Neonatal withdrawal

Those diagnosed with NAS may exhibit signs and symptoms that vary depending on various factors. Factors such as the type of drugs used by the birthing parent, how long the drugs were used, the amount of drug used that made it to the child, and associated with premature birth.^[3]

The drugs involved can include opioids, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs) ethanol, benzodiazepines, anticonvulsants, and muscle relaxants to name a few.^[4][5][1][6] Opioids have become the most associated with NAS due to the growing opioid crisis leading to increased opioid use among pregnant people. Although NAS generally includes opioid and nonopioid exposures, studies have shown that such cases have primarily resulted from in utero opioid exposure; thus, resulting in the use of Neonatal Opioid Withdrawal Syndrome (NOWS) as a subset of NAS.^[7][8][9] Neonatal abstinence syndrome does not happen in prenatal cocaine exposure (with babies exposed to cocaine in utero) in the sense that such symptoms are difficult to separate in the context of other factors such as prematurity or prenatal exposure to other drugs.^[10]

Although the main pathophysiology of NAS is still not fully understood, there are several potential mechanisms and pathways that are being investigated that may be related to the development of NAS caused by abnormal levels of neurotransmitters and inadequate expression of opioid receptors.^[4] Due to the differing substances that can lead to NAS, each substance can result in a different cause leading to the symptoms of NAS. ^[9] Examples of such differences include: opioid withdrawal resulting in decreases in serotonin and dopamine with an increase in corticotrophin, norepinephrine, and acetylcholine; TCA withdrawal resulting in a cholinergic rebound phenomenon; benzodiazepine withdrawal resulting in an increased release of g-aminobutyric acid (GABA); and methamphetamine withdrawal resulting in a decrease in dopamine, serotonin, and other monoamines. ^[9]

Several studies have shown that multiple risk factors, ranging from social aspects to genetics, can contribute to the severity of NAS and the recovery process. ^[4][9] Mutations in the genes for opioid receptor expression (mu-opioid receptors OPRM1, delta-OPRD1, and kappa-OPRK1 genes) and the dopamine metabolism pathway (COMT gene) have been associated with quicker recovery resulting in shorter duration of treatment. ^[11][4][9] Environmental influences that can affect expression of the aforementioned genes, like DNA methylation that results in decreased OPRM1 gene expression, have also been associated with increased severity of NAS. ^[4] Some non-genetic risk factors include smoking and methadone use of the birthing person during pregnancy that can result in increased severity of NAS. ^[9]

Objectives of management are to minimize negative outcomes and promote normal development.^[12] Supportive care is the first step in management, but this is typically not enough and is complemented with medication.

Non-medication based approaches to treat neonatal symptoms include swaddling the infant in a blanket, minimizing environmental stimuli, and monitoring sleeping and feeding patterns.^[13] Breastfeeding promotes infant attachment and bonding and is associated with a decreased need for medication. These approaches may lessen the severity of NAS and lead to shorter hospital stays.^[14]

Medication is used to relieve fever, seizures, and weight loss or dehydration.^[12] When medication is use for opiate withdrawal in newborn babies is deemed necessary, opiates are the treatment of choice; they are slowly tapered down to wean the baby off opiates.^[15] Phenobarbital is sometimes used as an alternative but is less effective in suppressing seizures; however, phenobarbital is superior to diazepam for neonatal opiate withdrawal symptoms. In the case of sedative-hypnotic neonatal withdrawal, phenobarbital is the treatment of choice.^[16][17] Clonidine is an emerging add-on therapy.^[18] Buprenorphine is under development as an alternative to morphine or methadone as initial therapy.^[19]

Opioids such as neonatal morphine solution and methadone are commonly used to treat clinical symptoms of opiate withdrawal, but may prolong neonatal drug exposure and duration of hospitalization.^[20] A study demonstrated a shorter wean duration in infants treated with methadone compared to those treated with diluted tincture of opium. When compared to morphine, methadone has a longer half-life in children, which allows for less frequent dosing intervals and steady serum concentrations to prevent neonatal withdrawal symptoms.^[21]

NAS rates correlate with rates of opioid use disorder among pregnant individuals in the population. The misuse of opioids, along with other illicit substances by this group has increased since the early 2000s, all this while cases and this problem are likely being underreported.^[15]

In 2012, a study inspected information on hospital discharges across 44 states in the United States, which totaled to 7.4 million discharges. Their goal was to measure NAS trends over the past 10 years. The study found that the number of pregnant individuals using opiates increased from 1.2 to 5.6 per 1,000 hospital births every year.^[22]

A 2013 study examined the incidence of neonatal abstinence syndrome in 28 states. The researchers found that this rate increased by about 300% (from 1.5 cases to 6.0 cases per 1,000 hospital births) during 1999 to 2013. Along with these results, there have been considerable differences in state NAS incidence, with lows and highs ranging from 0.7 per 1,000 births in Hawaii, to 33.4 per 1,000 births in West Virginia. This contrasts could potentially come as a result of illegal opioid use prevalence, difference in state to state opioid prescribing rates, and/or the use of NAS diagnosis, all making it difficult to average national incidence of NAS.^[23]

A 2017 Centers for Disease Control (CDC) report stated that the number of babies born with NAS increased nationally by 82% from 2010 to 2017. This correlates to a NAS rate of 7.3 per 1,000 hospital births. This increase was seen for the majority of the states that participated, however with variation between states. ^[24]

In 2023, the American Academy of Pediatrics (AAP) estimated that the incidence of NAS increased to 8.8 cases per 1,000 hospital births. This study also stated that this rate varied by region, agreeing with prior studies.^[25]

In 2024, a study evaluated the early results of the 2020 American Academy of Pediatrics guidelines for managing neonatal opioid withdrawal symptoms. These guidelines proposed using non-pharmacological approaches as first line treatment. The study itself saw a reduction in infant NICU admission and pharmacological treatments. ^[26] More data is needed to evaluate the change in incidence trends after implementation of these guidelines.

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Neonatal abstinence syndrome is a growing health issue amongst the country. While Ontario claims the highest rate of narcotic use in the country and one of the highest rates of prescription narcotic use in the world.^[29] Northern cities such as North bay are influential contributors. The number of neonates born with addiction or experiencing withdrawal symptoms are increasing at an undesirable rate in North Bay from 22 babies in 2012-2013 to 48 babies born with NAS in 2014-2015.^[30] Furthermore, North Bay Regional Health Centre was home to 10 NAS babies in January 2016 alone.^[31] The dramatic growth in numbers of neonates born with drug addiction will continue to grow if not confronted and managed in a way that is specific and appropriate for the city of North Bay.