund at birth, had major congenital anomalies, or died before day 3 of life
Methods	Infants were divided into early-caffeine (received within 2 days of birth) and late-caffeine (received after 2 days of birth) groups. The primary outcome was significant neurodevelopmental impairment at 18 to 24 months’ corrected age. Data were collected from the CNN database. Usual practice involved a 10 mg/kg loading dose of caffeine base with a maintenance dose of 2.5 to 5 mg/kg per day.
Duration	April 2009 to September 2011
Outcome Measures	Primary: Significant neurodevelopmental impairment Secondary: Odds of Bayley Scales of Infant and Toddler Development cognitive scores of <85, cerebral palsy, hearing impairment
Baseline Characteristics		Early-Caffeine Group (n= 1,545)	Late-Caffeine Group (n= 563)
	Maternal ethnicity - White	67.6%	68.9%
	Median gestational age, weeks (IQR)	27 (26–28)	26 (25–27)
	Median birth weight, grams (IQR)	950 (790–1110)	850 (700–1040)
	Median Apgar score at 5 min (IQR)	7 (6–8)	7 (5–8)
	Median SNAP-II score (IQR)	12 (7–18)	16 (9–29)
Results		Early-Caffeine Group (n= 1,545)	Late-Caffeine Group (n= 563)	aOR (95% CI)
	sNDI	14.9%	21.2%	0.68 (0.50–0.94)
	NDI	48.1%	54.7%	0.86 (0.67–1.11)
	CP	3.9%	7.9%	N/A
	Hearing impairment	6.8%	10.5%	N/A
	Bayley-III cognitive composite score <85	13.4%	17.6%	0.67 (0.47–0.95)
Adverse Events	No specific adverse events related to caffeine therapy were reported in the study.
Study Author Conclusions	Early caffeine therapy is associated with better neurodevelopmental outcomes compared with late caffeine therapy in preterm infants born at <29 weeks’ gestation.
Critique	The study's strengths include its large sample size and multicenter design, which enhance the generalizability of the findings. However, the retrospective nature and lack of detailed caffeine dosage information are limitations. Additionally, the study could not adjust for all potential confounders, and there was a higher rate of attrition bias due to loss to follow-up.

References:
[1] [1] Lodha A, Entz R, Synnes A, et al. Early Caffeine Administration and Neurodevelopmental Outcomes in Preterm Infants. Pediatrics. 2019;143(1):e20181348. doi:10.1542/peds.2018-1348

A Pilot Randomized Controlled Trial of Early versus Routine Caffeine in Extremely Premature Infants
Design	Prospective, double-blinded, randomized, placebo-controlled, pilot study N= 21
Objective	To compare the effects of early and late (routine) initiation of caffeine in nonintubated preterm neonates
Study Groups	Early caffeine (n= 11) Routine caffeine (n= 10)
Inclusion Criteria	Any newborn delivered between 23 and 28 and 6/7 weeks gestational age (GA) by best obstetric estimates
Exclusion Criteria	Major congenital anomaly including airway anomalies, congenital diaphragmatic hernia, or hydrops; known or discovered major cardiac defect other than patent ductus arteriosus (PDA), patent foramen ovale (PFO), or small ventricular septal defect; inability to have a peripheral or central catheter placed within the first 60 minutes of age; severe apnea or bradycardia in the first 10 minutes of age requiring emergent endotracheal intubation
Methods	Eligible neonates were randomly assigned to receive intravenous caffeine citrate 20 mg/kg infused over 15 minutes within the first 2 hours of age and then placebo at 12 hours of age (early caffeine group), or placebo in the first 2 hours of age and intravenous caffeine 20 mg/kg at 12 hours of age (routine caffeine group). A single blood sample was obtained at 13 hours of age for caffeine serum concentration measurement.
Duration	September 2013 to May 2014
Outcome Measures	Primary: Need for endotracheal intubation by 12 hours of age Secondary: Cerebral oxygenation, systemic and pulmonary blood flow, hemodynamics, hypotension treatment, oxygen requirement, head ultrasound findings
Baseline Characteristics		Early (n= 11)	Routine (n= 10)
	Mean maternal age, years	33 ± 2	30 ± 2
	Mean gravida/para	4 ± 3	3 ± 1
	Mean gestational age, weeks	27 ± 0.9	27 ± 0.9
	Mean birth weight, g	1,007 ± 169	1,005 ± 239
	Female (%)	6 (54)	5 (50)
Results		Early (n= 11)	Routine (n= 10)	p-value
	Required intubation by 12 h	3 (27%)	7 (70%)	0.08
	Required inotropes by 24 h	0	2 (20%)	0.21
	Superior vena cava flow, mL/kg/min	101 ± 25	77 ± 24	0.04
	Right ventricular output, mL/kg/min	273 ± 62	219 ± 43	0.03
Adverse Events	Cerebral oxygenation transiently decreased 1 hour after caffeine administration.
Study Author Conclusions	This pilot study demonstrated the feasibility of conducting such a trial in extremely preterm neonates. Early caffeine administration was associated with improved hemodynamics. Larger studies are needed to determine whether early caffeine reduces intubation, intraventricular hemorrhage, and related long-term outcomes.
Critique	The study was a well-designed pilot trial that demonstrated feasibility and provided insights into the potential benefits of early caffeine administration. However, it was underpowered to detect significant differences in intubation rates, and the small sample size limits the generalizability of the findings. Further research with larger sample sizes is needed to confirm these results and explore long-term outcomes.

References:
[1] Katheria AC, Sauberan JB, Akotia D, Rich W, Durham J, Finer NN. A Pilot Randomized Controlled Trial of Early versus Routine Caffeine in Extremely Premature Infants. Am J Perinatol. 2015;32(9):879-886. doi:10.1055/s-0034-1543981