Medication Assisted Treatment
Medication assisted treatment (MAT) is a first line therapy for OUD in pregnant women, recommended as part of a comprehensive treatment plan (Mozurkewich and Rayburn, 2014; SAMHSA, 2014; ACOG, 2016; WHO, 2014; ASAM, 2017). MAT involves the use of prescription medication to facilitate abstinence from illicit opioids by treating and preventing symptoms of withdrawal or blocking the euphoric effects of opioids. Three medications have been approved by the FDA for MAT: methadone, buprenorphine, and naltrexone.
When a pregnant woman uses short-acting illicit opioids, she and her fetus are in a continuous cycle of intoxication and withdrawal. Maternal opioid intoxication causes respiratory depression and can lead to aspiration and overdose. As opioid crosses the placenta and the fetus is affected by maternal respiratory depression, the fetus can experience hypoxemia, acidosis, intrauterine growth restriction (IUGR) and fetal demise. Maternal opioid withdrawal causes tachycardia, hypertension, nausea, vomiting, and increased metabolic demand, putting further stress on the fetus, which can lead to miscarriage, preterm labor, and premature rupture of membranes (Young and Martin, 2012). Illicit opioid use is highly correlated with other negative exposures, including unstable housing, criminality, violence, poor nutrition, infectious disease, untreated mental illness, polysubstance use, tobacco, and alcohol (Young and Martin, 2012).
Methadone and buprenorphine are synthetic opioids prescribed in place of illicit opioids to prevent cravings and mitigate withdrawal symptoms. This opioid replacement therapy (ORT) is part of a harm-reduction model. Regular dosing of methadone or buprenorphine maintains a steady state of opioid in the body, breaking the cycle of intoxication and withdrawal. Ideally, the dose is low enough to avoid central nervous system (CNS) depression but high enough to curb illicit substance use, thus mitigating its associated exposures.
The FDA approved the use of methadone to treat OUD in 1972 and it has been the mainstay of MAT for pregnant patients for decades. It is the most studied pharmacological treatment for OUD in pregnant women and the general population (Tran et al, 2017). Methadone is a full opioid agonist with a half-life of 8 to 59 hours (Lexicomp, 2016a). The long, unpredictable half-life can cause a lengthy delay induction or dose change to reaching a steady state. Thus, toxicity may not manifest for several days (Tran et al, 2017). Methadone has numerous drug interactions and increases the risk of CNS depression and QTc prolongation. (Lexicomp, 2016a).
Methadone is only administered at SAMHSA-certified opioid treatment centers. This model aims to reduce diversion and enhance patient safety by screening patients for other substances which, if taken in combination with methadone, can result in over sedation or overdose (SAMHSA, 2015). Patients must present at the clinic each day to receive their methadone dose. This can create challenges of access and interfere with activities of daily life, which may result in discontinuation of methadone treatment (Tran et al, 2017). Stable patients with a demonstrated record of treatment compliance and negative drug screens may qualify for take-home doses (SAMHSA, 2015). However, for some patients, the regular follow-up and daily clinical contact can be a source of additional support for pregnant women at a time when they are vulnerable to relapse. Though most methadone clinics have long waiting lists, federal guidelines require that pregnant women are given priority in accessing ORT (SAMHSA, 2015).
A Cochrane review found that methadone treatment was more effective than placebo in reducing heroin use and increasing treatment retention (Minozzi et al, 2013). Compared with buprenorphine, methadone is associated with higher levels of patient retention (Tran et al, 2017; Jones et al, 2010) and patient satisfaction (Mozurkewich et al, 2014).
Buprenorphine is a partial opioid agonist at the mu receptor and an opioid antagonist at the kappa receptor (Tran et al, 2017). It was approved by the FDA for OUD treatment in 2002. Because it is a partial agonist, buprenorphine has a ceiling effect for respiratory depression, lowering the risk of overdose compared to methadone (Tran et al, 2017), but buprenorphine can still cause CNS depression and concomitant use of other CNS depressants should be avoided (Lexicomp, 2017a).
Buprenorphine is administered sublingually as a tablet or film and is available as either a single agent or in a combination formulation with naloxone, an opioid antagonist. The dual-agent formulation is designed to prevent diversion and misuse. When taken sublingually, the naloxone has no effect but if the tablet or film is cooked down and injected it causes acute opioid withdrawal (reference). ACOG recommends that pregnant women use the single agent formulation to avoid additional fetal exposures and reduce the risk of precipitated withdrawal (ACOG, 2016).
Unlike methadone, buprenorphine is prescribed from outpatient health centers by clinicians trained in buprenorphine management. Buprenorphine induction is performed at a health center under physician supervision, but once the dose has been titrated up to a steady state, usually within a few days, the patient can fill the buprenorphine prescription at any pharmacy and self-administer the medication at home (Mozurkewich and Rayburn, 2014).
Patients who are polysubstance users and those who have historically used higher doses of street opioids may continue to report cravings while taking buprenorphine, which may explain the higher rates of discontinuation (Mozurkewich and Rayburn, 2014). However, a large study in Vermont found that pregnant women on buprenorphine were more likely to receive adequate prenatal care and still be on ORT at time of delivery than pregnant women taking methadone (Meyer et al, 2015). A meta-analysis also found women on buprenorphine were less likely to use illicit substances near time of delivery (Brogly et al, 2014) and one study found significantly lower rates of heroin, cannabis, and cocaine exposure in infants born to mothers buprenorphine than methadone (Lacroix et al, 2011). A recent study from Boston Medical Center (BMC) found that pregnant women treated with buprenorphine had an average of three more prenatal visits and were less likely to screen positive for illicit substances than those on methadone (Saia et al, 2017).
It should be noted that rather than highlighting the superiority of buprenorphine, the above-mentioned differences in outcomes between treatment groups may be illustrative of confounding factors associated these two groups. The role of social and environmental risk factors in treatment outcomes should not be overlooked. For example, a recent study of pregnant women with OUD in Pittsburgh found that those on buprenorphine were more likely to be older, married, employed, more educated, and have a history of prescription opioid use, whereas those on methadone were more likely to have Hepatitis C; use cocaine, benzodiazepines, and marijuana; and have a history of intravenous drug use (Krans et al, 2016). The Vermont study found that women on buprenorphine were more likely to have started ORT prior to conception or early in pregnancy (Meyer et al, 2015) and the BMC study noted that their treatment protocols recommend methadone over buprenorphine for more severe cases (Saia et al, 2017).
To date there is no conclusive evidence to suggest that methadone or buprenorphine is more effective in treating OUD and researchers caution that medication interventions are only one element of comprehensive treatment (Jones, 2013; Hand et al, 2017). ACOG, the WHO, and ASAM recommend either methadone or buprenorphine as first line treatments (WHO, 2014; ACOG, 2016; ASAM, 2017). The choice of methadone or buprenorphine should be made on a case-by-case basis in partnership with the patient. Patients who become pregnant while on methadone or buprenorphine should continue their treatment.
Additionally, a patient who has been stable on methadone and becomes pregnant should not switch to buprenorphine because of the risk of precipitated withdrawal (ACOG, 2016). The dose of methadone or buprenorphine should not be reduced when a patient who has been stable on ORT becomes pregnant, rather dosing should be guided by the patient’s symptoms (Tran et al, 2017; Mozurkewich and Rayburn, 2014; ACOG, 2016; ASAM, 2017). As gestation advances, the half-life of methadone may shorten to as little as eight hours due to the physiological effects of pregnancy, including slower gastrointestinal transit time, greater blood volume, and increased renal elimination. Higher doses of methadone and buprenorphine may be necessary in the second and third trimester (Mozurkewich and Rayburn, 2014). Some patients may benefit from twice daily dosing of methadone if they experience withdrawal symptoms later in pregnancy. Split dosing can increase the plasma level of methadone and may reduce the risk of illicit substance supplementation. Split dosing also causes less suppression of fetal neurobehavior than single dosing (Mozurkewich and Rayburn, 2014).
Naltrexone is an opioid antagonist that blocks the euphoric effects of opioids (Lexicomp, 2017c). It is available as a daily oral tablet or monthly depot injection. In the general population, oral naltrexone has been associated with poor treatment adherence and high mortality rates (Connery, 2015). There is limited evidence on the use of naltrexone among pregnant women, though one study did find that those who received the depot injection were significantly less likely to have a positive urine screen for illicit substances than those who received a placebo injection (Krupitsky et al, 2011 in Tran et al, 2017).
Naltrexone is not recommended as a first line MAT intervention for pregnant patients because any patient wishing to commence naltrexone treatment must undergo opioid detoxification and maintain an opioid-free period, thus increasing the risk of relapse (ACOG, 2016). One study found that the 44% of pregnant patients who were prescribed naltrexone had discontinued treatment within 6 months of initiation (Jones et al, 2012).
Effects of ORT on the fetus, infant, and child
Both methadone and buprenorphine are labeled as pregnancy category C by the FDA because of the high risk of neonatal abstinence syndrome (NAS) associated with prenatal exposure (Lexicomp, 2017a; Lexicomp, 2017b). NAS is the most well documented effect of maternal ORT on the fetus. Symptoms include high-pitched cry, irritability, difficulty sleeping, enhanced Moro reflex, hypertonicity, tremors, skin excoriation, difficulty feeding, vomiting, diarrhea, diaphoresis, sneezing, mottling, fever, nasal stuffiness, yawning, failure to thrive, excessive motor activity, regurgitation, hyperphagia, and myoclonia jerks (Jansson, 2017; McQueen and Murphy-Oikonen, 2016; Kocherlakota, 2014). Seizures occur in 2-11% of cases (Jansson, 2017). NAS is a significant risk factor for respiratory complications (Smith and Lipari, 2017).
Symptoms emerge as the infant enters withdrawal. The onset and duration of withdrawal varies by drug. Heroin has a shorter half-life (24 hours) and is associated with earlier onset of shorter duration of NAS, whereas methadone and buprenorphine are associated with later onset and longer duration. In infants exposed to methadone or buprenorphine, symptoms of NAS may not develop for up to five days (Jansson, 2017; Kocherlakota, 2014). All infants known or suspected to be at risk for NAS should remain inpatient for at least seven days for observation and assessment (Jansson, 2017).
NAS diagnosis is based on clinical signs and may be corroborated by maternal interview and neonatal toxicology screening (Jansson, 2017; McQueen and Murphy-Oikonen, 2016). The Neonatal Abstinence Scoring System (NASS), also referred to as the Finnegan Scoring System, and the Neonatal Drug Withdrawal Scoring System (NDWSS), also known as the Lipsitz Scale, are validated tools for assessing NAS severity and determining pharmacological treatment. Hospital protocols vary widely, but symptom scoring can be performed every three to four hours. Intra-observer variability is a challenge in all NAS symptom-rating tools. The NASS is used most frequently but the NDWSS is recommended by the AAP (Jansson, 2017; Kraft et al, 2016; McQueen and Murphy-Oikonen, 2016; Jones and Fielder, 2015).
Risk and protective factors for the development and severity of NAS are not well understood. Alterations in levels of the neurotransmitters norepinephrine, dopamine, and serotonin may play a role (Kraft et al, 2016). Lower rates of NAS in preterm infants (Jansson, 2017; Seligman et al, 2008; Kocherlakota, 2014) may be due to fetal brain immaturity, fewer opiate receptors, lower cumulative drug exposure, less placental transfer, delayed hepatic and placental metabolism, or less drug deposition because of lower fat content (Kraft et al, 2016).
Genetic factors and male gender may be associated with greater severity of NAS (Kocherlakota, 2014). Maternal polysubstance, specifically benzodiazepine exposure, is associated with longer NAS treatment (Seligman et al, 2008; Kocherlakota, 2014).
Many studies have found that the prevalence and severity of NAS is greater in infants exposed to methadone than buprenorphine (Nørgaard et al, 2015; Kakko et al, 2008; Gawronski et al, 2014; Brogly et al, 2014; Meyer at al, 2015; Wurst et al, 2016; Weigand et al, 2015). One Czech study even found that NAS was more severe with methadone exposure than heroin exposure (Binder and Vavrinkova, 2008). Buprenorphine is also associated with shorter duration of treatment and lower morphine doses (Brogly et al, 2014; Jones et al, 2010; Meyer et al, 2015; Weigand et al, 2015). Some studies have found that the risk of NAS increases with exposure to SSRIs and cigarette smoking (Patrick et al, 2015; Bakstad et al, 2008) while others have found no such relationship (Seligman et al, 2010).
The relationship between maternal methadone or buprenorphine dose and NAS remains unclear. Several studies have found no relationship between maternal dose and rate or severity of NAS (Seligman et al, 2010; O’Connor et al, 2016; Bakstad et al, 2009). However, an Australian study found that for each 5mg increase in maternal methadone dose, the risk of NAS increased 17% (Liu et al, 2010) and another study found that use of adjunctive phenobarbital to treat NAS (an indicator of severity) was associated with higher maternal methadone dose (Isemann et al, 2011).
Nonpharmacological interventions are first line treatment for NAS and should be implemented for all infants suspected or known to be at risk. Interventions include positioning (side-lying C position); swaddling; gentle vertical rocking; reducing tactile, auditory and visual stimuli; skin care for excoriation; small, frequent feedings; breastfeeding; supplemental feeding with calorie-dense formula, if necessary; parental involvement in care; and skin-to-skin (Jansson, 2017; Kocherlakota, 2014). A systematic review of nonpharmacological treatments found that breastfeeding and rooming-in were associated with shorter length of stay, lower NAS scores, less pharmacological treatment, and less agitation and better sleep in the infant (Edwards and Brown, 2016).
Breastfeeding is recommended for mothers maintained on ORT unless the mother is HIV positive, continues to use illicit substances, or has recently used illicit substances (Sachs and Committee on Drugs, 2016; ACOG, 2016; ASAM, 2017; Reece-Stremtan et a, 2015). The concentration of methadone and buprenorphine in breastmilk is relatively low: 3% and 2.4% of the maternal weight-adjusted dose, respectively (Sachs and Committee on Drugs, 2016). Risks associated with breastfeeding while on ORT include the potential for infant sedation and respiratory depression. Mothers should be educated on signs of sedation and nursing infants should be closely monitored (Lexicomp, 2017a; Lexicomp, 2017b).
The amount of methadone or buprenorphine in breast milk is insufficient to prevent NAS (Sachs and Committee on Drugs, 2016) therefore it is theorized that is associated delayed onset and lower severity associated with breastfeeding may be due to other therapeutic factors associated with breastfeeding, such as maternal-infant bonding (Jansson, 2017; Reece-Stremtan et al, 2015; ASAM, 2017; ACOG, 2016; Sachs and Committee on Drugs, 2013; Edwards and Brown, 2016). The rate of breastfeeding among U.S. women on methadone is approximately half that of the general population, which may be due to lack of support and encouragement by healthcare professionals and misinformation about the safety of breastfeeding while on ORT (Reece-Stremtan et al, 2015). Though there is no evidence linking abrupt discontinuation of breastfeeding with development NAS, but women who continue ORT are recommended to wean their infants gradually (Sachs and Committee on Drug, 2016; Jansson, 2017; Kocherlakota, 2014).
Liquid morphine sulfate and, less commonly, methadone, are used to treat NAS in infants whose symptoms are not adequately controlled with nonpharmacological interventions (Kraft et al, 2016; McQueen and Murphy-Oikonen, 2016; Kocherlakota, 2014; Jansson, 2017). The short half-life of morphine (3-4 hours) allows for frequent dose adjustment (Kraft et al, 2016). Because of its long half-life, methadone doses can only be adjusted twice per day, leading to challenges for dose titration (Kocherlakota, 2014).
Although one study found that the duration of treatment for infants who received methadone was 45% shorter than those treated with morphine (Patrick et al, 2014) there is no conclusive evidence on whether morphine or methadone is a better first-line treatment for NAS and research in this area continues (Kraft et al, 2016). To date, there are no documented cases of QT prolongation in neonates treated with methadone (Kraft et al, 2016).
Morphine or methadone dosing is based either on weight or symptom severity. There are no clinical trials comparing these two approaches (Kraft et al; 2016; McQueen and Murphy-Oikonen, 2016; Jones and Fielder, 2015) but Jones and Fielder point out that “smaller infants may have more opioid exposure and/or poly-drug exposure and therefore need more medication, as such a symptom-based treatment protocol may be the clinically more responsive approach” (Jones and Fielder, 2015, p. 16).
As more pregnant women are being treated for OUD with buprenorphine, clinicians and researcher have begun to investigate whether it may also be a suitable treatment for NAS. A study comparing the use of sublingual buprenorphine with oral morphine found that the median duration of NAS treatment and length of hospital stay were shorter in the buprenorphine group with no difference in the rate of cases requiring adjunctive phenobarbital between the groups (Kraft et al, 2017). However, most formulations of buprenorphine (and methadone) contain ethanol, the safety of which has not been established in infants (Kraft et al, 2016). Additionally, sublingual administration may be challenging in infants (Jansson, 2017).
Drug treatment for NAS can be augmented with second-line therapies if symptoms are not adequately controlled with morphine or methadone alone. Phenobarbital, also used to treat neonatal seizures, may be particularly effective for infants exposed to maternal polysubstance use (Kraft et al, 2016; Kocherlakota, 2014). It should be noted, however, that the dose of phenobarbital used in NAS treatment is not high enough to prevent seizures (Kocherlakota, 2014) and though phenobarbital appears to be safe and effective in the short-term, the safety profile in neonates has not been established (Kraft et al, 2016).
Clonidine, used off-label in adults to treat opioid withdrawal, has the advantage of being a non-opioid (Kraft et al, 2016). A systematic review found that clonidine may be effective in reducing length of treatment when used as in combination with opioids or as a monotherapy (Streetz et al, 2016). However, it carries the risk of hypotension during treatment and the potential for rebound hypertension and cardiac arrhythmia after treatment is discontinued (Kraft et al, 2016; Kocherlakota, 2014).
An infant with NAS can start to be weaned from pharmacological treatments once symptoms severity is trending downward and the infant is gaining weight (Jansson, 2017). Generally, an infant may be discharged once safely weaned from pharmacological treatments and stable for 24 hours (Jansson, 2017; Kocherlakota, 2014). In rare cases, infants may be discharged while still receiving pharmacological treatment and weaned slowly on an outpatient basis. A Canadian study found that infants who completed their morphine wean at home were less likely to return to the hospital for further withdrawal treatment (Kelly et al, 2014). Kraft and colleagues caution, however, that a short length of stay should not be the only indicator of effective NAS treatment, stating, “there may be individual mothers and infants for whom inpatient stay allows for stabilization of medical, social, environmental, and/or psychiatric issues,” (Kraft et al, 2016, p. 207).
There is no standard protocol for NAS treatment and research in this area continues. A recent study from the Yale New Haven Children’s Hospital investigated a novel approach to NAS treatment in methadone-exposed neonates. The intervention involved simplifying NAS assessments, standardizing and prioritizing non-pharmacological treatments including low stimulation environments (dimmed lights, muted television, low noise level) and supporting and coaching parents to engage in infant care through rooming-in, feeding on demand (breastfeeding except when contraindicated), and responding to crying. Parents also received education and counseling about what to expect in the hospital before delivery. Hospital staff used PRN morphine if nonpharmacological interventions were not sufficient but also practiced rapid morphine weaning, with dose decreases of up to 10% three times per day. Researchers found that after the new approach was implemented the average length of stay for neonates with NAS decreased from 22.4 days to 5.9 days and the portion of infants treated with morphine dropped from 98% to 14% with no reports of adverse events or readmission for NAS (Grossman et al 2017).
As the opioid epidemic continues and more pregnant women access ORT, the small body of literature on the short and long term effects of opioid exposure in-utero grows. However, data are still limited by small sample sizes, numerous confounding variables, and challenges in long-term follow-up (Kraft et al, 2016). Additionally, many studies include all opioid exposures, grouping ORT with illicit substances or polysubstance use. This presents a particular challenge for differentiating effects of buprenorphine or methadone as single exposures.
A few studies have shown a relationship between ORT and suppression of fetal neurobehavior, including lower fetal heart rate, fewer accelerations, and increased risk of nonreactive non-stress test (Salisbury et al, 2012; Jansson et al, 2012; Jansson et al, 2016). The risk of fetal neurobehavioral suppression may be greater with methadone exposure than buprenorphine exposure (Salisbury et al, 2012). Higher doses of buprenorphine (>13mg) are associated with increased risk of lower fetal heart rate and less heart rate variability (Jansson et al, 2016). Suppression may be most severe at the time of peak methadone and buprenorphine levels (Jansson et al, 2016; Jansson et al, 2012). Fetal exposure to cigarette smoke may also exacerbate suppression (Jansson et al, 2016).
A Danish cohort study found that the rate of malformation in opioid-exposed pregnancies, including buprenorphine and methadone, was almost double that of the general population. The most common were atrial and ventricular defects (Nørgaard et al, 2015). A Finnish study of children exposed to buprenorphine and other illicit substance found that the rate of birth defects was 10%, compared to 3.4% in the general population. Eye disorders were the most common, accounting for 11% of defects (Kivistö et al, 2015). In contrast, a Swedish study found no significant increase in congenital defects among buprenorphine-exposed neonates, but that the rate of congenital malformations in those exposed to methadone double that the general population. Cardiac malformations were most common (Wurst et al, 2016). Another study found no difference in the rate of congenital malformations between buprenorphine and methadone exposed groups, but noted that the rate in both groups were slightly higher background levels (Lacroix et al, 2011). A recent systematic review on congenital malformations in opioid-exposed pregnancies (including methadone and buprenorphine) found higher rates than the general population. The most common malformations were of the oral cleft, ventricular septum, and club foot. The authors noted, however, there were serious limitations in the data and that the results of the review did not indicate a definitive relationship between opioid exposure and congenital malformation (Lind et al, 2017).
Both buprenorphine and methadone exposure are associated with increased risk of low birth weight and preterm birth compared to the general population (Nørgaard et al, 2015; Konijnenberg and Meliner, 2011). However, in studies comparing birth weight of neonates exposed to methadone versus those exposed to buprenorphine, the buprenorphine groups generally have higher birth weights (Kakko et al, 2008; Meyer et al, 2015; Minozzi et al, 2013; Zedler et al, 2016), which may be explained by a trend toward longer gestation (Wurst et al, 2016; Zedler et al, 2016). Methadone exposure may also be associated with small head circumference, shorter length at birth, and low APGAR scores (Konijnenberg and Melinder, 2011; Zedler et al, 2016; Nørgaard et al, 2015).
One study found that children exposed in-utero to methadone were at greater risk of low body weight at age 5, shorter height at ages 2 and 5, and smaller head circumference at ages 2, 3, and 5 (Konijnenberg and Melinder, 2011). Regarding cognitive development, an Australian cohort study of children treated for NAS found that they had lower test scores in literacy and numeracy in grades 3, 5, and 7 (Oei et al, 2017). A study of children exposed in-utero to buprenorphine found that they were at higher risk of performing poorly in cognitive and language assessments at age 3 (Konijenberg and Melinder, 2011). A German study compared developmental outcomes in 1-year-olds prenatally exposed to opioids (mostly methadone) and nicotine versus nicotine-only exposure. The opioid and nicotine exposed children has lower scores in the Griffiths Development Quotient and higher rates of mild retardation and neurological abnormalities. Interestingly, there was no difference between children living with their biological parents versus those in the foster care system (Bunikowski et al, 1998).
Several studies highlight the importance of ongoing social and environmental exposures that may be highly correlated with maternal OUD on childhood outcomes. An Australian study found that infants with NAS were more likely to be readmitted to the hospital, experience a longer hospital stay during readmission, die while hospitalized, and be hospitalized for assault, poisoning, or a mental or behavioral disorder. The authors concluded that “NAS was the most important predictor of admissions for maltreatment and mental and behavioral disorders, even after accounting for prematurity, maternal age, and indigenous status” (Uebel et al, 2015, p. e811). A Finnish study also found that buprenorphine exposure in pregnancy was associated with a higher rate of suspected maltreatment, most commonly medical neglect, compared with the general population (Kivistö et al, 2015). Another study followed children born to pregnant women treated with methadone or buprenorphine who delivered at BMC between 2006 and 2010 and tracked their pediatric care at BMC associated facilities for an average of 25.7 months. The researchers found that the children in buprenorphine group were more likely to have a routine weight check and less likely to be seen for Hepatitis C exposure than those in the methadone group. (Humbarger et al, 2016).
Given the risk for NAS and limited data on long-term effects of ORT exposure, some patients and clinicians may consider detoxification. Opioid detoxification is not recommended for pregnant women because of its association with high rates of relapse, returning the fetus to the cycle of intoxication and withdrawal and other exposures associated with illicit substance use. It is currently only recommended if a patient refuses ORT and the only alternative is continued use of illicit substances. If detoxification is necessary, it should be performed at an inpatient facility under the supervision of a physician with experience in perinatal addiction, preferably in the second trimester to reduce the risk fetal demise and preterm labor (ACOG, 2016).
Not all clinicians agree with the ACOG recommendations. Advocates of opioid detoxification in pregnancy claim that the evidence of fetal demise is low and that patients should have the option of reducing the risk of neonatal abstinence syndrome (NAS) (Campbell, 2016; Pritham, 2014). A recent study from Tennessee looked at rates of relapse and NAS among four groups of patients (301 patients total) who underwent opioid detoxification during pregnancy: (1) acute detoxification while incarcerated, (2) inpatient detoxification with intense outpatient follow-up, (3) inpatient detoxification without intense outpatient follow-up, and (4) slow outpatient detoxification with outpatient follow-up. In the first, second, and fourth groups, the rates of relapse were 17.4% – 23.1% and the incidence of NAS was 17.2% – 18.5%. In the third group, which had no post-detox follow-up, 74% of patients relapsed and the incidence of NAS was 70.1% (Bell et al, 2016). An earlier study looked at factors associated with successful detoxification among pregnant women. Of the 95 patients in the cohort, 53 screened negative for illicit substances at the time of delivery. These patients were more likely to have had a longer inpatient detoxification admission (median 25 days vs. 15 days) and were less likely to leave before the completing the program (Stewart, et al, 2013). These studies highlight the importance of comprehensive treatment for pregnant patients with OUD. Psychotherapy and social services are key elements in any treatment plan.
Bakstad, B., Sarfi, M., Welle-Strand, G., and Ravndal, E. (2009). Opioid maintenance treatment during pregnancy: occurrence and severity of neonatal abstinence syndrome. European Addiction Research, 15, 128-134.
Bell, J., Towers, C., Hennessy, M., Heitzman, C., Smith, B., and Chattin, K. (2016). Detoxification from opiate drugs during pregnancy. American Journal of Obstetrics and Gynecology, 213(3).
Binder, T. and Vavrinkova, B. (2008). Prospective randomized comparative study of the effect of buprenorphine, methadone and heroin on the course of pregnancy, birthweight of newborns, early postpartum adaptation and course of the neonatal abstinence syndrome (NAS) in women followed up in the outpatient department. Neuroendocrinology Letters, 29(1), 80-86.
Brogly, S., Saia, K., Walley, A., Du, H., and Sebastiani, P. (2014). Prenatal buprenorphine versus methadone exposure and neonatal outcomes: systematic review and meta-analysis. American Journal of Epidemiology, 180(7), 673-686.
Bunikowski, R., Grimmer, I., Heiser, A., Metze, B., Schafer, A., and Obladen, M. (1998). Neurodevelopmental outcomes after prenatal exposure to opiates. European Journal of Pediatrics, 157, 724-730.
Campbell, W. (2016). Opioid detoxification during pregnancy: the door continues to open. American Journal of Obstetrics and Gynecology, 213(3).
Connery, H. (2015). Medication-assisted treatment of opioid use disorder: Review of the evidence and future directions. Harvard Review of Psychiatry, 23(2), 63-75.
DHSS and SAMHSA. (2015). Federal guidelines for opioid treatment programs. Retrieved from http://store.samhsa.gov/shin/content/PEP15-FEDGUIDEOTP/PEP15-FEDGUIDEOTP.pdf
Edwards, L. and Brown, L. (2016). Nonpharmacologic management of neonatal abstinence syndrome: an integrative review. Neonatal Newtork, 35(5), 305-313.
Gawronski, K., Prasad, M., Backes, C., Lehman, K., Gardner, D., and Cordero, L. (2014). Neonatal outcomes following in utero exposure to buprenorphine/naloxone or methadone. SAGE Open Medicine, 2.
Grossman, M., Berkwitt, A., Osborn, R., Xu, Y., Esserman, D., Shapiro, E., and Bizzarro, M. (2017). An initiative to improve the quality of care of infants with neonatal abstinence syndrome. Pediatrics, 139(6).
Humbarger, O., Galanto, D., Saia, K., Bagley, S., Wachman, E., and Brogly, S. (2016). Childhood health and development in a cohort of infants exposed prenatally to methadone or buprenorphine. Journal of Addiction Research & Therapy, 7(1).
Isemann, B., Meinzen-Derr, J., and Akinbi, H. (2011). Maternal and neonatal factors impacting response to methadone therapy in infants treated for neonatal abstinence syndrome. Journal of Perinatology, 31, 25-29.
Jansson, L. (2017). Neonatal abstinence syndrome. UpToDate. Retrieved from https://phstwlp2.partners.org:2057/contents/neonatal-abstinence-syndrome?source=search_result&search=opioid%20exposure%20pregnancy&selectedTitle=2~150
Jansson, L., Di Pietro, J., Elko, A., Williams, E., Milio, L., and Velez, M. (2012). Pregnancies exposed to methadone, methadone and other illicit substances, and poly-drugs without methadone: A comparison of fetal neurobehaviors and infant outcomes. Drug and Alcohol Dependence, 122, 213-219.
Jansson, L., Velez, M., McConnell, K., Spencer, N., Tuten, M., Jones, H., King, V., Gandotra, N., Milio, L., Voegtline, K., and DiPietro, J. (2016). Maternal buprenorphine treatment and fetal neurobehavioral development. American Journal of Obstetrics & Gynecology, 216, 529e1-8.
Jones, H. (2013). Treating opioid use disorders during pregnancy: historical, current, and future directions. Substance Abuse, 34, 89-91.
Jones, H., and Fielder, A. (2015). Neonatal abstinence syndrome: Historical perspective, current focus, future directions. Preventive Medicine, 80, 12-17.
Jones, H., Chisolm, M., Jansson, L, and Terplan, M. (2012). Naltrexone in the treatment of opioid-dependent pregnant women: the case for a considered and measured approach to research. Addiction, 108, 233-247.
Jones, H., Kaltenbach, K., Heil, S., Stine, S., Coyle, M., Arria, A., O’Grady, K., Selby, P., Martin, P., and Fischer, G. (2010). Neonatal abstinence syndrome after methadone or buprenorphine exposure. The New England Journal of Medicine, 363(24), 2320-2331.
Kakko, J., Heilig, M., and 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, 96, 69-78.
Kelly, L., Knoppert, D., Roukema, H., Rieder, M., and Koren, G. (2014). Oral morphine weaning for neonatal abstinence syndrome at home compared with in-hospital: an observation cohort study. Pediatrics Drugs, 17, 151-157.
Kivistö, K., Tupola, S., and Kivitie-Kallio, S. (2015). Prenatally buprenorphine-exposed children: health to 3 years of age. European Journal of Pediatrics, 174, 1525-1533.
Kocherlakota, P. (2014). Neonatal abstinence syndrome. Pediatrics, 134(2), e547-3561.
Konijnenberg, C. and Melinder, A. (2011). Prenatal exposure to methadone and buprenorphine: A review of the potential effects on cognitive development. Child Neuropsychology, 17(5), 495-519.
Kraft, W., Adeniyi-Jones, S., Chervoneva, I., Greenspan, J., Abatemarco, D., Kaltenbach, K., and Ehrlich, M. (2017). Buprenorphine for the treatment of the neonatal abstinence syndrome. New England Journal of Medicine, 376(24), 2341.
Kraft, W., Stover, M., and Davis, J. (2016). Neonatal abstinence syndrome: Pharmacologic strategies for mother and infant. Seminars in Perinatology, 40, 203-212.
Lacroix, I., Berrebi, A., Garipuy, D., Schmitt, L., Hammou, Y., Chaumerliac, C., Lapeyre-Mestre, M., Montastruc, J., and Damase-Miche, C. (2011). Buprenorphine versus methadone in pregnant opioid-dependent women: a prospective multicenter study. European Journal of Clinical Pharmacology, 67, 1053-1059.
Lexicomp. (2017a). Methadone: drug information. UptoDate. Retrieved from https://phstwlp2.partners.org:2057/contents/methadone-drug-information?source=preview&search=methadone&anchor=F194032#F194032
Lexicomp. (2017b). Buprenorphine: drug information. UptoDate. Retrieved from https://phstwlp2.partners.org:2057/contents/buprenorphine-drug-information?source=preview&anchor=F143027#F143027
Lexicomp. (2017c). Naltreone: drug information. UptoDate. Retrieved from https://phstwlp2.partners.org:2057/contents/naltrexone-drug-information?source=search_result&search=naltrexone&selectedTitle=1~68
Lind, J., Interrante, J., Ailes, E., Gilboa, S., Khan, S., Frey, M., Dawson, A., Honein, M., Dowling, N., Razzaghi, H., Creanga, A., and Broussard, C. (2017). Maternal use of opioids during pregnancy and congenital malformations: A systematic review. Pediatrics, 139(6).
Liu, A., Jones, M., Murray, H., Cook, C., and Nanan, R. (2010). Perinatal risk factors for the neonatal abstinence syndrome in infants born to women on methadone maintenance therapy. Australian and New Zealand Journal of Obstetrics and Gynecology, 50, 253-258.
McQueen, K. and Murphy-Oikonen, J. (2016). Neonatal abstinence syndrome. The New England Journal of Medicine, 375(25), 2468-2479.
Meyer, M., Johnston, A., Crocker, A., and Heil, S. (2015). Methadone and buprenorphine for opioid dependence during pregnancy: A retrospective cohort study. Journal of Addiction Medicine, 9(2), 81-86.
Minozzi, S., Amato, L., Bellisario, C., Ferri, M., and Davoli, M. (2013). Maintenance agonist treatments for opiate-dependent pregnant women. The Cochrane Library, 12.
Mozurkewich, E. and Rayburn, W. (2014). Buprenorphine and methadone for opioid addiction during pregnancy. Obstetrics and Gynecology Clinics of North America, 41, 241-253.
Nørgaard, M., Neilsson, M., and Heide-Jørgensen, U. (2015). Birth and neonatal outcomes following opioid use in pregnancy: A Danish population-based study. Substance Abuse: Research and Treatment, 9(S2), 5-11.
O’Connor, A., O’Brien, L., and Alto, W. (2016). Maternal buprenorphine dose at delivery and its relationship to neonatal outcomes. European Addiction Research, 22(3), 127-30.
Oei, J., Melhuish, E., Uebel, H., Azzam, N., Breen, C., Burns, L., Hilder, L., Bajuk, B., Abdel-Latif, M., Ward, M., Feller, J., Falconer, J., Clews, S., Eastwood, J., Li, A., Wright, I. (2017). Neonatal abstinence syndrome and high school performance. Pediatrics, 139(2).
Patrick, S., Kaplan, H., Passarella, M., Davis, M., and Lorch, S. (2014). Variation in treatment of neonatal abstinence syndrome in US children’s hospitals, 2004-2011. Journal of Perinatology, 34, 867-872.
Pritham, U. (2014). A program for pregnant women electing inpatient opioid detoxification. Journal of Obstetric, Gynecologic & Neonatal Nursing, 43 (Supplement 1).
Reece-Stremtan, S., Marinelli, K., and The American Academy of Breastfeeding. (2015). ABM clinical protocol #21: Guidelings for breastfeeding and substance use or substance use disorder, revised 2015. Breastfeeding Medicine, 10(3), 135-141.
Sachs, H. and Committee on Drugs (2013). The transfer of drugs and therapeutic into human breast milk: an update on selected topics. Pediatrics, 132(3), e796-e809.
Salisbury, A., Coyle, M., O’Grady, K., Heil, S., Martin, P., Stine, S., Kaltenbach, K., Weninger, M., and Jones, H. (2012). Fetal assessment before and after dosing with buprenorphine or methadone. Addiction, 107(S1), 36-44.
SAMHSA. (2014). Medication-assisted treatment for opioid addiction in opioid treatment programs. A Treatment Improvement Protocol. TIP 43. HHS Publication No. 12-4214. Rockville, MD.
SAMHSA. (2015). Methadone. Retrieved from https://www.samhsa.gov/medication-assisted-treatment/treatment/methadone
Seligman, N., Almario, C., Hayes, E., Dysart, K., Berghella, V., and Baxter, J. (2010). Relationship between maternal methadone dose at delivery and neonatal abstinence syndrome. The Journal of Pediatrics, 157(3), 428-433.e1.
Seligman, N., Salva, N., Edward, H., Dysart, K., Pequignot, E., and Baxter, J. (2008). Predicting length of treatment for neonatal abstinence in methadone-exposed neonates. American Journal of Obstetrics & Gynecology, 199, 396e1-396e7.
Stewart, R., Nelson, D., Adhikari, E., McIntire, D., Roberts, S., Dashe, J., and Sheffield, J. (2013). The obstetrical and neonatal impact of maternal opioid detoxification in pregnancy. American Journal of Obstetrics & Gynecology, 209(3).
Streez, V, Gidon, B., and Thompson, D. (2016). Role of clonidine in neonatal abstinence syndrome: a systematic review. Annals of Pharmacotherapy, 50(4), 301.
The American College of Obstetricians and Gynecologists. (2016). Committee Opinion. Number 524. Opioid abuse, dependence, and addition in pregnancy. Retrieved from https://www.acog.org/Resources-And-Publications/Committee-Opinions/Committee-on-Health-Care-for-Underserved-Women/Opioid-Abuse-Dependence-and-Addiction-in-Pregnancy
The American Society of Addiction Medicine. (2017). Public policy statement on substance use, misuse, and use disorders during and following pregnancy, with an emphasis on opioids. Retrieved from https://www.asam.org/docs/default-source/public-policy-statements/substance-use-misuse-and-use-disorders-during-and-following-pregnancy.pdf?sfvrsn=4
Tran, T., Griffin, B., Stone, R., Vest, K., and Todd, T. (2017). Methadone, buprenorphine, and naltrexone for the treatment of opioid use disorder in pregnant women. Pharmacotherapy. doi: 10.1002/phar.1958. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28543191
Uebel, H., Wright, I., Burns, L., Hilder, L., Bajuk, B., Breen, C., Abdel-Latif, M., Feller, J., Falconer, J., Clews, S., Eastwood, J., and Oei, J. (2015). Reasons for rehospitalization in children who had neonatal abstinence syndrome. Pediatrics, 136(4), e811-e820.
Weigand, S., Stringer, E., Stuebe, A., Jones, H., Seashore, C., and Thorp, J. (2015). Buprenorphine and naloxone compared with methadone treatment in pregnancy. Obstetrics & Gynecology, 125(2), 363-368.
WHO. (2014). Guidelines for the identification and management of substance use and substance use disorders in pregnancy. Retrieved from http://apps.who.int/iris/bitstream/10665/107130/1/9789241548731_eng.pdf
Wurst, K., Zedler, B., Joyce, A., Maciek, S., Murelle, E. (2016). A Swedish population-based study of adverse birth outcomes among pregnant women treated with buprenorphine or methadone: preliminary findings. Substance Abuse, 15(10), 88-97.
Young, J. and Martin, P. (2012). Treatment of opioid dependence in the setting of pregnancy. The Psychiatric Clinics of North America, 35, 441-460.
Zedler, B., Mann, A., Kim, M., Amick, H., Joyce, A., Murrelle, E., and Jones, H. (2016). Buprenorphine compared with methadone to treat pregnant women with opioid use disorder: a systematic review and meta-analysis of safety in the mother, fetus and child. Addiction, 111(12), 2115-2128.