Which symptoms would the RN observe in the newborn exhibiting symptoms of neonatal abstinence syndrome select all that apply?

Neonatal Abstinence Syndrome

Over the past decade, there has been a dramatic increase in the prevalence of neonatal abstinence syndrome (NAS), which manifests pursuant to passive addiction of the fetus to opioids (McQueen and Murphy-Oikonen 2016). The clinical manifestations of NAS primarily involve the central and autonomic nervous systems and the gastrointestinal system. They range from tremors and irritability to hyperpyrexia and seizures (Table 110.4). Symptom onset is within the first few days of life and varies depending on the half-life of the opioid. Identification of newborns at risk for NAS is important to ensure early intervention. In addition to self-report, procurement of biological specimens from the neonate can help to identify at-risk newborns. Scoring tools for at-risk newborns are essential and permit objective assessment (Hudak and Tan, 2012).

Ideally, initial care for the newborn with NAS should be nonpharmacological, which involves reducing exposure to noise and lights, minimizing handling, swaddling and holding the infant, and providing opportunities for nonnutritive sucking (McQueen and Murphy-Oikonen, 2016). Neonates should stay in the room with their mothers and be breastfed, if possible. Unfortunately, in most cases, nonpharmacological treatment is insufficient and treatment with oral morphine solution or methadone becomes necessary. There is emerging evidence for the use of sublingual buprenorphine as a first-line agent and for clonidine as a second-line agent. Children with NAS are more likely to have neuropsychiatric challenges, even after accounting for the numerous environmental and social factors associated with substance use (Uebel et al., 2015). As such, newborns with NAS merit close medical follow-up care and social services after discharge.

Abstract

Neonatal abstinence syndrome (NAS) results from physiological dependence secondary to in utero exposure to maternal illicit as well as prescription drugs. Over the last few decades a significant increase in the infants undergoing NAS has been noted. NAS severity depends on multiple factors including genetics, type, number, dose and duration of drug exposure. The first line of treatment should always be nonpharmacological methods such as skin-to-skin care, minimal stimulation environment, and breastfeeding if not contraindicated, while keeping the mother–infant dyad together. If despite these measures symptoms worsen then pharmacological treatment should be utilized and should be specific for each infant based on a pharmacological rationale rather than attempting to use a one size fits all strategy. The most commonly used first line of treatment medications are neonatal morphine sulfate and methadone. Additional adjunct medications for difficult-to-treat infant's include phenobarbital and clonidine as needed.

Neonatal Abstinence Syndrome

Neonatal abstinence syndrome will occur in 40% to 80% of neonates exposed to chronic opioids. Neonatal abstinence syndrome is difficult to observe at the patient level and difficult to absorb at the system level; therefore many efforts in the maternal care of OUD revolve around mitigating neonatal abstinence syndrome, as outlined as follows:

Smoking cessation: It is well known that neonatal abstinence syndrome is more severe and requires more days for treatment in newborns exposed to tobacco and opioids. If obstetric providers rely on motivational interviewing and the notion that most mothers do not want their babies to go through withdrawal, this can be powerful incentive to address smoking as well.54

Breastfeeding: Breastfeeding should also be recommended to women with OUD. Babies benefit from the nurturing behavior required for breastfeeding, receive the benefits of human milk, receive a trace amount of opioid in human milk, and are less likely to suffer severe neonatal abstinence syndrome.55,56 In addition, the oxytocin release encountered with lactation is of benefit to the mother in combating postpartum depression and relapse.

Lowering medication dose: Although it may make sense that lower doses of medication are preferred, the evidence is not convincing that maternal opioid maintenance dose correlates with neonatal withdrawal. Early studies found that neonatal abstinence syndrome was less likely in babies exposed to low doses of methadone,57 with a possible dose response effect.58 However, more recent work demonstrates that dose does not matter with regard to neonatal abstinence syndrome severity or length of treatment and in fact is associated with increased rates of illicit use.40,59–61 Therefore lowering medication dosing to prevent or attenuate neonatal abstinence syndrome is not an appropriate goal.

Maternal Detoxification: Original case reports suggested that fetal demise was a risk of withdrawal, and therefore withdrawal was to be avoided.32,62 What obstetric providers have learned from recent work is that detoxification is not as harmful to the fetus as previously thought because no adverse pregnancy outcomes were identified in multiple cohorts evaluated.63–65 However, the odds of successful maternal detoxification are low and the odds of relapse are high, which increases the danger of unintended overdose. In addition, there remains an 18% chance of neonatal abstinence syndrome even after detoxification. As such, maternal detoxification continues to be an area of investigation and broad recommendations cannot be made.

Abstract

Neonatal abstinence syndrome (NAS) is a constellation of signs and symptoms and is a consequence of the sudden discontinuation of fetal exposure to substances that were used or abused by the mother during pregnancy. The incidence of NAS is increasing; so are the length of stay and the need for pharmacologic therapy. Nonpharmacologic measures should be tried in all neonates before the initiation of pharmacologic therapy. Protocolized management is shown to decrease the length of stay and the length of treatment. Methadone and morphine are common medications used in the treatment of NAS. Either a weight-based or score-based approach to opioid dose can be used. Adjunct medications like phenobarbital and clonidine are helpful when monotherapy is not successful or when the maximum dose of opioid is reached. Breastfeeding decreases the need and the duration of pharmacotherapy. All NAS babies need to be followed up regularly. Further studies are needed to standardize the management of NAS.

Acute Pharmacologic Treatment

If the infant has 2 consecutive NAS scores ≥12 or 3 consecutive scores ≥8, pharmacologic therapy should be initiated (Fig. 2).

For opioid-related NAS, start morphine 0.05 to 0.08 mg/kg/dose PO q3-4h. If Finnegan scores remain elevated, morphine dose can need to be increased q8-12h as needed by 10% to 20% (max dose: 1.3 mg/kg/day). If maximum morphine dose is reached and the infant still exhibits significant NAS symptoms, phenobarbital can be added (see dosing below).

For nonopioid related NAS, start phenobarbital (loading dose 16 mg/kg PO once, followed by 1.5 to 2.5 mg/dose PO q12h). If Finnegan scores remain high, dose can be increased by 10% every 24 to 48 hr as needed.

Neonatal abstinence syndrome

Neonatal abstinence syndrome (NAS) is an adverse effect as the result of prolonged maternal opioid use, and the impact on infants is becoming more prevalent. Neonatal abstinence syndrome consists of a variety of symptoms that occurs in newborns following abrupt discontinuation of a variety of medications such as opioid agonists, partial opioid agonists, benzodiazepines, and antidepressants immediately prior to delivery. Clinical symptoms include jitteriness, inconsolable crying, and low birth weight, and seizures [1R]. NAS has been estimated to affect 5.8 per 1000 live hospital births, which averages one infant every 25 min. Over the past decade, the incidence of NAS has augmented 5- to 10-fold throughout the country. As the prevalence of NAS is increasing, new treatments emerge in order to minimize the adverse effects of opioid withdrawal in these newborns. Tapering doses of various opioid or partial opioid agonists are commonly used to minimize the withdrawal symptoms, but a single preferred agent remains controversial. According to the Vermont Oxford Network morphine was the pharmacological choice initially utilized in about 80% of neonates with NAS [3R]. However, new evidence indicates buprenorphine might offer better outcomes in infants. Buprenorphine is a full kappa (ĸ) opioid receptor antagonist and a partial mu (μ) agonist utilized in the management of moderate to severe pain in adults to treat opioid use disorder. In the Blinded Buprenorphine or Neonatal Morphine Solution (BBORN) study, sublingual buprenorphine was shown to decrease the treatment time and hospital length of stay when compared to morphine. The rates of adverse effects were not statistically different between the two treatment groups, which highlighted buprenorphine's potential as a new therapeutic option for the treatment in infants with NAS [2R]. Although this study showed promising results, more studies need to be conducted to determine the safety and efficacy of buprenorphine as a potential treatment for NAS. Regardless, definitive preferred opioid treatments in newborns with NAS that minimize adverse consequences and minimizes length of stay remains controversial [1R,2R,3R].

Neonatal Withdrawal Syndrome from Maternal Codeine

Neonatal withdrawal syndrome (NWS), also known as neonatal abstinence syndrome, is a constellation of signs and symptoms either due to prenatal exposure to addictive or prescription drugs or due to postnatal long-term use of opiates for pain control when the medications are discontinued abruptly. When codeine and other opioids are used for extended courses during pregnancy, there is potential risk of neonatal opioid dependence and subsequent withdrawal symptoms in the first few days of life, but the long-term consequences are still not clear. Maternal treatment of opioids in the third trimester, near the time of birth, is clearly a risk factor for NWS and requires careful monitoring by pediatricians caring for the newborn to avoid associated morbidities. Codeine withdrawal in neonates has been reported both in addicted and nonaddicted mothers. The signs of codeine withdrawal are similar to those of any opioid withdrawal. The first case of neonatal codeine withdrawal in a nonaddicted mother was reported in 1965 (Van Leeuwen, Guthrie, & Stange, 1965). Subsequently, a few case reports on this have been reported in nonaddicted mothers and are described in Table 1. The symptoms of neonatal codeine withdrawal syndrome typically begin within the first 24 h of birth, although the manifestations may be delayed for 48–72 h. The common presentations of NWS include tremulousness, irritability, inconsolability, seizure, poor feeding, vomiting, loose stools, tachypnea, tachycardia, and fever. Sometimes the diagnosis of NWS is delayed in nonaddicted mothers as compared to addicted mothers. Therefore, it is important to question details of medication intake and composition during pregnancy and the postpartum period.

Table 1. Case Reports of Neonatal Withdrawal Syndrome from Maternal Codeine Intake

MRI, magnetic resonance imaging; NICU, neonatal intensive-care unit.

NWS can be a life-threatening condition and can occur under situations that would not normally arouse suspicion before the onset of symptoms. The optimal treatment for NWS has not been established. Many scoring systems are used to assess the severity of NWS but none is perfect. Modified Finnegan Scores remain the most commonly used tool. The scoring system helps in monitoring, titrating, and terminating the therapy. The treatment of NWS consists of supportive (nonpharmacological) and pharmacological treatment (Kocherlakota, 2014). Primary treatment of neonatal withdrawal symptoms should be supportive because pharmacological therapy can prolong hospitalization and exposes the infant to additional agents that are often not necessary. The supportive therapy consists of gentle handling, swaddling, frequent feeding with high caloric formula, dim lighting with low noise, and careful avoidance of waking the sleeping infants. Pharmacological therapy is indicated: (1) for serious symptoms such as seizure, poor feeding, diarrhea, and vomiting resulting in severe dehydration and significant weight loss, (2) when supportive therapy fails to control the signs and symptoms, and (3) when the withdrawal symptom scores are persistently high. Morphine is the most common pharmacological agent used in NWS. Morphine decreases the incidence of seizure, improves feeding, eliminates diarrhea, decreases agitation, and can control severe symptoms.

A Neonatal Abstinence Syndrome

NAS presents as a constellation of symptoms that is potentially fatal, resulting from withdrawal from exposure to psychotropic drugs during pregnancy and most commonly described for offspring of opiate users. However, withdrawal from many psychoactive drugs, such as selective serotonin reuptake inhibitors and antipsychotics, can potentially produce symptoms.7 The symptoms of NAS can range from minor problems, such as difficulty sleeping, feeding, and impaired temperature regulation, to more serious problems, such as failure to thrive, seizures, and respiratory distress. Several scales have been developed to assess NAS, the first and most common being that developed by Finnegan et al.8 Symptoms following methadone maintenance typically begin 72 h postpartum and treatment usually consists of morphine, methadone, or buprenorphine along with nonpharmacological supportive care (i.e., soothing techniques).

There have been several excellent reviews on the occurrence of NAS. One study of 290,605 women in the United States on Medicaid who received a prescription for an opiate during pregnancy, dichotomized the women into short-term or long-term users and assessed them according to cumulative opiate dose (using a morphine-equivalent scale) and the occurrence of NAS in the newborn.4 This study found that exposure to prescription opioid analgesics produces a low incidence of NAS (about 6/1000 cases), while exposure to illicit opiates and additional risk factors, such as opiate misuse, brings the risk to about 220/1000 cases.4 Alcohol, other psychotropic drugs, and tobacco use increased the occurrence compared to prescription opiates alone but not nearly to the degree associated with opiate misuse.4 Overall, long-term (>30 days) prescription opiate use compared to short-term use, as well as late (extending to 3rd trimester) use, increased the risk of NAS.4 Therefore, across a large sample of pregnant women receiving Medicaid and prescribed at least one opiate during pregnancy, the risk of NAS in the newborn is low, particularly for those newborns exposed only briefly to opiates during the 1st and 2nd trimesters. Risk increases substantially with concomitant use of other substances9 and particularly opiate misuse as reported by many authors. Studies of women who are opiate dependent show that up to 94% of the newborns exhibit some degree of NAS.10 A review and metaanalysis of 67 studies of methadone-maintained women concluded that there was a clear relationship between opiate use during pregnancy and NAS, but that there was no difference in the relative risk of NAS in offspring of women maintained on high-dose versus low-dose methadone.10 This is an important finding, as women who are maintained on methadone during pregnancy may be advised to increase the dose as pregnancy proceeds due to pharmacokinetic considerations or to reduce the dose to minimize the extent and severity of the NAS. The risk of dose reduction lies in the possibility that the woman will relapse to illicit opiate use to avoid withdrawal and subsequently expose the fetus to substantially greater risk compared to controlled methadone maintenance.10 This issue is reflected in the report by the American College of Obstetricians and Gynecologists, which supports supervised detoxification of women using heroin during pregnancy to minimize the risk for NAS but warns that relapse rates are very high and women should be put into methadone maintenance instead of undergoing withdrawal.11

In 2002, buprenorphine, a partial μ-opiate receptor agonist, became approved for opiate-dependent persons, including pregnant patients. A recent metaanalysis that sought to compare newborn outcomes from women receiving buprenorphine to those receiving methadone concluded that newborns of buprenorphine-receiving women showed a lower risk of NAS, shorter mean hospital stay, and lower morphine dose needed for treatment than those methadone-receiving women.12 Overall the buprenorphine-exposed infants were more healthy (proper gestational age, height, weight, etc.) than the methadone-exposed infants. However, the authors cautioned that in practice, women given buprenorphine are typically more psychologically stable than those given methadone. Methadone maintenance requires daily clinic visits and is generally used with less-compliant women. Therefore, the results may be biased, as the two populations of mothers differ on several characteristics not controlled in these studies.12 Another review of 44 studies, however, also found that buprenorphine-exposed infants exhibited less severe NAS and no deleterious early developmental effects.13

Drug withdrawal

Four patients with methadone withdrawal psychosis have been described [86].

The neonatal abstinence syndrome occurs in 30–80% of infants whose mothers have taken opiates during pregnancy. The incidence is higher in those whose mothers have a history of opioid dependence and are taking methadone maintenance than in those who are taking methadone for chronic pain [87]. The methadone blood concentration may be a useful predictor of the likelihood of severe withdrawal requiring treatment, but clinical assessment by a standardized scoring system is still required to determine the need to treat the neonatal abstinence syndrome [88].

Opiate dependent patients (n = 48) admitted to a specialist in-patient drug treatment service were withdrawn from opiates using a 10-day methadone reduction schedule [89]. Patients withdrawn from higher doses of methadone reported more severe withdrawal symptoms, but the effect was not strong.

Clinical Findings

Classic neonatal withdrawal or abstinence syndrome consists of a wide variety of CNS signs of irritability, gastrointestinal and feeding problems (diarrhea, hyperphagia or poor feeding), autonomic signs of dysfunction (fever, sweating, sneezing), and respiratory symptoms (Tables 12-3 and 12-4). These symptoms are most often related to gestational opioid exposure, but are relatively nonspecific, with the differential diagnosis including infection, meningitis, hypocalcemia, hyponatremia, intracranial hemorrhage, seizures, and stroke. The signs of neonatal serotonin syndrome (or selective serotonin reuptake inhibitor withdrawal) may also mimic the signs of neonatal opioid abstinence syndrome (Boucher et al, 2008; Moses-Kolko et al, 2005). The timing of withdrawal signs from specific drug exposures can often be anticipated; for example, heroin withdrawal usually occurs within 24 hours of birth, whereas methadone withdrawal symptoms typically begin later, at approximately 48 to 72 hours after birth. The incidence of neonatal abstinence syndrome (NAS) in infants of women using heroin or methadone is high, with wide ranges reported between 16% and 90% (Agarwal et al, 1999; Boer et al, 1994; Maas et al, 1990; van Baar et al, 1994), and between 30% and 91% of infants with signs of NAS receive pharmacologic treatment for NAS with inpatient stays averaging 3 weeks (Dryden et al, 2009; Kuschel, 2007). Premature infants generally have milder signs of withdrawal and often show alternating periods of hyperactivity and lethargy, with tremors seen less commonly. The mortality rate for these infants is less than 1% (Boer et al, 1994). Death is rarely associated with withdrawal alone, but usually occurs as a consequence of prematurity, infection, and severe perinatal asphyxia.

A number of evaluation tools are used to assess the severity of opioid withdrawal after birth. The neonatal abstinence score is a scale based on nursing observations of the severity of signs of withdrawal (Finnegan et al, 1975) and is the most widely used scale. The Lipsitz score was developed at the same time and is simpler to use, with a score greater than 4 indicating withdrawal. Green and Suffet (1981) introduced the Neonatal Narcotic Withdrawal Index as a rapid physician-based evaluation for neonatal signs of withdrawal. The use of these scoring systems allows more objective quantification of the severity of the infant’s withdrawal and the response to treatment. These scoring systems have shown good interobserver reliability and can improve clinicians’ ability to treat the withdrawing infant appropriately (Anand and Arnold, 1994; Franck and Vilardi, 1995).

The goal of medical management of opioid withdrawal is to avoid serious symptoms of NAS, such as seizures, and to maintain the infant’s comfort while enabling the infant to feed, sleep, and gain weight in an appropriate manner. There are a number of reported threshold scores for initiating pharmacologic treatment (Finnegan NAS scores between 7 and 12) (Kuschel, 2007), but none of these choices have been examined in a scientific manner. The decision to begin treatment or to wean treatment should be influenced by the absolute score and other factors, such as the infant’s age, comorbidities, other conditions leading to abnormal behavior, and a daily evaluation of the abnormal clinical elements observed in the scoring system (Kuschel, 2007). Standard medical practice is to combine both developmental and behavioral methods with pharmacologic interventions as necessary to control symptoms and signs of narcotic abstinence.