What is the evidence?

See the evidence matrix in Epistemonikos below.

We found two systematic reviews [9-10], which included two primary studies [13],[14], both randomized trials.

This table and the summary are based on both trials.

What type of patients did the studies include? *

One trial [13] included 30 term infants diagnosed with neonatal hypoxic-ischemic encephalopathy.

The other study [14] included 25 preterm or term infants diagnosed with neonatal hypoxic-ischemic encephalopathy.

Exclusion criteria were not reported in either trial [13],[14].

What type of interventions did the studies include? *

Both trials [13],[14] compared melatonin and hypothermia therapy versus hypothermia monotherapy.

The doses of melatonin used in one trial [13] were 10 milligrams per kilogram of body weight per day by orogastric tube, completing five doses in total.

The doses of melatonin used in the other trial [14] were five milligrams per kilogram of body weight per day by the intravenous route, completing three doses in total.

Both trials [13],[14] used manual hypothermia controlled with ice packs for three days for both the intervention and control groups.

What type of outcomes were measured?

The trials reported multiple outcomes, which were grouped by the systematic reviews as follows:

• Mortality
• Normal neurological examination at six months.
• Neurodevelopment delay at six and 18 months.
• Seizures
• Alterations in brain magnetic resonance imaging.

The follow-up of one trial [13] was six months, while the follow-up of the other study [13] was 18 months.

About the levels of evidence (GRADE)*

⊕⊕⊕⊕ 
High: the research provides a very good indication of the likely effect. The probability that the effect is substantially different† is low.

⊕⊕⊕◯
Moderate: the research provides a good indication of the likely effect. The probability that the effect is substantially different† is moderate.

⊕⊕◯◯
Low: research provides some indication of the likely effect. However, the probability that the effect will be substantially different† is high.

⊕◯◯◯
Very low: research does not provide a reliable estimate of the likely effect. The probability that the effect is substantially different† is very high.

*This is also called 'quality of evidence' or 'confidence in the effect estimate'.
†Substantially different = a difference large enough to affect a decision.

To whom this evidence applies and to whom it does not apply

• The evidence presented applies to patients diagnosed with neonatal hypoxic-ischemic encephalopathy who have not received treatment for this pathology.

About the outcomes included in this summary

• Mortality, normal neurological examination at six months, and adequate neurodevelopment at 18 months were included as these are the most critical outcomes for patients and their caregivers, according to the authors of this review.
• The outcomes of seizures and brain magnetic resonance imaging alterations were evaluated, despite being secondary outcomes, since they are associated with worse response to treatment and worse neurological prognosis in the medium and long term.
• The outcomes included in the summary are those considered relevant for decision-making by the authors, coinciding with those reported by the systematic reviews.

Harm/benefit balance and certainty in evidence

• When comparing the benefits and risks between the two therapies, it is not possible to establish whether the combined treatment decreases mortality or the probability of presenting alterations reflected on brain magnetic resonance imaging because the certainty of the existing evidence has been evaluated as very low. In addition, melatonin use may increase the likelihood of normal neurologic examination at six months (low certainty of the evidence), normal cognition at 18 months (low certainty of the evidence), and probably decreases the likelihood of seizures (moderate certainty of the evidence).
• On the other hand, no adverse effects associated with the combination of both therapies are reported compared to hypothermia monotherapy.
• However, it is not possible to perform a correct harm/benefit balance analysis regarding the use of melatonin, given the current uncertainty in the evidence, so other aspects should be considered for decision-making.

Costs

• The included systematic reviews did not perform a cost-effectiveness analysis between the two treatments.
• Melatonin is a drug with low cost and wide availability. It is available in various presentations, including three, five, and 10-milligram tablets and in one milligram per milliliter solution for intravenous application.
• Therefore, a cost-effectiveness analysis of the two therapies is essential.

What do patients and their caregivers think

• Although many physicians favor combination therapy, uncertainty remains as to its potential superiority compared to hypothermia monotherapy.
• In addition, the ideal route of administration, dosage, and duration of melatonin treatment has not yet been studied or defined.
• Caregivers are likely to prefer melatonin addition over treatment with hypothermia alone as monotherapy, given the potential benefit of melatonin use, its low cost, and the absence of reports of adverse effects associated with its use.

Differences between this summary and other sources

• This summary's conclusions align with the two included systematic reviews [9-10] because, given the evidence's uncertainty, it is impossible to establish a treatment's superiority.
• When comparing with international clinical guidelines, it is noted that both the Japanese Society of Neonatology [11] and the Spanish Clinical Practice Guideline [12] state that there is controversy about the superiority of combination therapy compared to monotherapy. Consequently, further studies are needed, which can be extrapolated to the results of this review.

Could this information change in the future?

• The likelihood that future evidence will change the conclusions of this summary is high due to current uncertainty.
• We identified a systematic review on the PROSPERO platform comparing combination therapy with hypothermia monotherapy for neonatal hypoxic encephalopathy that may shed new light on the topic [19].
• Two trials were found on the National Institutes of Health (NIH) ClinicalTrials.gov platform comparing combination therapy versus hypothermia monotherapy for hypoxic neonatal encephalopathy [20-21]. Both studies are still in the recruitment phase and may shed new light on the topic once concluded.
• In addition, further studies evaluating the optimal dose and additive effects of melatonin over a longer time frame are needed because of its potential influence on neuromodulation following asphyxiation.