Neonatal withdrawal | |
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Other names | Neonatal abstinence syndrome |
Specialty | Pediatrics |
Neonatal withdrawal or neonatal abstinence syndrome (NAS) or neonatal opioid withdrawal syndrome (NOWS) is a withdrawal syndrome of infants after birth caused by in utero exposure to drugs of dependence, [1] most commonly opioids. Common signs and symptoms include tremors, irritability, vomiting, diarrhea, and fever. [2] [3] [4] NAS is primarily diagnosed with a detailed medication history and scoring systems. [5] First-line treatment should begin with non-medication interventions to support neonate growth, though medication interventions may be used in certain situations. [6]
In 2017, approximately 7.3 per 1,000 hospitalized infants in the United States were diagnosed with NOWS. [7] [8] Not all opioid-exposed infants will show clinical signs of withdrawal after birth. Clinical signs range from mild to severe, depending on the quantity and type of substance exposure. [9]
The most common form on neonatal withdrawal occurs after in utero exposure, however, iatrogenic withdrawal can also occur after medications are used to treat critically ill infants after they are born.
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Drug and alcohol use during pregnancy can lead to many health problems in the fetus and infants, including neonatal abstinence syndrome (NAS). The onset of clinical presentation typically appears within 48 to 72 hours of birth but may take up to 8 days. [9] [10] The signs and symptoms of NAS may be different depending on which substance the mother used. [11]
Common signs and symptoms in infants with NAS may include: [2] [3] [4]
The drugs involved can include opioids, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitor (SNRIs), tricyclic antidepressants (TCAs), ethanol, and benzodiazepines. [1] [11] [12] Opioids may be more likely to cause NAS than other substances due to an increase in its usage. [13] Exposure to heroin and methadone claimed to be correlated with a 60 to 80% occurrence of neonatal withdrawal, whereas buprenorphine has been associated with a lower risk. [14] Neonatal abstinence syndrome does not happen in prenatal cocaine exposure. Prematurity and exposure to other drugs may instead be the cause of symptoms. [15]
The main mechanistic pathway of prescribed and illicit substance-induced NAS is the hyperactivity of the central and autonomic nervous system and gastrointestinal tract [16] There are several potential mechanisms and pathways that have been proposed, which includes the interaction between the neurotransmitters and lack of adequate expression of opioid receptors. [13] However, the main pathophysiology of this syndrome remains unknown. [13] Most of the opioid induced NAS are due to opioid exposure during pregnancy for pain relief, misuse, or abuse of prescribed opioids or other medication-assisted treatment of opioid use disorder. [10]
The presence of withdrawal in the neonate can be confirmed by taking a detailed medical history from the mother. The medical history should include physical and mental health problems, prescription and non-prescription medication use, nutritional supplement use, history of alcohol and substance use, childhood adversities, cultural and social beliefs, past traumatic experiences, and infectious diseases such as HIV. [17] Since the medical history of the birth giver may not be available immediately after delivery, some testing needs to be done in the infant to confirm possible exposure. Infant's urine, meconium, umbilical cord tissue or hair can be used for testing. [13] [17] The timing of urine sample collection is critical because some drugs may become undetectable after they are metabolized and eliminated from the body. Also, urine test results can only confirm if the fetus was exposed to drugs a few days before birth. [13] Meconium testing can be used to confirm drug exposure in earlier stage of pregnancy, but the collecting process is more difficult. [17] Umbilical cord tissue testing is a relatively new testing method and its accuracy is still controversial. [17] The mother's blood and urine sample should also be collected for drug screening. [18] Chest X-rays can confirm or infirm the presence of heart defects. [19] [1]
Depending on what hospital setting the infant is in, different scoring systems are used for assessing the severity and the need for medication treatment in neonatal withdrawal syndrome. [5] One challenge with existing clinical predication tools is that they were designed to assess opiate withdrawal only. The Finnegan Neonatal Abstinence Scoring System (FNASS), or its modified version is the most widely used prediction tool currently in the United States. [16] The FNASS tool focuses on 21 signs of neonatal opioid withdrawal, and a score from 0 to 5 is assigned based on the severity of the symptom. The measurement needs to be repeated every two to four hours. [20] [21] The cutoff for initiation, escalation or de-escalation of medication treatment may be varied. A 2019 review shows that "most institutions using the FNASS have protocols that call for starting or increasing pharmacologic treatment after an infant has received three FNASS scores ≥8 or two scores ≥12." [21] However, there are limitations to the FNASS tool. The repeated measurements may delay treatment and result in increased treatment need. In order to assess some of the signs in the measurement process, infants will be stimulated as opposed to minimizing stimulation recommended in non-medication treatment. [21] A study also indicates that the FNASS tool "has not been validated to show utility in improving outcomes for infants with NAS". [16]
Neonatal withdrawal is prevented by the mother abstaining from illicit or prescribed substances. In some cases, a prescribed medication may need to be discontinued during the pregnancy to prevent addiction by the infant. Early prenatal care can identify addictive behaviors in the mother and family system. [22] Referrals to treatment centers is appropriate. [19] Some prescribed medicines should not be stopped without medical supervision, or harm may result. Suddenly stopping a medication can result in a premature birth, fetal complications, and miscarriage. [8] It is recommended that pregnant individuals discuss medication, alcohol, and tobacco use with their health-care provider and to seek assistance to abstain when appropriate. She may need medical attention if she is using drugs non-medically, using drugs not prescribed to them, or using alcohol or tobacco. [1]
There are several strategies to prevent the incidence of NAS, those include: [10]
However, there are some barriers to prevention which includes lack of consensus to screening tools to identify substance use while pregnant, stigma, provider bias, and legal consequences. [10]
Treatment depends on the drug involved, the infant's overall health, abstinence scores (FNASS scoring system), and whether the infant was born full-term or premature. It is recommended to observe and provide supportive measure to infants who are at risk of neonatal abstinence syndrome in the hospital. [26] Infants with severe symptoms may require both supportive measures and medicines. [27] Treatment for NAS may require the infant to stay in the hospital for weeks or months after birth. The average hospital stay in the United States for infants requiring treatment for NAS is 16 days for infants who do not require medication treatment and 23 days for those requiring medications. [28]
The goal of treatment is to minimize negative outcomes and promote normal development. [29] Infants may be prescribed a drug similar to the one the mother used during pregnancy, and slowly decrease the dose over time. [30] This helps wean the infant off the drug and relieves some withdrawal symptoms.
First-line treatment should begin with non-medication interventions to support maturation of the neonate. It is not clear if one type of non-medication therapy is better than another. [31] Common non-medication approaches include physical environment adjustments, swaddling, and breastfeeding.
Infants with NAS symptoms may have hypersensitivity to light and sounds. Techniques such as darkening the room and eliminating surrounding sounds work to lessen the neonate's visual and auditory stimuli. [13]
Limited data suggests that "rooming in", or keeping the mother and infant in the same room after birth, is associated with a reduced need for medication treatment for NAS (20-60% reduction in need for medications), reduced total medication treatment days (8-13 day reduction), a shortened length of hospitalization (3-17 day hospital days reduction), and a 2 fold higher rate of successful breastfeeding initiation. [28]
Swaddling (wrapping an infant firmly in a blanket) can help improve sleep, develop nerves and muscles, decrease stress, and improve motor skills. [32]
Infants with NAS may have problems with feeding or slow growth, which require higher-calorie feedings that provide greater nutrition. [32] In a small randomized controlled trial evaluating infants with NAS due to in utero methadone exposure, high calorie feedings was not associated with decreased rates of NAS medication treatment nor a reduction in hospital stay, however it was associated with a greater rate of weight gain in the first 21 days of life. [28] [33] It is beneficial to give smaller portions more often throughout the day. [1] Breastfeeding promotes infant attachment and bonding, and is associated with a decreased need for medication, may lessen the severity of NAS, and lead to shorter hospital stays. [34] [28]
Most pregnant women who are taking buprenorphine or methadone can safely breastfeed their infant. Both buprenorphine and methadone remain in the human milk at low concentrations, which will reduce signs and symptoms of NAS and likely decrease the treatment time. However, there are exclusions in which it is not safe to breastfeed, such as an HIV-positive mother and a mother with history of street drug use or multiple illicit drug use. [17] [11]
Although non-medication intervention remains first-line treatment, pharmacological intervention, when appropriate and indicated, can improve signs of neonatal withdrawal. [6] There is insufficient evidence to recommend one medication over others in the treatment of opioid associated NAS, however methadone, morphine and buprenorphine are the most commonly used first line medications. [28]
Common medications used in the treatment of NAS include:
Opioids have shown to improve symptoms to a clinically safe level but may not affect length of hospital stay. [35] Its common to slowly taper down to wean the infant off. [12] Methadone and morphine are the opioids that are most commonly used in the treatment of NAS. [28]
Limited evidence suggests that the opioid partial agonist buprenorphine was associated with shorter hospital stays and shorter treatment durations when compared to morphine, methadone, or a tincture of opium in the treatment of opiate associated NAS, including in utero buprenorphine exposure related NAS. [28]
Sedatives such as phenobarbital or diazepam are less effective at symptom control compared to opioids but can reduce length of hospital stay. [35] A 2021 systematic review found low-certainty evidence that phenobarbital lengthened hospital stays but resulted in a return to birth-weight more rapidly. Low-certainty evidence also showed phenobarbital reduced treatment failure rates compared to diazepam and chlorpromazine. [35]
When compared to opioids, clonidine was just as effective at improving clinical symptoms. [35] There was low-certainty evidence of increased hospitalization days with clonidine and opioid compared to phenobarbital and opioid. [36]
Additional medication is used to relieve fever, seizures, and weight loss or dehydration. [29]
Treatment of mothers for opioid use disorder during pregnancy with methadone or buprenorphine has been associated with reduced infant NAS complications at birth, specifically reduced medication treatment days and reduced infant withdrawal scores. [28] In two small randomized controlled trials, infants whose mothers were treated with buprenorphine (as compared to methadone) had fewer NAS medicaiton treatment days as well as lower symptom based withdrawal scores. [28] [37] [38] Regarding the potential for neurodevelopmental delay in infants with NAS, maternal treatment with buprenorphine or methadone for NAS showed no differences in infant neurodevelopmental outcomes at 4 months (as assessed by the Bayley Scales of infant and toddler development) or visual development (as assessed by visual evoked potentials) at 36 months. [28]
A 2018 meta-analysis reported that newborns diagnosed with NAS are more likely to recover with non-medication intervention when roomed with family during their hospital stay compared to newborns diagnosed with NAS that are treated in newborn intensive care unit. [39]
Data are limited and more research needs to be conducted to properly evaluate long-term outcomes in children with a prior diagnosis of NAS. [40] However, long-term monitoring into adolescence may be necessary as a 2019 meta-analysis gave evidence of some longterm cognitive and physical side effects associated with prenatal opioid exposure. [41]
A 2012 study analyzed information on 7.4 million discharges from 4,121 hospitals in 44 states, to measure trends and costs associated with NAS over the past decade. The study indicated that between 2000 and 2009, the number of pregnant women using opiates increased from 1.19 to 5.63 per 1,000 hospital births per year. [42]
In 2017 the Centers for Disease Control (CDC) reported an increase of diagnosis of NAS to 7 cases every 1,000 births with indiscrimination to state or demographic group. Additionally, the CDC reported in 2019 that 7% of pregnant individuals self-reported use of opioids at some point in their pregnancy. [43]
A 2018 review of NAS reports that the epidemiology of NAS continues to change and evolve. Though opioids are still the most common drug reported in diagnosis of NAS, there are instances where opioids are not the only class of drug the infant is exposed to during pregnancy. Diagnosis of NAS continues and is substantially greater in rural areas compared to urban areas. As the epidemiology continues to change and evolve calls for the need for more research and standardization of treatment. [16]
A 2020 literature review published by the Saskatchewan Prevention Institute reports that NAS has significantly increased in England, Western Australia, and Canada within the last decade, noting that current statistics may be underestimated as reluctance to report can be attributed to stigma associated with diagnosis or differing protocols amongst institutions. From 2016 to 2017 Canada overall reported 1,850 diagnosis of NAS. [44]
Methadone, sold under the brand names Dolophine and Methadose among others, is a synthetic opioid agonist used for chronic pain and also for opioid use disorder. It is used to treat chronic pain, and it is also used to treat addiction to heroin or other opioids. Prescribed for daily use, the medicine relieves cravings and removes withdrawal symptoms. Withdrawal management using methadone can be accomplished in less than a month, or it may be done gradually over a longer period of time, or simply maintained for the rest of the patient's life. While a single dose has a rapid effect, maximum effect can take up to five days of use. After long-term use, in people with normal liver function, effects last 8 to 36 hours. Methadone is usually taken by mouth and rarely by injection into a muscle or vein.
Drug withdrawal, drug withdrawal syndrome, or substance withdrawal syndrome, is the group of symptoms that occur upon the abrupt discontinuation or decrease in the intake of pharmaceutical or recreational drugs.
Clonidine, sold under the brand name Catapres among others, is an α2a-adrenergic agonist medication used to treat high blood pressure, ADHD, drug withdrawal, menopausal flushing, diarrhea, spasticity, and certain pain conditions. The drug is often prescribed off-label for tics. It is used orally, by injection, or as a transdermal skin patch. Onset of action is typically within an hour with the effects on blood pressure lasting for up to eight hours.
Opioid use disorder (OUD) is a substance use disorder characterized by cravings for opioids, continued use despite physical and/or psychological deterioration, increased tolerance with use, and withdrawal symptoms after discontinuing opioids. Opioid withdrawal symptoms include nausea, muscle aches, diarrhea, trouble sleeping, agitation, and a low mood. Addiction and dependence are important components of opioid use disorder.
Buprenorphine, sold under the brand name Subutex among others, is an opioid used to treat opioid use disorder, acute pain, and chronic pain. It can be used under the tongue (sublingual), in the cheek (buccal), by injection, as a skin patch (transdermal), or as an implant. For opioid use disorder, the patient must have moderate opioid withdrawal symptoms before buprenorphine can be administered under direct observation of a health-care provider.
Physical dependence is a physical condition caused by chronic use of a tolerance-forming drug, in which abrupt or gradual drug withdrawal causes unpleasant physical symptoms. Physical dependence can develop from low-dose therapeutic use of certain medications such as benzodiazepines, opioids, stimulants, antiepileptics and antidepressants, as well as the recreational misuse of drugs such as alcohol, opioids and benzodiazepines. The higher the dose used, the greater the duration of use, and the earlier age use began are predictive of worsened physical dependence and thus more severe withdrawal syndromes. Acute withdrawal syndromes can last days, weeks or months. Protracted withdrawal syndrome, also known as post-acute-withdrawal syndrome or "PAWS", is a low-grade continuation of some of the symptoms of acute withdrawal, typically in a remitting-relapsing pattern, often resulting in relapse and prolonged disability of a degree to preclude the possibility of lawful employment. Protracted withdrawal syndrome can last for months, years, or depending on individual factors, indefinitely. Protracted withdrawal syndrome is noted to be most often caused by benzodiazepines. To dispel the popular misassociation with addiction, physical dependence to medications is sometimes compared to dependence on insulin by persons with diabetes.
Substance dependence, also known as drug dependence, is a biopsychological situation whereby an individual's functionality is dependent on the necessitated re-consumption of a psychoactive substance because of an adaptive state that has developed within the individual from psychoactive substance consumption that results in the experience of withdrawal and that necessitates the re-consumption of the drug. A drug addiction, a distinct concept from substance dependence, is defined as compulsive, out-of-control drug use, despite negative consequences. An addictive drug is a drug which is both rewarding and reinforcing. ΔFosB, a gene transcription factor, is now known to be a critical component and common factor in the development of virtually all forms of behavioral and drug addictions, but not dependence.
A methadone clinic is a medical facility where medications for opioid use disorder (MOUD) are dispensed-—historically and most commonly methadone, although buprenorphine is also increasingly prescribed. Medically assisted drug therapy treatment is indicated in patients who are opioid-dependent or have a history of opioid dependence. Methadone is a schedule II (USA) opioid analgesic, that is also prescribed for pain management. It is a long-acting opioid that can delay the opioid withdrawal symptoms that patients experience from taking short-acting opioids, like heroin, and allow time for withdrawal management. In the United States, by law, patients must receive methadone under the supervision of a physician, and dispensed through an Opioid Treatment Program (OTP) certified by the Substance Abuse and Mental Health Services Administration and registered with the Drug Enforcement Administration.
Clorazepate, sold under the brand name Tranxene among others, is a benzodiazepine medication. It possesses anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant properties. Clorazepate is an unusually long-lasting benzodiazepine and serves as a prodrug for the equally long-lasting desmethyldiazepam, which is rapidly produced as an active metabolite. Desmethyldiazepam is responsible for most of the therapeutic effects of clorazepate.
Lofexidine, sold under the brand name Lucemyra among others, is a medication historically used to treat high blood pressure; today, it is more commonly used to help with the physical symptoms of opioid withdrawal. It is taken by mouth. It is an α2A adrenergic receptor agonist. It was approved for use by the Food and Drug Administration in the United States in 2018.
Gray baby syndrome is a rare but serious, even fatal, side effect that occurs in newborn infants following the accumulation of the antibiotic chloramphenicol. Chloramphenicol is a broad-spectrum antibiotic that has been used to treat a variety of bacteria infections like Streptococcus pneumoniae as well as typhoid fever, meningococcal sepsis, cholera, and eye infections. Chloramphenicol works by binding to ribosomal subunits which blocks transfer ribonucleic acid (RNA) and prevents the synthesis of bacterial proteins. Chloramphenicol has also been used to treat neonates born before 37 weeks of the gestational period for prophylactic purposes. In 1958, newborns born prematurely due to rupture of the amniotic sac were given chloramphenicol to prevent possible infections, and it was noticed that these newborns had a higher mortality rate compared with those who were not treated with the antibiotic. Over the years, chloramphenicol has been used less in clinical practice due to the risks of toxicity not only to neonates, but also to adults due to the risk of aplastic anemia. Chloramphenicol is now reserved to treat certain severe bacteria infections that were not successfully treated with other antibiotic medications.
Women should speak to their doctor or healthcare professional before starting or stopping any medications while pregnant. Non-essential drugs and medications should be avoided while pregnant. Tobacco, alcohol, marijuana, and illicit drug use while pregnant may be dangerous for the unborn baby and may lead to severe health problems and/or birth defects. Even small amounts of alcohol, tobacco, and marijuana have not been proven to be safe when taken while pregnant. In some cases, for example, if the mother has epilepsy or diabetes, the risk of stopping a medication may be worse than risks associated with taking the medication while pregnant. The mother's healthcare professional will help make these decisions about the safest way to protect the health of both the mother and unborn child. In addition to medications and substances, some dietary supplements are important for a healthy pregnancy, however, others may cause harm to the unborn child.
Buprenorphine/naloxone, sold under the brand name Suboxone among others, is a fixed-dose combination medication that includes buprenorphine and naloxone. It is used to treat opioid use disorder, and reduces the mortality of opioid use disorder by 50%. It relieves cravings to use and withdrawal symptoms. Buprenorphine/naloxone is available for use in two different forms, under the tongue or in the cheek.
The Finnegan scoring system is used to quantify and diagnose neonatal withdrawal or abstinence (NAS) syndrome. This is a withdrawal syndrome of infants, caused by the cessation of the administration of licit or illicit drugs. Neonatal abstinence syndrome is a group of problems that occur in a newborn who was exposed to addictive opiate or other drugs in utero. There are two types of NAS: prenatal and postnatal. Prenatal NAS is caused by discontinuation of drugs taken by the pregnant mother, while postnatal NAS is caused by discontinuation of drugs directly to the infant. The twenty-one signs of withdrawal are scored. The scoring assessment is based upon the pathological significance and severity of the symptoms. Symptoms can be managed with medication. Though lengthy, it remains when used by trained clinicians. Bias and subjectivity can have some affect. The Finnegan scale is also used to assess the effectiveness of treatment and recovery of the infant. Assessment is performed and then scored. A daily score is calculated. The decision to treat the infant may be based upon a higher score. The Finnegan scale is used with assessment of comorbidities, prematurity, and clinician experience to guide treatment.
Alcohol use in pregnancy includes use of alcohol at any time during gestation, including the time before a mother-to-be is aware that she is pregnant. Alcohol use at some point during pregnancy is common and appears to be rising in prevalence in the United States.
Clinical Opiate Withdrawal Scale (COWS) is a method used by registered practitioners to measure the severity of a patient's opioid withdrawal symptoms. This method consists of a series of 11 topics each comprising 4 - 5 common symptoms experienced by a patient undergoing opioid withdrawal. In each topic a rank is given depending on what the patient responds to. Generally, 0 is considered to be no symptom shown and 4 or 5 is considered to be the most common and severe symptom shown. These results are then added up and a final diagnosis is made based on the value obtained. This test is crucial as it allows the practitioner to assess the physiological and psychological behaviours of the patient as well as the severity of each symptom during the duration of the examination. The results are grouped into 3 categories of mild, moderately severe and severe. Mild consists of 5 to 12 points, moderately severe consists of 13 to 24 points and anything above 36 points is severe and requires direct medical attention.
Hendrée E. Jones is a researcher on women's substance abuse disorders and its impact on children. She is a professor in the Department of Obstetrics and Gynecology at the University of North Carolina School of Medicine, and adjunct professor in the University of North Carolina College of Arts & Sciences Department of Psychology and Neuroscience. Jones is the executive director of the UNC Horizons Program, which is a comprehensive drug treatment program for mothers and their drug-exposed children. She is a consultant for the Substance Abuse and Mental Health Services Administration, the United Nations, and the World Health Organization.
Opioid withdrawal is a set of symptoms arising from the sudden withdrawal or reduction of opioids where previous usage has been heavy and prolonged. Signs and symptoms of withdrawal can include drug craving, anxiety, restless legs, nausea, vomiting, diarrhea, sweating, and an increased heart rate. Opioid use triggers a rapid adaptation in cellular signalling pathways that means, when rapidly withdrawn, there can be adverse physiological effects. All opioids, both recreational drugs and medications, when reduced or stopped, can lead to opioid withdrawal symptoms. When withdrawal symptoms are due to recreational opioid use, the term opioid use disorder is used, whereas when due to prescribed medications, the term prescription opioid use disorder is used. Opioid withdrawal can be helped by the use of opioid replacement therapy, and symptoms may be relieved by the use of medications including lofexidine and clonidine.
Opioid agonist therapy (OAT) is a treatment in which prescribed opioid agonists are given to patients who live with Opioid use disorder (OUD). In the case of methadone maintenance treatment (MMT), methadone is used to treat dependence on heroin or other opioids, and is administered on an ongoing basis.
Opioid use during pregnancy can have significant implications for both the mother and the developing fetus.