Two Seizure Medicines for Newborns: Which One, and Why It Matters

A large 2026 review compared the two main drugs used to stop seizures in newborn babies — and found they work about equally well, but one is gentler

When a newborn baby has a seizure, it is frightening for everyone — the family and the medical team alike. A new research review published in 2026 pulled together 26 earlier studies, covering nearly 10,000 babies, to answer a question that has lingered for decades: of the two medicines doctors most often reach for first, which is the better choice? The short answer is reassuring and practical. Both medicines stop seizures about equally well, but one of them — levetiracetam — tends to cause fewer dangerous side effects than the older standard, phenobarbital. This article explains what that means for babies and their families.

Why Seizures in Newborns Are Such a Big Deal

A seizure is a burst of abnormal electrical activity in the brain. In newborns, seizures are one of the most common brain emergencies, happening in roughly one to four out of every 1,000 births, and more often in babies born early [1]. They are almost never "just" a seizure — they are usually a sign that something has stressed the brain, such as a shortage of oxygen around the time of birth, bleeding, infection, or a chemical imbalance. When seizures keep happening or last a long time, they can add to the risk of later difficulties with learning and movement, which is why doctors treat them quickly [2]. Stopping the seizures fast, and safely, is the goal.

The Problem With the Old Standard

For more than fifty years, the first medicine given to a seizing newborn has almost always been phenobarbital. It became the standard mostly because it was cheap, widely available, and familiar — not because it was proven to be the best [3]. And it has real shortcomings. A landmark study back in 1999 showed that a first dose of phenobarbital stops seizures in only about half of babies [4]. There is a second, subtler problem: phenobarbital can make the visible shaking stop while the abnormal electrical storm continues silently in the brain, where only a brain-wave monitor (an EEG) can detect it [5]. On top of that, phenobarbital can lower a baby's blood pressure, slow their breathing, and make them very drowsy — serious concerns in already-fragile newborns [6].

Because of these drawbacks, doctors began turning to a newer medicine called levetiracetam. It can be given through a vein, has few interactions with other drugs, and does not seem to depress blood pressure or breathing the way phenobarbital does [7]. Over time it moved from being a "backup" medicine to a first choice in many neonatal intensive care units. But the picture was not simple: one carefully designed trial found that phenobarbital actually stopped seizures somewhat better than levetiracetam when used first, even though levetiracetam caused fewer side effects [8]. Families and doctors were left without a clear answer, and earlier attempts to combine the evidence were too small to settle it [9].

What the New Review Did

To get a clearer picture, researchers gathered every comparison study they could find — published up to September 2025 — in which newborns were given either levetiracetam or phenobarbital as their first seizure medicine [10]. They combined 26 studies (13 of them randomized trials, the most rigorous kind, and 13 that followed babies treated in routine care) into one large analysis covering 9,854 babies. Combining studies this way gives a more reliable answer than any single small study could.

What They Found

The findings come down to three clear points.

First, the two medicines stop seizures about equally well. When the researchers pooled all the studies, there was no meaningful difference between levetiracetam and phenobarbital in how often a baby's seizures came under control [10]. In plain terms, choosing one over the other is unlikely to mean more or fewer seizures.

Second, levetiracetam causes fewer serious side effects. Babies given phenobarbital were roughly three times more likely to have a side effect overall. In particular, dangerously low blood pressure was much more common with phenobarbital, and slowed breathing was also more common with it [10]. For a tiny, sick baby, avoiding a drop in blood pressure or a breathing problem is genuinely important — it can mean avoiding a breathing tube or extra medicines to support the heart.

Third, the medicines were equally safe when it came to survival. The risk of death was the same with both drugs [10]. So because they work equally well and carry the same survival outcomes, the decision can reasonably come down to which medicine is gentler for a particular baby.

It helps to understand why side effects matter so much in this setting. A newborn in intensive care, especially one born early or one who had a difficult birth, is often already working hard to keep blood pressure and breathing stable. A medicine that lowers blood pressure or slows breathing can tip a fragile baby over the edge — sometimes leading to a breathing tube, a ventilator, or extra drugs to support the heart [2]. So a medicine that controls seizures without adding those stresses is genuinely valuable, even if it does not stop seizures any better. That is the heart of why this review's safety finding is encouraging: it points to a way to treat the seizures while leaving the rest of the baby's delicate balance undisturbed.

It also helps to know how doctors actually tell whether the medicine is working. Because seizures in newborns can continue silently in the brain even after the visible movements stop, the most reliable way to check is a brain-wave monitor (EEG) attached to the baby's scalp [5]. Many NICUs use a simplified, continuous version of this monitor. If your baby is on seizure medicine, you may see these soft sensors on their head — they are painless, and they let the team see what the medicine is doing beneath the surface rather than guessing from the outside. Asking the team whether your baby is being monitored this way, and what the monitor is showing, is a perfectly reasonable question.

What This Means for Families

If your baby is in the NICU and the team chooses levetiracetam, this review helps explain why: it appears to be just as effective at stopping seizures while being easier on a baby's blood pressure and breathing, which is especially valuable for the most fragile infants [2]. If the team chooses phenobarbital, that is also a reasonable, guideline-supported choice — it is a long-trusted medicine, and doctors know it well. Either way, the most important things are that the seizures are treated quickly, that the baby is closely monitored (ideally with a brain-wave monitor), and that the team looks for and treats the underlying cause.

It is also fair to know the limits of this research. The babies in these studies were quite different from one another — some born early, some at term, with different causes for their seizures — and the medicines were not always given at perfectly matched doses, which makes the comparison less than perfect [10]. The researchers were confident about the safety advantage of levetiracetam, but less certain about fine differences in how well each drug works, and they were especially cautious about long-term effects on development, where good information is still thin [11]. This is an honest, important caveat, not a reason for alarm.

If you are a parent in this situation, a few questions can help you take part in the decision: What is causing my baby's seizures, and is that cause being treated? Which medicine are you using first, and why that one for my baby? Is my baby being watched with a brain-wave monitor, and is it showing that the seizures have stopped? What is the plan if the first medicine does not work? None of these questions second-guesses the team — they simply help you understand a fast-moving situation. Newborn seizures are frightening, but they are common, treatable, and well understood, and the team caring for your baby makes these decisions routinely [10]. The decades-long search for better treatments [4] is precisely why a baby today has safer options than a baby a generation ago.

What Researchers Are Working On Next

The big unanswered question is no longer just "which medicine stops more seizures," but "which medicine best protects a baby's developing brain over the months and years that follow." Answering that will take new, carefully designed trials that use brain-wave monitoring to confirm seizures, match the doses fairly, and follow children well past their first birthday to track their development [10]. Researchers are also testing entirely new types of seizure medicines for newborns that work in different ways [12]. For now, families can take comfort in a solid, practical conclusion: there are two good options for treating newborn seizures, both work, and doctors can choose the one that is safest for each individual baby.

References

  1. Glass HC, Pham TN, Danielsen B, Towner D, Glidden D, Wu YW. Antenatal and intrapartum risk factors for seizures in term newborns: a population-based study, California 1998–2002. J Pediatr. 2009;154(1):24–28. doi:10.1016/j.jpeds.2008.07.008 ↩
  2. Pisani F, Spagnoli C, Falsaperla R, Nagarajan L, Ramantani G. Seizures in the neonate: a review of etiologies and outcomes. Seizure. 2021;85:48–56. doi:10.1016/j.seizure.2020.12.023 ↩
  3. Glass HC, Kan J, Bonifacio SL, Ferriero DM. Neonatal seizures: treatment practices among term and preterm infants. Pediatr Neurol. 2012;46(2):111–115. doi:10.1016/j.pediatrneurol.2011.11.006 ↩
  4. Painter MJ, Scher MS, Stein AD, et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med. 1999;341(7):485–489. doi:10.1056/NEJM199908123410704 ↩
  5. Scher MS, Alvin J, Gaus L, Minnigh B, Painter MJ. Uncoupling of EEG-clinical neonatal seizures after antiepileptic drug use. Pediatr Neurol. 2003;28(4):277–280. doi:10.1016/S0887-8994(02)00621-500621-5) ↩
  6. El-Dib M, Soul JS. The use of phenobarbital and other anti-seizure drugs in newborns. Semin Fetal Neonatal Med. 2017;22(5):321–327. doi:10.1016/j.siny.2017.07.008 ↩
  7. McHugh DC, Lancaster S, Manganas LN. A systematic review of the efficacy of levetiracetam in neonatal seizures. Neuropediatrics. 2018;49(1):12–17. doi:10.1055/s-0037-1608653 ↩
  8. Sharpe C, Reiner GE, Davis SL, et al. Levetiracetam versus phenobarbital for neonatal seizures: a randomized controlled trial. Pediatrics. 2020;145(6):e20193182. doi:10.1542/peds.2019-3182 ↩
  9. Qiao MY, Cui HT, Zhao LZ, Miao JK, Chen QX. Efficacy and safety of levetiracetam vs. phenobarbital for neonatal seizures: a systematic review and meta-analysis. Front Neurol. 2021;12:747745. doi:10.3389/fneur.2021.747745 ↩
  10. Moawad MHED, Elettreby AM, Alkhawaldeh IM, et al. Levetiracetam versus phenobarbital as first-line therapy for neonatal seizures: a comprehensive systematic review and meta-analysis with meta-regression of 26 studies involving 9,854 neonates. BMC Pediatr. 2026;26:222. doi:10.1186/s12887-026-06539-6 ↩
  11. Maitre NL, Smolinsky C, Slaughter JC, Stark AR. Adverse neurodevelopmental outcomes after exposure to phenobarbital and levetiracetam for the treatment of neonatal seizures. J Perinatol. 2013;33(11):841–846. doi:10.1038/jp.2013.116 ↩
  12. Soul JS, Bergin AM, Stopp C, et al. A pilot randomized, controlled, double-blind trial of bumetanide to treat neonatal seizures. Ann Neurol. 2021;89(2):327–340. doi:10.1002/ana.25959 ↩