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Combating neonatal abstinence syndrome amid opioid crisis
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In July, the CDC reported that, following their peak in 2010, overall opioid prescriptions have declined as much as 18% through 2015. However, the CDC also noted that there remains significant regional variation for opioid prescription, especially at the county level where prescribing actually increased 23%.
Despite no overall change in the amount of pain reported by Americans, sales of opioids have nearly quadrupled in the U.S. since 1999, according to the CDC. Likewise, deaths from prescription opioids —including household names such as Vicodin (acetaminophen and hydrocodone, AbbVie), OxyContin (oxycodone; Purdue Pharma) and Percocet (oxycodone and acetaminophen, Endo Pharmaceuticals) — also quadrupled in that period.
Photo by: Vanderbilt University
Often attributed to escalating numbers of Americans seeking relief from chronic pain — approximately 25 million adults in the U.S. report experiencing daily pain, with an additional 23 million reporting severe recurring pain episodes — the stark increase in opioid prescriptions, coupled with growing heroin use, have led to what many have labeled an ‘opioid epidemic’.
As one of the worst drug crises in American history —surpassing even the numbers of the ‘crack epidemic’ in the 1980s — the opioid epidemic has resulted in significant economic burden on the U.S., measuring as much as $28 billion for health care and substance abuse treatment, according to a 2016 study by Florence and colleagues in Medical Care. However, an unanticipated cost of the opioid epidemic has been passed on to the next generation in the form of neonatal withdrawal, otherwise known as neonatal abstinence syndrome (NAS).
Although much of the national discourse has remained focused on adult opioid users, neonatologists and pediatricians across the country have been treating unprecedented rates of infants with withdrawal symptoms, as well as respiratory and feeding difficulties, low birth weight, and seizures that often accompany this condition. As a substantial burden on already overtaxed hospital systems, especially neonatal intensive care units, NAS requires immediate implementation of preventive screening and treatment during pregnancy, as well as standardization of postnatal treatment for infants undergoing withdrawal, to curtail its staggering growth.
To gain insight into how the opioid epidemic continues to impact this silent demographic, Infectious Diseases in Children spoke with several authorities in the field of neonatology and pediatrics, from researchers focusing on the best possible treatments for newborn victims of opioid abuse to those directly treating these infants daily.
An unanticipated boom
Between 1999 and 2013, the CDC reported that the overall NAS incidence in the U.S. increased 383%, from 1.5 per 1,000 hospital births in 1999, to 6.0 per 1,000 hospital births in 2013 — an upsurge attributed to a rise in the use of both prescription and illicit opioids among pregnant women, as well as the increased use of methadone or morphine for the treatment of opioid addiction.
“We have seen a pretty rapid increase in opioid use over the last 15 years, and prescriptions for opioid pain relievers grew by about fourfold,” Stephen W. Patrick, MD, MPH, MS, assistant professor of pediatrics and health policy at Vanderbilt University said in an interview with Infectious Diseases in Children. “In 2012, 259 million prescriptions were written for opioid pain relievers. Although the U.S. consumes about 80% of the world’s opioids, it represents only about 4.6% of the world population.”
In a 2015 study in the Journal of Perinatology, Patrick and colleagues indicated that states with the highest rates of prescription opioid use would also exhibit the highest rates of NAS, with the highest incidence rates in Kentucky, Tennessee, Mississippi and Alabama. Compounding the statewide NAS disparity, the pattern of opioid use has expanded from inner-city, low-income populations, with disproportionate increases in the incidence of NAS and maternal opioid use in rural counties compared with urban counties.
In a research letter published in JAMA Pediatrics, Nicole Villapiano, MD, a Robert Wood Johnson Clinical Scholar and pediatrician at the University of Michigan Mott Children’s Hospital, noted that although nationwide incidence rates for NAS and maternal opioid use had increased fivefold over the previous decade, the overall proportion of infants diagnosed with NAS from rural communities rose from 12.9% to 21.2%.
In parallel with rising rates of hepatitis C and overdose deaths associated with opioid use, the growing incidence of NAS in rural communities highlights the necessity for improved access to opioid use prevention and treatment services for women. However, this public health mission is often complicated by the fact that NAS is difficult to detect in pregnant women and even more difficult to prevent among women who were unaware they were pregnant while using opioids.
According to a study by Heil and colleagues in the Journal of Substance Abuse Treatment, approximately nine out of 10 pregnancies that occur among women who use opioids were unplanned: Among these pregnancies, 34% were mistimed, 27% were unwanted, and 26% of mothers did not know that they were pregnant.
“The only way to prevent NAS is to avoid opioid exposure during pregnancy,” Villapiano said in an interview. “Our first goal is to prevent women from using opioids in the first place, which often means addressing mental health and chronic pain issues that if untreated, are common precursors to opioid use and dependence. If a woman is still dependent on opioids when she becomes pregnant, we want to make sure she gets treated with a medication like buprenorphine or methadone that will ensure her safety during pregnancy and improve the health of her infant when she eventually delivers.”
Although methadone is available as a treatment for opioid addiction during pregnancy — condoned by the American Congress for Obstetricians and Gynecologists for women with opioid dependency — information on prior opioid exposure from the mother is paramount to the future well-being of the infant a because no other prevention or early detection methods are currently available.
Detection and treatment
“Information on what kinds of substances or medications a mother might be taking during pregnancy is probably our best estimate [of whether an infant will develop NAS],” Jean Ko, PhD, from the Division of Reproductive Health within the National Center for Chronic Disease Prevention and Health Promotion at the CDC, told Infectious Diseases in Children. “Signs of NAS are typically evident 48-72 hours after birth. Some hospitals may try to keep the infants that they know have been exposed for just a little longer to make sure that there are not any delayed signs of NAS before discharge.”
In the interview, Ko noted that several states have pushed to preemptively identify individuals at risk for having infants with NAS, namely women who may be using opioids or have opioid use disorder while pregnant, to provide the most comprehensive care possible to the mother-infant duo. These at-risk women are then put in contact with the appropriate health service teams which can follow them throughout their pregnancy and postpartum periods. However, unless the mother discloses her opioid use, there are few ways to implement early intervention prior to birth.
“I think that one of the barriers to exposure is disclosure during pregnancy. Some women may be very reluctant to describe opioid use during pregnancy for fear of Child Protective Services taking their baby away or the stigma of opioid use, especially during pregnancy,” Karen McQueen, RN, PhD, associate professor of nursing at Lakehead University, said in an interview. “However, many women are also less reluctant to disclose because they are concerned about their unborn infant. They want providers to have the information to make necessary decisions.”
Treatment for these mothers may include supervised medication therapy with methadone or morphine, but treatment for infants with withdrawal symptoms ranges from nonpharmacological methods — including breast-feeding if safe and rooming with the mother or reducing environmental stimuli — to the use of morphine, methadone or buprenorphine.
“A big question has been whether to use morphine or methadone,” Walter Kraft, MD, professor and director of the Clinical Research Unit and Division of Clinical Pharmacology at Thomas Jefferson University, said. “There is quite a bit of heterogeneity in terms of dose regimens for both drugs –what dose to start at, how fast to go up and how quickly to wean doses – with no established standard regimen.”
To determine whether medication should be used, scoring is typically administered using the Finnegan Neonatal Abstinence Scoring System, which assesses possible NAS symptoms, including high-pitched crying, poor feeding or tremors, as well as sleeping habits, consolability, fever or irritability among others. According to McQueen, if an infant scores greater than or equal to 8 on two consecutive assessments, medication is appropriate for the treatment of their symptoms.
“Think about it like a blood pressure cuff or a thermometer: Both are instruments that need to be calibrated to make sure they are as accurate as possible to allow clinicians to make decisions based on them,” Kraft said in an interview. “In the same fashion, nurses who spend all day with the child need training in administration so there is consistency and standardized scoring between assessors.”
Disparities in care
Standardization of care may be uniform within individual hospitals and NICUs; however, there is no current consistency in the way infants with NAS are treated throughout the U.S. This disparity is partly due to the lack of research concerning when interventions should be used, dosages of medication needed and other best practices.
“Many experts will say that a large part of the problem is that NICUs around the country were not ready for this increase in NAS infants,” McQueen said. “I think that, in general, we are moving pretty quickly in terms of trying to get research and data together so that we can better care for both pregnant women and their infants.”
The unpreparedness of NICUs for the influx of infants with NAS was highlighted in a study by Patrick and colleagues published in Pediatrics, which found that among 199 hospitals within the U.S., only 44.8% had a policy that standardized the use of a scoring system. Additionally, the researchers found that less than half (44.6%) had created policies on breast-feeding for mothers with an infant who had substance exposure, whereas only 68.0% had specific policies in place for pharmacologic treatment of NAS.
In an earlier study in the Journal of Perinatology, Patrick and colleagues had determined that length of hospital stay for infants also varied by institution, with two fold differences found in risk-adjusted time spent in a hospital. This variation is not only causes an increase in time need to address these infants, but it is also monetarily expensive.
In 2012, this length of stay, included with the cost of birth, accounted for $1.5 billion, according to CDC — infants with NAS who required pharmacological therapy had a mean length of stay of 23 days, costing $93,000 in hospital bills, compared with the average 3-day length of stay and $3,000 cost attributed to other infants.
Patrick told Infectious Diseases in Children that despite the efforts to prevent disparities in care, there are several aspects of the health care system where there is exceptional variation in the standard of care from state to state: NAS is clearly one of them.
“We know that just doing the same thing every time with adjustments made for new research improves outcomes,” Patrick said. “There has not been significant focus on NAS overall, and its rapid rise has caught hospitals and providers off-guard. It is not something that many people had seen until recently. A summation of best practices, communication about information available, and standardizing scores and other aspects of care would be a step forward.”
Despite the lack of uniformity, there have been treatments with demonstrated efficacy, and hospitals nationwide have begun to implement these methods. Evidence-based practices continued to be used, including morphine and methadone as first line treatment, although a recent study by Kraft and colleagues in The New England Journal of Medicine suggests that buprenorphine may be associated with shorter lengths of hospital treatments and stays than morphine.
According to study results, buprenorphine was associated with a 42% decrease in the length of treatment vs. standard morphine. Kraft noted that the average length of treatment needed for infants administered buprenorphine was 15 days compared with 28 days using morphine; additionally, length of hospital stays for infants given buprenorphine averaged 21 days vs. 34.5 days for infants given morphine.
“At the moment, it is not clear whether opioid exposure in utero has any negative long term effects on these infants,” Villapiano said. “More research is needed in this area.”
NAS and federal legislation
In November 2015, President Barack Obama signed bipartisan legislation, the Protecting Our Infants Act of 2015 (POIA), into law. Introduced by Senate Majority Leader Mitch McConnell (R-Ky) and Sen. Bob Casey (D-Pa) and by Rep. Katherine Clark (D-Mass.) and Steve Stivers (R-Ohio) — all from states hard hit by the opioid epidemic — the law was intended to support existing efforts to maternal opioid use and abuse, and provide recommendations for diagnosing and treating infants suffering from withdrawal.
POIA also required governmental organizations, including the Department of Health and Human Services and the CDC, to conduct studies, create guidelines and recommendations regarding prevention and treatment, support states in data collection regarding NAS and encourage public health initiatives to reduce the prevalence of the condition.
In 2016, in a rare near-unanimous vote, Congress voted in favor of passing the Comprehensive Addiction and Recovery Act (CARA), sweeping legislation intended to tackle the opioid epidemic head-on by addressing the full continuum of care from primary prevention to recovery support. Signed into law by President Obama in July 2016, the provisions of the law included significant changes to expand access to addiction treatment services, overdose reversal medications, more stringent monitoring of prescribing practices and initiatives to increase outreach related to NAS.
“This comprehensive bill lays the groundwork to turn the tide on the opioid epidemic, which is killing 129 people a day,” Gen. Arthur T. Dean, chairman and CEO of the Community Anti-Drug Coalitions of America, said in a statement.
Although the Obama administration had originally requested $1.1 billion to battle the far-reaching branches of the opioid epidemic, the law only authorized $181 million in funding. Multiple proposed amendments by Senate Democrats to provide $600 million in emergency funding for the bill were blocked by Republicans, who argued that $400 million was available to CARA as part of the omnibus spending bill passed in 2015.
A resolution passed in September 2016 added approximately $7.1 million in funding for CARA, yet remained $920 million short of the original requested.
However meager its funding, the status of such landmark legislation is currently in limbo. With the changes proposed by President Donald J. Trump to repeal and replace the Affordable Care Act, health initiatives such as CARA and POIA could be in jeopardy.
In the recently proposed Senate health care bills intended to replace the Affordable Care Act, Republican leadership has outlined significant cuts to Medicaid funding; yet more than 80% of hospital costs for newborns with NAS were paid by state Medicaid programs. In all, the legislation would cut $772 billion from Medicaid funding by 2026.
“I think there is nothing direct about infants with NAS under the proposed legislation that passed the House,” Patrick said. “However, this proposal substantially changes Medicaid in was that really appear to cause shift to states and creates per capita caps. I think that is worrisome for what that might do to Medicaid moving forward, and we know that is an important safety net for those with opioid use disorder and infants with NAS.”
Some experts are concerned about what the future legislation holds for infants with NAS and their mothers; however, Dr. Ko noted that it is too early to speculate what might occur under the proposed changes.
Even if proposed Medicaid cuts are removed from the new Senate health care bill — President Trump has repeatedly remarked that there will be “no cuts to Social Security, Medicare and Medicaid” — strategic changes to the “essential health benefits” for those covered under Medicaid expansion could drastically alter what services state Medicaid programs are required to offer, including mental health and substance abuse services.
“There are many ways that policies may help prevent NAS, but the focus needs to be shifted from the infant to the woman before she becomes pregnant.” Villapiano said. “Nobody wants to see an infant that is dependent on opioids. Most infants with NAS and mothers with opioid dependence in pregnancy are insured my Medicaid, however, there is currently significant division in Congress about funding for the Medicaid program. Medicaid funding cuts may mean that a young low-income woman dependent on opioids may not have access to health care coverage and treatment for their opioid dependence. I am concerned that cuts to the Medicaid program could exacerbate the spike in of maternal opioid use and NAS we have seen in the last decade.” – by Katherine Bortz
- Florence CS, et al. Medical Care. 2016. doi: 10.1097/MLR.0000000000000625.
- Guy GP Jr., et al. MMWR Morb Mortal Wkly Rep 2017. doi: 10.15585/mmwr.mm6626a4.
- Heil SH, et al. J Subst Abuse Treat. 2011. doi:10.1016/j.jsat.2010.08.011.
- Ko JY, et al. MMWR Morb Mortal Wkly Rep. 2017. doi:10.15585/mmwr.mm6531a2.
- Kraft WK, et al. N Engl J Med. 2017. doi:10.1056/NEJMoa1614835.
- Meldrum ML. Am J Public Health. 2017. doi:10.2105/AJPH.2016.303297.
- Patrick SW, et al. Pediatrics. 2016. doi:10.1542/peds.2015-3835.
- Jean Ko, PhD, can be reached at the CDC, Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, 1600 Clifton Road, Atlanta, GA, 30329.
- Walter Kraft, MD, can be reached at Thomas Jefferson University, Department of Pharmacology and Experimental Therapeutics, 132 South Tenth Street, 1170 Main Building, Philadelphia, PA 19107; email: Walter.Kraft@jefferson.edu.
- Karen McQueen, RN, PhD, can be reached at Lakehead University, Thunder Bay, 955 Oliver Road, Thunder Bay, ON, P7B 5E1.
- Stephen Patrick, MD, MPH, MS, can be reached at the Vanderbilt University School of Medicine, Department of Pediatrics, 11111 Doctors’ Office Tower, Nashville, TN 37232-9544.
- Nicole Villapiano, MD, can be reached at the University of Michigan, Robert W. Johnson Foundation Clinical Scholars Program, 2800 Plymouth Road, Ann Arbor, MI 48109-2800; email: gergen@med.umich.edu.
Disclosures: Ko, Kraft, McQueen, Patrick and Villapiano report no relevant financial disclosures.