Drug use during pregnancy has potentially serious medical consequences for mothers and their infants. Drug exposure during pregnancy is estimated through drug tests and interviews with the mother. Per the 2013 National Survey on Drug Use and Health, 5.4 percent of pregnant women aged fifteen to forty-four used illicit drugs. According to Gawronski et al. (2014), there has been a 375 percent increase in the number of women seeking treatment for opioid use disorder (OUD) during pregnancy. The New England Journal of Medicine conducted a study focusing on pregnant women who used heroin during their pregnancy. Within this study, the authors analyzed data from 299 neonatal intensive care units (NICU) across the United States from 2004 to 2013. From the 674,845 infants admitted to the neonatal intensive care units, 10,327 infants had neonatal abstinence syndrome (NAS; Tolia et al., 2015). Between 2004 and 2013, the number of cases of NAS increased from seven cases per one thousand infants to twenty-seven cases per one thousand infants (Tolia et al., 2015). In addition, from 2000 to 2009, the cost of treating infants with NAS has increased by more than 35 percent from $39,400 to $53,400 per infant (Jones et al., 2014).
NAS is a drug-withdrawal syndrome that infants experience after in utero exposure to opioids. The symptoms of NAS varies with the opioid, the maternal drug history, maternal metabolism, net drug transfer across the placenta, placental metabolism, infant metabolism, and excretion, as well as other symptoms (Hudak, Tan, Committee on Drugs, Committee on Fetus and Newborn, & American Academy of Pediatrics, 2012). The number of reported incidences of NAS varies considerably. It has been estimated that up to 95 percent of infants exposed to opioids in utero experience withdrawal, and 50 percent require treatment which can result in long hospital stays (Gawronski et al., 2014). The signs of neonatal withdrawal of heroin often begin within twenty-four hours of birth whereas withdrawal from methadone usually commences around twenty-four to seventy-two hours after birth (Hudak et al., 2012). The symptoms of NAS can include hypertonia, autonomic instability, irritability, poor sucking reflex, impaired weight gain, and seizures (Tolia et al., 2015). There has been a rise in opioid use in the United States which has led to a threefold increase in the number of cases of NAS (Tolia et al., 2015).
Data on NAS incidence rates is currently available only from twenty-five out of the fifty US states (Figure 1), which highlights the urgent need to collect more data on NAS across the entire US. NAS incidence rates appear to be highly variable with over thirty cases per one thousand births in Maine, New Hampshire, and West Virginia; 10.1 to 30.0 per one thousand births in Massachusetts, Maryland, and Kentucky, and only 1.1 to 10.0 per one thousand births in the remaining states for which data was available.
NAS is, thus, a serious problem in several states and appears to be on the increase nationwide (Tolia et al., 2015). Different treatment methods exist both pre- and postnatal that involve methadone, buprenorphine, and morphine, but many health practitioners are still unsure about which approach works best in which situation (pre-/postnatal). This article will provide an exhaustive literature review on these different approaches and will explore the following questions:
Neonatal abstinence syndrome (NAS) has recently become a point of public interest in multiple arenas including: the media, public policy, addiction medicine, neonatology, and pediatrics (Jones & Fielder, 2015). This increased interest and concern is directly related to an increase of cases. Recent research showed that from 2000 to 2009 there appeared to be a threefold increase in NAS incidence rates (Patrick et al., 2012). Within that same time-period, prenatal maternal opioid use has been estimated to have more than quadrupled from 1.2 percent to 5.6 percent (Jones & Fielder, 2015). With heightened public concern as well as a rise in prenatal maternal opioid use, NAS assessment and screening is becoming increasingly important. However, one of the biggest difficulties with NAS is to accurately identify those infants that are at a risk of withdrawal.
A significant turning point in understanding and treating NAS was the development of the Neonatal Abstinence Scoring System (NASS), which is also known as the Finnegan Scoring System (Finnegan, Connaughton, Kron, & Emich, 1975). The NASS is considered the most popular NAS measure, with 52 percent to 65 percent of all NAS studies employing this technique (O’Grady, Hopewell, & White, 2009). Modified versions of the NASS are utilized in both research and clinical practice. Currently, the SSM Health St. Louis facilities are implementing the Modified Finnegan Scoring Tool. The advantage of this scoring system is its comprehensiveness. The NASS contains what developers considered the twenty most common signs of neonatal withdrawal with these symptoms further ranked into subgroups of increasing severity (Jones & Fielder, 2015). These include:
- Excessive crying
- Excessive sleeping
- Tremors
- Increased muscle tone
- Excoriation
- Generalized seizures
- Hyperthermia
- Yawning, sweating, nasal stuffiness, and sneezing
- Poor feeding
- Vomiting
- Loose stools
- Failure to thrive
- Irritability
Elements within each group can be scored from one (considered least clinically significant) up to five (perceived to be the most clinically significant). Infants scoring an eight or greater are recommended to receive pharmacologic therapy (Jansson, Velez, & Harrow, 2009). The NASS is administered every four hours to ultimately quantify the severity of NAS and to guide treatment. Despite the thoroughness of the NASS, with up to thirty-two items requiring scores, there are still several limitations. First, for a health worker to be able to deliver a reliable diagnosis, the amount of training required to implement this scoring measure correctly is considerable. Second, even with highly trained raters, some elements such as noting the difference between mild and marked tremors (Jones & Fielder, 2015) remain difficult and may elude proper and accurate judgment. Third, there is limited research examining the internal-consistency and reliability of the NASS. Further, and rather interestingly, due to changes in neonatal care, neonates are now left to sleep on their backs which effectively renders two NASS indicators obsolete: the measure of excoriation, or redness of the skin; and the presence of skin that is broken or bleeding at the knees and nose (Zimmermann-Baer, Nötzli, Rentsch, & Bucher, 2010).
Another commonly used tool in the assessment of NAS is the Lipsitz Neonatal Drug-Withdrawal Scoring System (NDWSS). Unlike the more complex NASS, this scale contains only eleven items and each symptom is scored on a scale from zero to three based on the severity of symptoms that include tremors, irritability, reflexes, stools, muscle tone, and skin abrasions (Jones & Fielder, 2015). Additionally, a score of zero or one is appointed for repetitive symptoms such as sneezing, yawning, vomiting or fever (Jones & Fielder, 2015). The NDWSS scale has also been recommended by the American Academy of Pediatrics as it uses a moderately simple scoring method. Significant signs of withdrawal can be correctly identified with an accuracy of 77 percent and infants are recommended for pharmacological treatment if they obtain a total score of five or higher (Jones & Fielder, 2015). Other tools that are available for NAS assessment include the Neonatal Withdrawal Inventory and the Neonatal Narcotic Withdrawal Index. Both these measures are quicker than the NASS, and have been more thoroughly studied using psychometric methods (Jones & Fielder, 2015).
At SSM Health St Louis, infants that are identified as prenatally opioid exposed are evaluated, starting at birth, with an intake of their vital signs and a modified version of the Finnegan Neonatal Abstinence Scoring System (Jansson et al., 2009). All infants that are opioid exposed must have continuous monitoring for potential medical issues such as respiratory depression. Using the scoring system, infants are rated every three hours throughout the duration of their hospital stay. This system of scoring is crucial in its reflection of the infant’s overall neurobehavioral range (Jansson et al., 2009). The assigned caregiver for the infant, typically a nurse, administers this assessment. The use of an assigned nurse is key as the symptoms can vary considerably and the more time that is spent with the infant to understand his or her signs and symptomatology of NAS, the more accurate the scoring and following treatment can be. Assessment tools are thus highly imperative in the development of a course of treatment for an infant suffering from NAS.
Buprenorphine
Buprenorphine has become an increasingly popular opioid treatment style in the last decade. Buprenorphine is a semisynthetic opioid and a highly lipid soluble base that is similar in structure to morphine (Kacinko, Jones, Johnson, Choo, & Huestis, 2008). Although buprenorphine and methadone both act on the u-opioid receptor, each has a unique pharmacology (Jones et al, 2014). Buprenorphine is a partial u-agonist and k-antagonist with approximately 50 percent oral bioavailability due to extensive first-pass metabolism (Jones et al., 2014). Due to this composition, buprenorphine has lower intrinsic activity, makes death by overdose less likely than with methadone, is only a partial opioid, which may cause less severe NAS, and has a longer duration of action than methadone (Jones et al., 2014).
Buprenorphine is administered as a tablet or film which are both available through maintenance clinics and MD practices in the United States as well as abroad (Jones et al., 2014). Buprenorphine avoids the extreme fluctuations in opioid blood concentration that occurs with opioid abuse and which places both the mother and the fetus under physiological stress (Unger et al., 2011). Methadone has been the preferred treatment in the United States for withdrawal from opioids for the past forty years, but recently buprenorphine has increasingly been used as a method for withdrawal from opioids. Both buprenorphine and methadone reduce opioid cravings and alleviate withdrawal symptoms without the safety risks associated to using drugs (Unger et al., 2011). Due to the success of buprenorphine in OUD treatment, studies involving pregnant women have been completed to assess the effects of opioid exposure on the fetus. One such study was carried out at the National Institute on Drug Abuse (NIDA) and consisted of a clinical trial to test whether buprenorphine was a safe and effective alternative treatment for OUD during pregnancy. The study named The Maternal Opioid Treatment: Human Experimental Research (MOTHER) hypothesized that buprenorphine maintenance may have the same advantages for pregnant women treated with methadone, but the infant may have less neonatal distress (Unger et al., 2011). The MOTHER study recruited 175 women who had sought treatment for OUD at six treatment centers in the United States and one center in Austria. The women who participated in the study were from six to thirty weeks pregnant and those who chose to participate in the study were first treated with morphine, stabilized on the morphine dose, and then either given buprenorphine or methadone maintenance treatment for the remainder of their pregnancy. The MOTHER study was double blind to improve validity of the findings.
Of the 175 women who initially participated in the MOTHER study, 131 continued until giving birth. There were no significant differences between buprenorphine and methadone maintenance treatment regarding maternal weight gain, positive drug screens at birth, percentage of abnormal fetal presentations or need for a C-section, need for analgesia during delivery or serious medical complications at delivery (Unger et al., 2011). The only significant differences were observed in those infants whose mothers were treated with buprenorphine compared to those on methadone. The former experienced milder NAS compared to those exposed to methadone (Unger et al., 2011). For women on buprenorphine, the length of their hospital stay, the duration of withdrawal, and the total dose of morphine administered, were all significantly lower compared to the values for women on methadone treatment (Figure 2). The main conclusion of the study was that buprenorphine is as safe an option as methadone for women who are pregnant, especially for those who are new to treatment or who become pregnant while on buprenorphine (Unger et al., 2011).
Gawronski et al. (2014) compared outcomes between pregnant women who had been on buprenorphine and those who had been exposed to methadone. Their study population consisted of 150 women who were receiving maintenance treatment for OUD. Fifty-eight of the 150 women in the study were treated with buprenorphine while ninety-two were treated with methadone. The comparison was based on factors such as gestational age, birth weight, prematurity, admission to neonatal intensive care unit, and length of stay (Gawronski et al., 2014). The results showed both infant groups to be similar although NAS occurred less frequently among buprenorphine (64 percent) compared to the group treated with methadone (80 percent; Gawronski et al., 2014). The authors concluded that buprenorphine did not have any adverse neonatal outcomes, but further research would be necessary to fully examine the safety of the drug for the infant.
No long-term studies on the effects of buprenorphine on infants have been carried out. Kayemba-Kay’s & Laclyde (2003) conducted long-term studies on the effects of buprenorphine exposure on infants and conducted a follow-up study of thirteen infants born to addicted mothers under buprenorphine maintenance therapy. At the time of birth, NAS occurred in eleven of the thirteen cases, and ten of the eleven infants required treatment. At the following check-up, seven cases presented transient lower limb hypertonia, jerky movements, and jitteriness. These transient motor abnormalities were all within the normal milestone limits and completely resolved in 85 percent of cases.
Salo et al. (2009) conducted a study comparing emotional availability and child developmental status in caregiver-child relationships with prenatally buprenorphine-exposed and nonexposed three-year-old children. The study included twenty-one prenatally buprenorphine-exposed fetuses and thirteen nonexposed fetuses. The buprenorphine-exposed fetuses scored lower on maternal sensitivity, nonhostility, child responsiveness, involvement, and also on the Bayley Cognitive and Language scales compared to their nonexposed counterparts (Salo et al., 2009). This study showed buprenorphine may have long-term effects on a child’s emotional availability, parental self-efficacy, and cognitive functioning although further tests must be completed to identify all effects of buprenorphine.
Buprenorphine is a safer alternative for methadone during pregnancy. The research shows buprenorphine to have no harmful side effects for the infant in the short-term and, in some cases, buprenorphine even led to less severe symptoms in NAS compared to methadone. Further research needs to be completed to examine the long-term effects of buprenorphine on childhood milestones and brain development.
Methadone
Methadone is both a standard treatment for the management of pregnant women with an OUD and babies born with NAS. Since methadone use varies, it is important to know the effects on a fetus prenatally and as a postnatal treatment method for NAS.
As described in Cleary et al. (2010), compared to women who continue their illicit drug use during pregnancy, women on methadone maintenance therapy have been associated with better attendance at antenatal care, reduced maternal morbidity, and improved neonatal outcomes, including higher birth weight. While there are many arguments in favor of using methadone maintenance therapy during pregnancy, NAS is a potential and important negative consequence of such treatments (Cleary et al., 2010). It is estimated that the incidence rate of NAS after methadone exposure in utero may lie anywhere between 13 to 94 percent (Cleary et al., 2010). Although NAS is treatable, it commonly leads to prolonged hospital stays for the infant and can interrupt mother-infant bonding (Cleary et al., 2010). There are a variety of studies that have demonstrated diverging opinions on which factors of methadone maintenance therapy most affect NAS.
Cleary et al. (2010) found that there were no significant statistical differences in incidence rates of NAS among neonates of women maintained on low versus women on high methadone doses at delivery. A study done by Liu, Jones, Murray, Cook, and Nanan (2010) looked at possible correlations between maternal methadone dose and other risk factors and the development of NAS requiring treatment. They found that the timing and mode of delivery as well as the last maternal methadone dose were significant risk factors for the development of NAS requiring treatment (Liu et al., 2010). A different study by Kaltenbach et al. (2012) also found very little differences between NAS outcomes regarding methadone dosage. Babies conceived on methadone did not exhibit more severe neonatal abstinence than infants exposed to methadone during part of the gestational period only (Kaltenbach et al., 2012). It appears the amount and duration of methadone usage by pregnant women does not affect the severity of an infant’s NAS. However, while it does not affect the incidence, duration or severity of NAS, a study by Cleary et al. (2012) demonstrated that neonates exposed to prenatal doses of 80 mg and above did require higher cumulative doses of morphine to treat the NAS.
Although methadone maintenance therapy is often seen as the standard of care for pregnant women with an OUD, new research increasingly calls this approach into question. Gaalema et al. (2012) compared NAS in methadone versus buprenorphine exposed infants and found that the buprenorphine exposed infants fared much better as they had a milder and more limited NAS compared to methadone-exposed infants. The study also established that buprenorphine exposed infants required less morphine to treat NAS and had a significantly shorter duration of hospitalization. In addition, the timing of NAS treatment differed in that buprenorphine exposed infants needed pharmacological treatment significantly later than their methadone-exposed counterparts who required treatment, on average, within twenty-four hours of being born. Based on these findings, Gaalema et al., (2012) hypothesized that the difference between both treatments and the effects on infants could be explained by differences in the transplacental transfer and/or the pharmacokinetics of both medications.
The use of methadone maintenance therapy for pregnant woman has long been in dispute because of the negative consequences for the fetus, mainly NAS. Nevertheless, compared to a continued heroin use, methadone maintenance treatment has been associated with improved perinatal outcomes such as birth weights, fewer preterm births, and lower morbidity (Cleary et al., 2012).
In the methadone literature, we can distinguish between three main lines of research:
- Studies examining the effect of methadone dose
- Comparative studies examining treatment of pregnant women with methadone versus buprenorphine and the outcome for the infant
- Whether methadone or morphine are the better treatment for babies with NAS
It appears that while methadone is a better option compared to continued heroin use, other treatments exist that lead to improved outcomes for the exposed infant. Buprenorphine is the most studied alternative and has been shown to be an effective treatment for pregnant women diagnosed with OUD, both shortening the duration and mitigating the effects of NAS compared to methadone.
Morphine
Generally, of all the available approaches to NAS treatment, opioid compounds such as morphine and methadone are considered the most effective in the postnatal treatment of infants. The oral administration of alcohol free morphine is the most common initial therapeutic approach used by many hospitals today. Morphine decreases the occurrence of seizures, progresses feeding for the infant, eliminates diarrhea, reduces agitation, and can help controlling some of the more severe symptoms (Jansson et al., 2009). Additionally, morphine treatment is comparatively safe and better suited for NAS management.
As a treatment for NAS, morphine has also proved to be more effective than methadone yielding shorter hospital stays, less treatment required, and consequently cost savings for the hospital. Young, Hager, and Spurlock (2015) conducted a study comparing outcomes between treatments with oral morphine sulfate and oral methadone. The study used a retrospective chart and discovered that neonatal intensive care unit length of stay was reduced by thirty-two days and the hospital length of stay was decreased by thirty days for infants who had been treated with morphine sulfate rather than oral methadone. The overall length of treatment was also reduced for infants in the oral morphine group by approximately thirty-two days. This study also examined differences in the cost associated with both treatments. Not surprisingly, and mainly due to their much shorter hospital stay, the cost for the oral morphine sulfate group was reduced by approximately $41,584 per patient. The following graph shows a comparison between morphine and methadone as a treatment for NAS.
Limitations
Several limitations were found while conducting this literature review. These include the general lack of available research, the possibility of underreporting prenatal drug use, inherent limitations in the assessments used for treating NAS, and the Medicaid restrictions that prohibit medication assisted treatment. First, no studies have been published on the long-term effects of buprenorphine. While this could be because buprenorphine is a relatively new course of treatment for NAS, the long-term effects of buprenorphine on these infants is largely unknown. Therefore, time and more research are needed before a final verdict on the effectiveness of this treatment regarding infant development can be made.
Second, we are faced with the more general problem of the underreporting of mothers using opioids while pregnant; this can lead to inaccurate statistics on the prevalence rates of prenatal exposure to opioids. Without accurate statistics and mothers willing to admit to prenatal opioid use, it becomes challenging to recruit mothers to participate in studies to further research these treatment options.
Third, there are limitations with the assessments used. Hospitals and treatment centers often do not use the same assessments for NAS (Zimmermann-Baer et al., 2010). Additionally, the training required to utilize the scoring measure is extensive which can lead to problems of reliability and reproducibility. Lastly, due to changes in neonatal care, some of the measures in the assessment systems may be outdated and require updating to match newer improved models of care (Zimmermann-Baer et al., 2010).
Fourth, there are issues with low income mothers maintaining medical insurance. For many pregnant women, obtaining and maintaining Medicaid coverage is a large barrier to treatment (J. Shyken, personnel communication, November 1, 2016). If a woman’s Medicaid is suspended, she often loses access to her medication assisted treatment preventing her from receiving the necessary drugs to help herself and her fetus.
Future Directions
After reviewing the available literature on the best course of treatment for NAS, several plausible future directions for research could be identified. These include studies on the long-term effects of buprenorphine, better treatment options, and Medicaid expansion. First, more research is needed to investigate the long-term effects of buprenorphine on milestones and brain development as such studies are simply inexistent at present and potential long-term effects on infants are, thus, unknown. As heroin and narcotic use increases, it is necessary to have more treatment providers to help pregnant women. Currently, many treatment centers do not address substance use disorder and relapse effectively. Instead of realizing that relapse is a part of recovery, many programs discharge participants if they relapse. These treatment centers often do not provide adequate care for people and their individual recovery process (J. Shyken, personnel communication, November 1, 2016). Third, in states that have not passed Medicaid expansion, like Missouri, access to treatment for women is limited (J. Shyken, personnel communication, November 1, 2016). In the future, Medicaid expansion must be made a priority to ensure women’s access to medication assisted treatment as many women currently lack healthcare coverage for necessary treatment options (J. Shyken, personnel communication, November 1, 2016).
Conclusion
There are several treatment options for NAS: methadone, buprenorphine, and morphine. While methadone has been the treatment of choice for many years, recent studies have shown that it is not an ideal treatment for OUD and NAS and is increasingly being phased out in favor of more modern treatment methods. Research suggests that morphine is the better course of postnatal treatment for NAS while buprenorphine is better suited to lessen the effects of NAS on the infant (Young et al., 2015; Jansson et al., 2009).
The information outlined in this article stresses several implications for medical, social work, public health, and addiction professionals, particularly regarding the importance of proper assessment and basing a client’s course of treatment on, but not limited to: NAS assessment, recovery history, health care coverage, etc.; furthermore, while not the focus of this particular article, treatment for NAS should also honor a client’s right to self-determination and being a part of choosing the course of treatment that is right for them and their infant. A changing health care landscape will call for proper education and collaborative decision making from both client and provider. Finally, although many studies speak of the short-and mid-term benefits of these two novel courses of treatment, there are no studies on their long-term effects and further research would be needed to better reach a conclusive verdict.
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