Abstract
Objective:
There is a lack of knowledge about the relative safety and efficacy of naltrexone for the treatment of pregnant individuals with opioid and/or alcohol use disorder, including the range of outcomes, in both the pregnant individual and the infant, over the course of peripartum period. Our objective was to describe these outcomes in a cohort of pregnant individuals on naltrexone.
Methods:
In this prospective case series, 7 pregnant individuals with opioid use disorder (OUD) or alcohol use disorder (AUD) treated with naltrexone were followed from pregnancy through 12 months post-delivery. Clinical treatment protocols and outcomes related to safety and efficacy during pregnancy, delivery, and the postpartum perioid are described.
Results:
There were 4 pregnant individuals with OUD and 3 with AUD, of which 3 were managed with oral and 4 with extended-release naltrexone. The mean gestational age at study enrollment was 21.7 (SD 12) weeks. Of the 7 participants, there was no return to non-prescribed opioid use and 2 who experienced a return to alcohol use over the course of the study. All individuals delivered vaginally at a mean of 37 weeks gestation without any peripartum pain difficulties. Five (71.4%) of the individuals remained on naltrexone 12 months post-delivery. There were no reported fetal anomalies and one preterm delivery. None of the infants developed neonatal opioid withdrawal syndrome.
Conclusions:
For pregnant individuals with OUD or AUD treated with naltrexone, there were low rates of return to non-prescribed use and reassuring pregnant person and infant outcomes to 12 months postpartum.
Keywords: Naltrexone, pregnancy, opioid use disorder, alcohol use disorder
INTRODUCTION:
Substance use disorders remain a pressing national health priority, particularly opioid use disorder (OUD) and alcohol use disorder (AUD) during the pregnancy and postpartum period.1 OUD in pregnancy impacts an estimated 1.5 per 1000 pregnant individuals in the U.S, with wide variability per region of the country.2 In 2018, binge-drinking alcohol impacted an estimated 4% of pregnant individuals in the U.S.3 The first-line standard of care pharmacologic treatment for non-pregnant individuals with moderate to severe AUD is treatment with naltrexone with demonstrated reduction in alcohol consumption in randomized trials.4 However, naltrexone use for pregnant individuals with AUD has previously not been studied.
For OUD in pregnancy, the current standard of care is treatment with an opioid agonist medication such as methadone or buprenorphine, both which been associated with improved pregnant person and infant outcomes.5 Naltrexone is another accepted option for treatment of OUD in non-pregnant individuals, demonstrating comparable outcomes to other forms in medication for OUD (MOUD) in some studies, particularly in select patient population with OUD motivated to end their non-prescribed use.6–7 Overall, naltrexone has not been well studied in pregnant individuals with OUD. Individuals taking naltrexone who become pregnant and their clinicians are left with uncertainty about what the best option is for MOUD during the pregnancy and postpartum period.
Naltrexone is available in both an oral daily formulation, and a monthly extended-release (XR) injectable formulation.8 Initiating or discontinuing naltrexone during the pregnancy holds additional concerns, including the possibility of fetal distress, risk for destabilization during the pregnancy, and increased risk for overdose.9–10 Previous retrospective cohort studies of the use of naltrexone in pregnancy have demonstrated equivalent pregnancy and infant outcomes compared with methadone or buprenorphine.10–13 Infants exposed to naltrexone in-utero in the absence of opioid exposure should not exhibit neonatal opioid withdrawal syndrome (NOWS), thus have a much lower rate of neonatal intensive care unit admission with shorter infant hospitalizations.10–11
Despite these promising preliminary studies, there remain significant gaps in knowledge, specifically about the safety and efficacy of naltrexone during pregnancy and postpartum period, pain management during labor, breastfeeding safety, stability in recovery over the peripartum period, and the full range of neonatal and childhood outcomes. Therefore, the objective of this study was to present a detailed case series of individuals treated with naltrexone during the pregnancy and first 12 months postpartum, including a full range of pregnant person and infant outcomes in order to help guide clinical management.
METHODS:
Subject enrollment:
The present case series is part of a multi-site prospective cohort study, taking place at Boston Medical Center and the University of North Carolina called the MOM NEST Study (NCT 03718104). The MOM NEST study compares outcomes of individuals treated with naltrexone versus buprenorphine-naloxone during pregnancy, examining genetic associations, pharmacokinetics, safety, efficacy, and neurodevelopmental outcomes of infants out to 12 months of age. The focus of this in-depth case series is the 7 participants treated with naltrexone who were all enrolled from Boston Medical Center. Boston Medical Center has a dedicated peripartum integrated care program for pregnant and postpartum individuals with substance use disorders called Project RESPECT, providing substance use disorder care, obstetrical care, case management services, psychiatric consultation, and social work services from pregnancy through two years after delivery. This study was approved by the Boston University Medical Campus and University of North Carolina institutional review boards.
To be considered eligible for the naltrexone group, pregnant people had to be stabilized on naltrexone for the treatment of OUD or AUD before approach for the study, at least 18 years of age, English-speaking, willing to attend study visits at Boston Medical Center, and have a singleton pregnancy. Multiple gestation pregnancies were excluded from the study due to the higher risk for pregnancy complications that could influence the primary study outcomes. Though patients were eligible for clinical treatment with naltrexone regardless, individuals were excluded from study eligibility if they were currently incarcerated at the time of approach for consent, had a severe psychiatric illness or cognitive impairment limiting the ability to provide informed consent, or were over 34 weeks gestation at the time of approach. Participants were enrolled in the study between November 2018 and May 2022.
Clinical treatment protocol:
Participants were treated per the routine Boston Medical Center care protocol for individuals on naltrexone (Figure 1) Those who were stable on XR naltrexone or oral naltrexone prior to becoming pregnant were first scheduled for a consultation with Project RESPECT to review the treatment options and naltrexone protocol and to discuss risks and benefits. The XR naltrexone group received 380 mg every 28 days intramuscular gluteal injection, and the oral group received anywhere from 50–150 mg daily. The decision of whether or not to transition the XR naltrexone group to oral prior to delivery (after 36 weeks gestation) was on an individual basis. Patients may be transitioned to oral naltrexone and continued on this until admission for labor or discontinued 24 hours prior to scheduled C-section. All attempts are made to avoid naltrexone administration for 24 hours prior to delivery when possible.
FIGURE 1: Boston Medical Center Clinical Management Protocol for Naltrexone in Pregnancy.
Clinical management protocol for pregnant individuals taking oral or extended-release naltrexone.
Labor pain management consisted of options of nitrous oxide, intravenous opioids, or epidural anesthesia (fentanyl), with the option to avoid opioids per patient request. After vaginal deliveries, those who were transitioned to oral naltrexone were re-started on XR naltrexone 380mg as early as 48 hours post-delivery. Postpartum pain was managed with non-steroidal anti-inflammatory medications. For those who required Cesarean delivery, all medications were scheduled (Ketorolac, ibuprofen, acetaminophen, and hydromorphone). Re-starting of XR naltrexone was delayed until post-operative pain was controlled with non-steroidal anti-inflammatory medications alone. Breastfeeding was encouraged for those on naltrexone without any use of non-prescribed substances at the time of delivery.
Study protocol and data collection:
The study protocol included serial study visits in each trimester (goal 6 study visits per pregnancy) with questionnaire administration related to medical health and substance use, a delivery hospitalization visit, a 4-week postpartum visit, every other month phone calls postpartum, then a 12-month postpartum follow-up visit. Participants were asked about any perceived side effects from their naltrexone at every study encounter. Electronic medical records were also reviewed monthly for any adverse events not reported during the study visits such as re-hospitalizations or emergency room visits. Additional electronic medical record data collected included pregnancy and infant outcomes (medical problems, medications, co-exposures, delivery outcomes, NOWS outcomes, hospitalizations, emergency room visits, routine care ultrasounds, routine care non-stress tests, urine toxicology tests). All data were entered into a secure electronic study database (REDCap).
Statistical methods:
All demographic and outcome variables were summarized for the participants using means and t-tests for continuous variables and percent distributions and chi-square test of independence for categorical variables. For potentially recurring events, any occurrence of an adverse event or return to use was reported at any time point.
RESULTS:
During the time period of the study, there were 10 pregnant individuals on naltrexone managed at Boston Medical Center. Three were never approached due to the COVID-19 pandemic with temporary cessation of enrollment in any prospective studies from April - September 2020. Of the 7 individuals approached, all 7 consented for the study. One individual with AUD participated in the study twice with 2 consecutive pregnancies. Of the 4 pregnancies in persons with OUD, 3 were on XR naltrexone and 1 on oral naltrexone. For the 3 pregnancies in persons with AUD, 2 were on oral naltrexone and 1 on XR naltrexone (Table 1). The mean gestational age at study enrollment was 21.7 weeks (SD 12.1 weeks). Six out of the 7 individuals initiated on naltrexone pre-pregnancy and all were initiated on naltrexone before approach for the study. Most participants were White Non-Hispanic with public insurance.
Table 1:
Birthing person baseline and pregnancy characteristics of 7 individuals on naltrexone
| Variable | Mean (SD) or n(%) |
|---|---|
| Age at study enrollment (years) – Mean (SD) | 32.7 (6.9) |
| Gestational age (weeks) at study enrollment – Mean (SD) | 21.7 (12.1) |
| Gravidity – Mean (SD) | 3.8 (3.5) |
| Parity – Mean (SD) | 1.4 (1.5) |
| Diagnosis for utilization of naltrexone – N(%) | |
| Alcohol use disorder | 3 (42.9%) |
| Opioid use disorder | 4 (57.1%) |
| Formulation of naltrexone – N(%) | |
| Oral | 3 (42.9%) |
| Extended release | 4 (57.1%) |
| Naltrexone initiated – N(%) | |
| Pre-pregnancy | 6 (85.7%) |
| During pregnancy | 1 (14.3%) |
| Ethnicity – N(%) | |
| Non-Hispanic | 6 (85.7%) |
| Hispanic | 0 |
| Unknown | 1 (14.3%) |
| Race – N(%) | |
| White | 7 (100%) |
| Education level – N(%) | |
| High school | 3 (42.9%) |
| Some college | 2 (28.6%) |
| Other/missing | 2 (28.6%) |
| Health insurance status – N(%) | |
| Medicaid insurance | 5 (71.4%) |
| Private insurance | 2 (28.6%) |
| Adverse Childhood Experiences (ACES) score – Mean (SD) | 3.8 (4.1) |
| Gestational age (weeks) at presentation to prenatal care – Mean (SD) | 13.1 (12.6_ |
| Number of prenatal visits – Mean (SD) | 12.6 (9.2) |
| Nicotine use disorder during third trimester – N(%) | 5 (71.4%) |
| Co-morbidities – N(%) | |
| Depression | 6 (85.7%) |
| Anxiety | 4 (57.1%) |
| Post-traumatic stress disorder | 5 (71.4%) |
| Attention deficit hyperactivity disorder | 3 (42.9%) |
| Hepatitis C infection | 3 (42.9%) |
| Pregnancy complications – N(%) | |
| Premature rupture of membranes | 1 (14.3%) |
| Gestational hypertension | 5 (71.4%) |
| Pre-eclampsia | 1 (14.3%) |
| Gestational diabetes | 1 (14.3%) |
| Preterm labor | 1 (14.3%) |
| Oligohydramnios | 1 (14.3%) |
Pregnancy and delivery outcomes are shown in Table 2. There were no reported fetal anomalies. One individual had an occurrence of a non-reassuring fetal heart tracing with an abnormal fetal heart rate indicating possible fetal distress, otherwise non-stress tests and biophysical profiles done for routine care purposes were reassuring. The mean gestational age at delivery was 37.0 weeks (SD 4.0), with one preterm delivery between 24–29 weeks due to premature rupture of membranes and preterm labor in the setting of cervical insufficiency. All individuals had epidural anesthesia during labor with fentanyl. All individuals delivered vaginally. Of the 4 individuals on XR naltrexone, 2 transitioned to oral naltrexone from XR naltrexone prior to delivery and re-initiated on XR naltrexone at 2- and 7-days post-partum respectively. Postpartum, none of the individuals had reported issues with pain control with acetaminophen and ibuprofen and/or ketorolac being utilized exclusively. The mean birthing person length of hospitalization was 2.3 days (SD 0.5) with no reported immediate post-partum complications. Though all were eligible to breastfeed per hospital guidelines, only 3 individuals initiated breastfeeding.
Table 2:
Delivery outcomes and infant characteristics of 7 birthing person – infant dyads on naltrexone
| Variable | Mean (SD) or n(%) |
|---|---|
| Birthing person outcomes | |
| Fetal anomalies – N(%) | 0 |
| Non-reassuring fetal heart tracing in pregnancy – N(%) | 1 (14.3%) |
| Gestational age (weeks) at delivery – mean (SD) | |
| All pregnancies | 37.0 (4.0) |
| Full-term pregnancies (n=6) | 38.4 (1.4) |
| Mode of delivery – N(%) | |
| Vaginal | 7 (100%) |
| Caesarian | 0 |
| Epidural anesthesia during labor – N(%) | 7 (100%) |
| Total amount of epidural fentanyl (mg) | 0.89 (0.82) |
| Use of additional analgesic medications during labor – N(%) | 0 |
| Switch from extended release to oral naltrexone prior to delivery – N(%) | 2 (50%) |
| Length of hospitalization (days) – Mean (SD) | 2.3 (0.5) |
| Postpartum pain medications – N(%) | |
| Opioids | 0 |
| Keterolac | 1 (14.3%) |
| Acetominophen | 7 (100%) |
| Ibuprofen | 7 (100%) |
| Postpartum complications – N(%) | 0 |
| Intensive care unit care – N(%) | 0 |
| Eligible to provide breastmilk to infant – N(%) | 7 (100%) |
| Initiated breastfeeding – N(%) | 3 (42.9%) |
| Infant outcomes | |
| Infant gender – N(%) | |
| Male | 3 (42.9%) |
| Female | 4 (57.1%) |
| Birth weight (grams) – mean (SD) | |
| All infants | 2698 (1227) |
| Full-term infants (n=6) | 3148 (330) |
| Birth weight percentile – Mean (SD) | 42.4 (20.4) |
| Head circumference (cm) – mean (SD) | |
| All infants | 33.1 (2.8) |
| Full-term infants (n=6) | 34.1 (0.9) |
| Head circumference percentile – mean (SD) | 49.3 (23.7) |
| APGAR Scores – Mean (SD) | |
| 1 minute | 7.7 (1.4) |
| 5 minute | 7.4 (2.9) |
| Neonatal intensive care unit admission – N(%) | 2 (28.6%) |
| Infant diagnosed with Neonatal Opioid Withdrawal Syndrome – N(%) | 0 |
| Infant complications – N(%) | |
| Respiratory distress syndrome | 1(14.3%) |
| Feeding difficulties | 1(14.3%) |
| Infection | 1(14.3%) |
| Transient tachypnea of the newborn | 1(14.3%) |
| Jaundice requiring phototherapy | 1(14.3%) |
| Hypoglycemia requiring intravenous fluids | 1(14.3%) |
| Other | 1(14.3%) |
| Infant length of hospitalization (days) – Mean (SD) | |
| All infants | 14.7 (32.3) |
| Full-term infants (n=6) | 2.5 (0.8) |
| Discharged in custody of birth parent | 7 (100%) |
For the infants, the mean birth weight was in the 42nd percentile with head circumference in the 49th percentile (Table 2). None of the infants were monitored for NOWS given the lack of any confirmed in-utero opioid exposure that would necessitate NOWS scoring, and two infants required admission to the newborn intensive care unit secondary to prematurity and transient tachypnea of the newborn. Additional infant co-morbidities during the delivery hospitalization were related to the one infant’s prematurity diagnosis. All infants were discharged home in the custody of the birth parent.
Participants were asked about any of a list of potential side effects, per Lexicomp drug reference tool for naltrexone.14 Side effects as reported by the patients as likely related to their naltrexone are shown in Table 3. All reported side effects were in the four individuals taking XR naltrexone; there were no reported side effects in the oral naltrexone group. One individual reported nausea, fatigue, dizziness, vomiting, decreased appetite, runny nose or cough, and trouble sleeping; two reported diarrhea, irregular heartbeat, and leg swelling. None of the individuals reported injection site reactions or withdrawal symptoms.
Table 3:
Side effects reported in pregnant and postpartum individuals on naltrexone
| Side effect | n(%) |
|---|---|
| Nausea | 1 (14.3%) |
| Fatigue | 1 (14.3%) |
| Dizziness | 1 (14.3%) |
| Vomiting | 1 (14.3%) |
| Decreased appetite | 1 (14.3%) |
| Diarrhea | 2 (28.6%) |
| Runny nose or cough | 1 (14.3%) |
| Trouble sleeping | 1 (14.3%) |
| Irregular heartbeat | 2 (28.6%) |
| Edema or hands or feet | 2 (28.6%) |
Note, all reported side effects were in the extended-release group (none in the oral group)
Participants were followed for 12 months post-delivery. Of the 4 participants with OUD, none had a return to non-prescribed opioid use. Of those with AUD, two had a return to alcohol misuse over the course of the study at 2 and 8 months after delivery. Of note, this was one individual who participated in the study over the course of two consecutive pregnancies in which the individual was on oral naltrexone for one pregnancy and XR naltrexone for the other pregnancy. There were no episodes of overdose reported. Looking at retention for medication treatment for their substance use disorder at 12 months, 5 (71%) were still on naltrexone at 12-months. One of the individuals transitioned to buprenorphine, and one stopped all medication treatment shortly after delivery.(Table 4)
Table 4:
12-month birthing person and infant outcomes
| Variable | Mean (SD) or n(%) |
|---|---|
| Maternal outcomes | |
| Return to non-prescribed use at any time point – N(%) | 2 (28.6%) |
| Overdose at any time point – N(%) | 0 |
| Medication for OUD at 12 months – N(%) | |
| No Medication for OUD | 1 (14.3%) |
| Oral Naltrexone | 0 |
| Extended-release naltrexone | 5 (71.4%) |
| Buprenorphine (sublingual) | 1 (14.3%) |
| Birthing person emergency room visit – N(%) | 0 |
| Birthing person re-hospitalization – N(%) | 2 (28.6%) |
| Child outcomes | |
| Parental custody at 12 months – N(%) | 5 (71.4%) |
| Weight (kg) at 12 months corrected gestational age – mean (SD) | 9.4 (1.3) |
| Head circumference (cm) at 12 months corrected gestational age – mean (SD) | 45.6 (1.6) |
| Fetal alcohol spectrum disorder diagnosis – N(%) | 1 (14.3%) |
| Child medical conditions – N(%) | |
| Recurrent respiratory infections | 1 (14.3%) |
| Ear infection | 1 (14.3%) |
| Feeding problem | 1 (14.3%) |
| Colic | 1 (14.3%) |
| Eye problems | 1 (14.3%) |
| Motor delay | 1 (14.3%) |
| Child emergency room visit – N(%) | 2 (28.6%) |
| Child re-hospitalization – N(%) | 1 (14.3%) |
Abbreviations: OUD = opioid use disorder
For child outcomes, 5 (71%) remained in birthing parent custody at 12 months of age, with the two children removed from custody born to the same one individual who experienced the return to use. All infants continued to be followed at our hospital for pediatric care over the course of the first year after delivery allowing for review of their electronic health records for all participants, however there was some loss to follow-up for study visits related to the COVID-19 pandemic. For child health outcomes, the preterm infant had medical diagnoses associated with prematurity including episodes of respiratory infections, feeding, and eye problems; this infant also had associated emergency room visits and re-hospitalizations for respiratory illnesses. There was one infant with suspected fetal alcohol spectrum disorder noted due to some dysmorphic facial features and motor delays in development. Of note, this pregnancy was complicated by on-going alcohol use in early pregnancy prior to the initiation of naltrexone treatment.(Table 4)
DISCUSSION:
In this prospective case series, we followed 7 pregnancies closely from early pregnancy through 12-months postpartum as they were treated with naltrexone for the treatment of OUD or AUD. We found that individuals have overall reassuring pregnancy and neonatal outcomes with few reported side effects or adverse outcomes. Return to non-prescribed use over the first year postpartum was low and infant outcomes to 12 months were overall reassuring.
This is the first prospective cohort study to our knowledge of naltrexone in pregnant and postpartum individuals. Previous reports have been from retrospective cohorts, lacking the longitudinal follow-up to 12 months, serial questionnaire data, or evaluation of patient reported side effects. The findings of this study for delivery outcomes are consistent with our previous retrospective cohort study of 6 individuals treated with naltrexone during the pregnancy which identified favorable pregnancy outcomes, no rates of return to non-prescribed use during the pregnancy, and no infants with a diagnosis of NOWS.10 A previous study by Towers et al of 121 pregnancy individuals on naltrexone compared with 109 on methadone or buprenorphine found equivalent obstetrical outcomes, no significant difference in rates of birth anomalies, and significantly lower rates of NOWS.11 Kelty et al also compared birth outcomes of pregnancies maintained with naltrexone (n=68) versus methadone or buprenorphine (n=199) retrospectively and found similar results.15 There was variability across previous studies in terms of the oral versus XR naltrexone.
Despite the strengths of this prospective case series, this study does have some limitations. First, we are limited by our small sample size due to the very small number of patients on naltrexone in our geographic region. This is consistent with our recent national survey demonstrating an overall lack of providers of naltrexone for pregnant individuals in the U.S.16 In addition, we had some loss to follow-up related to COVID-19 and patients moving out of the area. There was variability in AUD vs OUD, and in the oral versus XR formulations of naltrexone. We were also limited in that none of the participants delivered via C-section, limiting our ability to assess intra-operative and/or post-operative pain management in this cohort.
The conduct of randomized clinical trials in pregnant patients with substance use disorders is inherently challenging. Future studies should attempt to enroll larger prospective cohorts with comparison groups on buprenorphine, methadone, and/or other medication treatments for AUD. There is also a need for an in depth look at neurodevelopmental outcomes after naltrexone exposure in pregnancy. Additional information on the pharmacokinetics and breastmilk safety of naltrexone in this population are also greatly needed. Lastly, any differences in outcomes based on underlying diagnosis of AUD versus OUD, or formulation of naltrexone would be helpful to explore in future studies.
CONCLUSIONS:
In summary, naltrexone is a potential treatment option for individuals with AUD and OUD in pregnancy with overall reassuring pregnancy and neonatal outcomes. Additional studies with larger sample sizes are needed in order to provide evidence-based clinical care management of these pregnancies.
ACKNOWLEDGEMENTS:
The authors would like to thank the participants, the Boston Medical Center Project RESPECT and University of North Carolina Horizon’s programs, the Maxwell Finland Laboratory for Infectious Disease at Boston Medical Center, and the entire MOM NEST study staff, particularly Breanna Isley, Jeffery Boateng, Hira Shrestha, Nicole Iannella, Aneya Sousa, Chloe Deflorimonte, Emmy Smith, and Jenny Kwon. Funding for this study was provided by the National Institute of Health R01 HD96798 (to E.Wachman).
CONFLICTS OF INTEREST AND SOURCES OF FUNDING:
The authors have no conflicts of interest to disclose. This study was funded by the NIH (R01 HD96798 to E. Wachman).
Footnotes
PRE-PRINT POLICY STATEMENT: This manuscript was not posted on a preprint server.
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