Running head: NEONATAL ABSTINENCE SYNDROME

Neonatal Abstinence Syndrome Jillian L. Olvera California State University, San Bernardino

Running head: NEONATAL ABSTINENCE SYNDROME Neonatal Abstinence Syndrome Opiate use among pregnant women in the United States is at an all time high. The National Survey on Drug Use and Health reported that abuse of illegal substances by pregnant women was at 3.4% in 2004-05 (Jones, O'Grady, Johnson,Velez, & Jansson, 2010) and rose to 4.5% in 2009 (Hudak & Tan, 2012). This emerging trend has encouraged the use of pharmacotherapy drugs like methadone, buprenorphine, and morphine in order to maintain and suppress withdrawal symptoms during pregnancy (Kakko, Heilig, & Sarmon, 2008; Hudak & Tan, 2012). However, this type of drug maintenance has increased the chances of the fetus and newborn becoming addicted to these types of narcotics. The neonate (newborn) is unable to regulate its homeostasis and therefore will often undergo distress caused by opioid withdrawal.

This has led to the development of neonatal withdrawal or neonatal abstinence syndrome (NAS), where the neonate undergoes a series of opiate withdrawal symptoms. NAS is an infantile generalized disorder characterized by signs and symptoms indicating dysfunction of the autonomic nervous system, gastrointestinal tract, and respiratory system (Jones et al., 2005). The limitations of research and contrasting findings about the use of different pharmacotherapy drugs, suggests that there is a need for better methodological studies to help better understand and treat NAS. Causes, Symptoms, and Effects NAS is caused by intrauterine drug exposure due to maternal drug use or maternal drug maintenance. A study conducted by Coyle et al. (2012) found that 50-80% of neonates born to addicted mothers would develop NAS, which is similar to the findings by Jansson et al. in 2005 and Burns and Mattick in 2006 that reported 48-94% and 37-88% will develop NAS (Jansson, DiPietro, Elko, & Velez, 2010; Burns & Mattick, 2007; Johnson, Jones, & Fischer, 2003). Illicit

Running head: NEONATAL ABSTINENCE SYNDROME drug use includes opioids like cocaine, opium, and heroin and prescription drugs like codeine, oxycodone, Demerol, and Vicodin among others (Hudak & Tan, 2012). NAS includes a variety of symptoms such as (but not limited to) tremors, sleep apnea, hypertonicty, abnormal crying, sneezing, tachypnea (abnormally rapid breathing), vomiting, diarrhea, fever, poor sucking, convulsions, poor feeding, and frequent yawning (Ebner et al., 2007). Intrauterine exposure to

certain drugs may cause congenital anomalies and/or fetal growth restriction, increase the risk of preterm birth, produce signs of withdrawal or toxicity in the neonate, or impair normal neurodevelopment (Hudak & Tan, 2012). NAS symptoms on average, surface between 48-72 hours after birth (Jansson et al., 2010). Although there is a gap in the research regarding the long-term effects of neonatal opiate exposure, it has been linked to delayed or unexpressive brain responses in the neonates ears (Lester et al., 2003). On the contrary, Lester et al. concluded that there was no data significant enough to show that the two are related. The research is limited in this area because most participants do not continue seeking treatment past one month or after NAS treatment has expired. Illicit drug use by pregnant women is largely underrepresented for several reasons: underreporting, unreliable answers regarding drug use in study interviews, and a lack of urine and/or biological sample collections (Hudak & Tan, 2012). In addition, this condition is greatly underreported as research shows that the mother often chooses to forego prenatal care or does not report illicit drug use. When the mother abuses opiates, the adverse effects are not always clear. Because the child may or may not become dependent on the drug use in the womb, fetal distress may occur. In order to limit fetal distress and maternal withdrawal symptoms, a system of pharmacotherapy is utilized. Maintenance

Running head: NEONATAL ABSTINENCE SYNDROME

Pharmacotherapy is a form of medical treatment by means of drugs. This form of therapy is used as a safer way to limit maternal and fetal distress, as opposed to immediate detox, which has proved to be harmful to both mother and fetus (Jones, Jansson, OGrady, & Kaltenbach, 2013). In addition, this form of treatment reduces the chances of danger to the fetus while in utero. In fact, a majority of addiction professionals are supporters of pharmacotherapy as a way of suppressing NAS (Johnson et al., 2003). As a result, pharmacotherapy is a system used to limit the fetus experience with the spontaneity of opiate withdrawal. However, this often leads to the infant developing some form of neonatal abstinence syndrome. The drugs that are most highly researched and frequently used include methadone, buprenorphine, and morphine, but there are others i.e. phenobarbital (Ebner et al., 2007). Although the Food and Drug Administration have not officially accepted buprenorphine and methadone, these are still considered the standard of care for treating pregnant women with addiction (Jones et al., 2008). Methadone is the most widely recommended pharmacotherapy drug by doctors in treating opiate withdrawal in pregnant women (Jones et al., 2013). Methadone is a painkiller similar to morphine, with longer lasting effects used as a substitute for heroin or morphine addiction. This form of maintenance has been shown to decrease illicit drug behavior due to the similar effects it has on the body, as well as reducing the mothers risk of relapsing (Jones et al., 2008). It has also been proven to increase the chances of the mother receiving prenatal care, which can aid in averting maternal and fetal withdrawal distress that has been known to cause fetal death (Lim, Prasad, Samuels, Gardner, & Cordero, 2008). Methadone maintenance is the method studied most extensively (Ebner et al., 2006) and is considered the standard of care in the United States (Gaalema, Heil, Badger, Metayer, & Johnson, 2013).

Running head: NEONATAL ABSTINENCE SYNDROME

However, mothers maintained on methadone have shown to give birth to neonates with a higher rate of NAS (Jones et al., 2005). These results have led researchers to believe that the dosage of methadone given to the mother coincides with the severity of the NAS symptoms (Jones et al., 2013). Many studies dispute whether or not it has a greater effect on NAS compared to other drug maintenance therapies. Lim et al. (2009) found that the dosage of methadone in the mother correlates with the length of time for treatment of NAS in the infant. Moreover, Lim et al. (2009) concluded that for every dose of 5.5 mg of methadone given to the mother resulted in an extra day of pharmacotherapy. Jones et al. (2004) also found that medication was given at three times the rate for NAS in fetuses subjected to methadone in utero. However, in terms of differences between methadone and buprenorphine, most studies found no substantial differences (Jones et al., 2005). Buprenorphine is another painkiller used in therapy drug replacement (pharmacotherapy). This form of drug is being used more as an alternative to methadone maintenance as it is said to limit the longevity of NAS effects, if the symptoms are present. In a study conducted by H. E Jones et al. (2006), buprenorphine exposed infants required 89% less morphine on average to treat withdrawal and 43% less time recovering in a hospital setting (Coyle et al., 2012; Jones et al., 2006). Buprenorphine is being tested as a safer alternative pathway of drug maintenance because of the successful trials seen in non-pregnant addicts (adult). Although buprenorphine yields the same opiate like effects as methadone, there are certain constraints on the individual and physiological effects buprenorphine is able to produce (Jones et al., 2010). Research suggests that buprenorphine has a less detrimental effect on respiratory repression and minimal NAS after maintenance is withdrawn (Jones et al., 2010). In addition, Jones et al. (2004) reported that infants exposed to buprenorphine had a reduction in the time spent in the hospital

Running head: NEONATAL ABSTINENCE SYNDROME and were less likely (only 20%) to suffer from NAS than those exposed to methadone. This study was the first of its kind to compare both methadone and buprenorphine with such specific stipulations. Patients receiving buprenorphine were more likely to stop receiving treatment in

comparison to those treated with methadone. However, use of this drug is still in its early stages, therefore there may be unforeseen risks. One risk may be possible toxic or teratogen agents that can cause malformations in embryos (Johnson et al., 2003). However, there are other alternatives to treating opioid withdrawal in neonates. Although slow oral release morphine is an option, it is often used as a co-therapy alongside methadone and buprenorphine, but used in smaller doses. There have been positive results when using morphine hydrochloride, but there is not enough supporting evidence in the study to fully support this statement (Ebner et al., 2007). A study conducted by Ebner et al. (2007) showed that neonates born to mothers receiving slow oral release morphine had a higher incidence of NAS, but less treatment time than those treated with phenobarbital. Although this study presented small differences in phenobarbital and morphine, there are no real statistical differences (Ebner et al., 2007). Measurement There are several different scales used to measure the severity and aspects of NAS. There is no set general standard used amongst hospitals to determine this, but one of the three scale models is usually used. Loretta Finnegan originally published the Finnegan scale in 1975, as a scoring system for NAS from a clinical and investigative standpoint (Zimmerman-Baer, Notzli, Rentsch, & Bucher, 2009). The scale is based upon the 21 item signs and symptoms based on the three body systems disturbances: central nervous system, metabolic/vasomotor/respiratory, and gastro-intestinal. All symptoms are placed into one of

Running head: NEONATAL ABSTINENCE SYNDROME these three categories. Points are administered based on severity. This scale has been modified as new discoveries have been made to better assess and identify neonatal abstinence syndrome (Hudak & Tan, 2012). The Apgar score is a scale of identifying and summarizing the health of a newborn child at a 1-mintute interval then at the 5-minute interval. The score is based upon 5 categories:

breathing efforts, heart rate, muscle tone, reflexes, and skin tone. Each is given a score of 0,1 or 2. Zero being not at all or none, and 2 being the maximum. The Apgar score was used intermediately in a study conducted by H.E Jones et al. in 2010, as a form of secondary measurement of neonatal outcomes. The Neonatal Intensive Care Unit Network Neurobehavioral Scale, which is a modified version of the Finnegan scale, is a tool most often used to analyze the differences in the outcomes between neonates exposed to buprenorphine and methadone (Jones et al., 2010). It evaluates neurobehavioral organization, neurological reflexes, active and passive tone, motor functioning, stress signatures, and neonates that are at risk for drug withdrawal (Jones et al., 2010). Unfortunately, there is no set standard for how to treat or measure neonatal withdrawal, as it can be subject to the area and population within a given area. For example, areas with higher rates of illicit drug use, and a large population of women that are of childbearing age, will often be more experienced in treating NAS (Johnson et al., 2003). Many hospitals are not trained in these types of circumstances and are approached on a case-by-case basis. Furthermore, the lack of education about treating NAS leads to the confusion of the doctors and their patients (Jones et al., 2008). Jones et al. (2012) used a clinical staff that specialized in NAS procedures during the MOTHER study, which they believed would help produce more accurate findings. Sadly, this was only a controlled experiment and everyday clinics do not specialize in this type of care.

Running head: NEONATAL ABSTINENCE SYNDROME Thus, there is an immediate need to educate clinicians on the protocol for treating pregnant

opiate addicts. In addition, there have been reports of higher incidence of NAS in male neonates than in female, but did not have a higher incidence of needing treatment (Holbrook & Kaltenbach, 2010). Studies have shown no significant correlation between sex and NAS (Holbrook & Kaltenbach, 2010; Unger et al., 2011). However, previous research has produced conflicting outcomes, which indicates a gap in the research of sex and NAS correlation (Unger et al., 2011). Conclusion Consequently, there is also a significant lack of research in response to the long-term effects that these therapeutic drugs have on the development of the neonate (Hunt, Tzioumi, Collins, & Jeffery, 2008). A majority of studies focus on the effectiveness of a drug maintenance treatment that limits distress on the fetus; long-term effects are not an immediate concern. Hunt et al. (2008) reports that the environment plays a potent role in the long-term effects of the neonate. Once again, the continuation of research in this area is critical (Hunt et al., 2008). Follow-up research is needed in order to address the pending questions regarding intrauterine exposure on newborns. Underreporting is also a big concern because the population of pregnant women abusing opiates may be considerably higher than the small percentage that is accounted for. For this reason, research is sadly limited due to the small sample size of each trial (Jones et al., 2005; Coyle et al., 2012; Johnson et al., 2003). Specifically, it is limited to the participants of the study and the drug use reported. Since there are an inadequate number of cases treated, research is based solely on this small number. Furthermore, the small sample size and lack of continued participation proved to be the most detrimental to the experiments. The small samples

Running head: NEONATAL ABSTINENCE SYNDROME do not allow for researchers to detect risks on a large population scale (Kakko et al., 2008). In

addition, testing on infants is a delicate subject with many ethical issues coming into play, which is why it is not highly publicized as an emerging problem in our society. There is also a lack of research in regards to how different types of illicit and opioid drugs (i.e. cocaine, heroin) directly correlate with the severity of NAS. In closing this literature was written to educate people on the silenced public health issue plaguing the health of newborns. Also, to inform the audience of the emerging trend of opioid abuse among pregnant women that has led to more and more infants developing NAS. Moreover, to increase knowledge of pharmacotherapy drugs used on infants to treat NAS. Furthermore, this literature was meant to encourage more research on alternatives for treating NAS and hopefully to learn more about the effects these drugs have long-term.

Running head: NEONATAL ABSTINENCE SYNDROME I. Reference List

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Burns, L., & Mattick, R. (2007). Using population data to examine the prevalence and correlates of neonatal abstinence syndrome. Drug and Alcohol Review , 487-492. Coyle, M., Salisbury, A., Lester, B., Jones, H., Lin, H., Graf-Rohrmeister, K., et al. (2012). Neonatal neurobehavior effects following buprenorphine versus methadone exposure . Addiction , 63-73. Ebner, N., Rohrmeister, K., Winklbaur, B., Baewert, A., Jagsch, R., Peternell, A., et al. (2007). Management of neonatal abstinence syndrome in neonates born to opioid maintained women. Drug and Alcohol Dependence , 131-138. Gaaelma, D., Heil, S., Badger, G., & Metayer, J. (2013). Time to intiation of treatment for neonatal abstinence syndrome in neonates exposed in utero to buprenorphine or methadone. Drug and Alcohol Dependence , 266-269. Holbrook, A., & Kaltenbach, K. (2010). Gender and NAS: Does sex matter? Drug and Alcohol Dependence , 156-159. Hudak, M., & Tan, R. (2012). Neonatal Abstinence Syndrome. Journal of The American Academy of Pediatrics , e540-e560. Hunt, R., Tzioumi, D., Collins, E., & Jeffrey, H. (2008). Adverse neurodevelopment outcome of infants exposed to opiate in-utero. Early Human Development , 29-35. Jansson, L., DiPietro, J., Elko, A., & Velez, M. (2010). Infant autonomic functioning and neonatal abstinence syndrome. Drug and Alcohol Dependence , 198-204. Johnson, R., Jones, H., & Fischer, G. (2003). Drug and Alcohol Dependence . Use of buprenorphine in pregnancy: patient management and effects on the neonate , S87-S101.

Running head: NEONATAL ABSTINENCE SYNDROME Jones, H., Fischer, G., Heil, S., Kaltenbach, K., Martin, P., Coyle, M., et al. (2012). Maternal Opioid Treatment: Human Experimental Research (MOTHER)- approach, issues and lessons learned. Addiction , 28-35. Jones, H., Jansson, L., O'Grady, K., & Kalthenbach, K. (2013). The relationship between

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maternal methadone dose at delivery and noenatal outcome: Methodological and design considerations. Neurotoxicology and Teratology , 110-115. Jones, H., Johnson, R., Jasinski, D., O'Grady, K., Chisholm, C., Choo, R., et al. (2005). Buprenorphine versus methadone in the treatment of pregnant opioid-dependent patients: effects on the noenatal abstinence syndrome. Drug and Alcohol Dependence , 1-10. Jones, H., Kaltenbach, K., Heil, S., Stine, S., Coyle, M., Arria, A., et al. (2011). Neonatal Abstinence Syndrome after Methadone or Buprenorphine Exposure. New England Journal of Medicine , 2-17. Jones, H., Martin, P., Heil, S., Kaltenbach, K., Selby, P., Coyle, M., et al. (2008). Treatment of opioid-dependent pregnant women: Clinical and research issues. Journal of Substance Abuse Treatment , 245-259. Jones, H., O'Grady, K., Johnson, R., Velez, M., & Jansson, L. (2010). Infant Neurobehavior Following Prenatal Exposure to Methadone or Buprenorphine: Results From the Neonatal Intensive Care Unit Network. Substance Use and Misuse , 2244-2257. Kakko, J., Heilig, M., & Sarman, I. (2008). Buprenorphine and methadone treatment of opiate dependence during pregnancy: Comparison of fetal growth and neonatal outcomes in two consecutive case series. Drug and Alcohol Dependence , 69-78.

Running head: NEONATAL ABSTINENCE SYNDROME Lester, B., LaGasse, L., Seifer, R., Tronick, E., Bauer, C., Shankaran, S., et al. (2003). The Maternal Lifestyle Study (MLS): Effects of Prenatal Cocaine And/Or Opiate Exposure On Auditory Brain Response At One Month. The Journal of Pediatrics , 279-285. Lim, S., Prasad, M., Samuels, P., Gardner, D., & Cordero, L. (2009). High Dose methadone in pregnant women and its effect on duration of neonatal abstinence syndrome. American Journal of Obstetrics and Gynecology , 70.e1-70.e5.

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Unger, A., Jagsch, R., Baewert, A., Winklbaur, B., Rohrmeister, K., Martin, P., et al. (2011). Are Male Neonates More Vulnerable to Neonatal Abstinence Syndrome Than Female Neonates? Gender Medicine , 355-364. Zimmermann-Baer, U., Notzli, U., Rentsch, K., & Bucher, H. (2010). Finnegan neonatal abstinence scoring system: normal values for first 3 days and weeks 5-6 in non-addicted infants. Addiction , 524-528.