Opioid Use Disorders During Pregnancy

By Ahizechukwu C. Eke, MD, PhD, MPH

Associate Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore

Currently, the United States faces an enormous opioid crisis, with opioid use disorder (OUD) being the leading cause of morbidity and mortality in some states.¹ The number of pregnant people with OUD increased from 1.5 cases per 1,000 hospital deliveries to 6.5 cases per 1,000 hospital deliveries in the United States between 1999 and 2014, a more than four-fold rise.² Because of the serious morbidity and mortality linked to OUD during pregnancy and postpartum, including the risk of preterm birth, intrauterine fetal growth restriction, low birth weight, small for gestational age, stillbirth, neonatal abstinence syndrome (NAS), postpartum depression, and maternal and neonatal mortality, OUD during pregnancy and postpartum continues to be a serious public health problem.³ Thus, proper identification and management of pregnant and postpartum people with OUD is crucial.

History and Screening

At the initial prenatal visit, it is important to take a thorough history of substance use to recognize and distinguish between general substance use and opioid dependence/abuse in the context of medical care, since patients who take opioids during pregnancy comprise a heterogeneous population.⁴ Testing for sexually transmitted infections (STIs, including human immunodeficiency virus [HIV], hepatitis B and C, gonorrhea, and syphilis) and screening for depression and other behavioral health conditions are important at the initial prenatal visit, since the prevalence of STIs is higher in people with OUD.⁵ To effectively manage OUD during pregnancy and meet the complex needs of this patient population, a multifaceted strategy involving a wide range of medical, social, and behavioral treatments is necessary. The services of addiction medicine, mental health specialists, pain management specialists, obstetricians, maternal fetal medicine specialists, obstetric anesthesia, social services, pediatricians, and infectious diseases specialists are critically important.

Universal screening for OUD during pregnancy is fundamental, since it provides a potential avenue for interventions that can improve maternal health and fetal well-being. The American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine recommend giving all pregnant women a quick substance use screening questionnaire that, if necessary, would result in a quick behavioral intervention and referral.^4,6 Several questionnaires, including the National Institute on Drug Abuse (NIDA) quick screen; Substance Use Risk Profile-Pregnancy (SURP-P) scale; 4Ps screening tool; Drug Abuse Screening Test (DAST-10); Car, Relax, Alone, Forget, Friends, Trouble (CRAFFT); and Wayne Indirect Drug Use Screeners (WIDUS), are validated and have been used successfully in pregnant people with OUD.^4,6 The results of the screening questionnaires, if positive, may lead to recommendations for a urine toxicologic screening/confirmatory assays or other maternal biologic assays during pregnancy. Although universal toxicologic testing has been the norm for many years in the United States, several treatment centers have moved toward medically indicated biologic testing for OUD during pregnancy. Some of the medical indications for testing include the unconscious pregnant patient, pregnant persons presenting with unexplained severe hypertension or placental abruption, patients with unexplained endocarditis during pregnancy, and patients with needle track marks, which suggest recent drug use.⁶

Medical-Assisted Therapy

Every pregnant person with OUD should be given access to medical-assisted therapy (MAT) with methadone or buprenorphine as first-line treatment.^4,6 The objectives of using MAT during pregnancy are to reduce opioid cravings, reduce maternal complications, and ease withdrawal symptoms. Methadone, a full mu-opioid receptor agonist, is effective in treating perinatal OUD.⁷ However, pregnant people must receive daily doses of methadone under close observation in a clinic that is accredited for treating opioid addiction.⁷

Buprenorphine is a partial mu-opioid receptor agonist similar to morphine but with greater potency and with agonist-antagonist properties.^7,8 The advantage of buprenorphine compared to methadone is the ability to prescribe it in office-based settings, devoid of the bottlenecks with prescribing methadone.⁸ However, a buprenorphine waiver program first must be completed prior to being able to prescribe buprenorphine.

The Maternal Opioid Treatment Experimental Research (MOTHER) study, the largest MAT randomized trial to date comparing the efficacy and safety of methadone vs. buprenorphine in pregnant people, compared the maternal and fetal outcomes of 175 pregnant people with OUD who received buprenorphine vs. methadone.⁹ Newborns exposed to buprenorphine during pregnancy required less medication to treat NAS and had shorter treatment and hospital stays than newborn infants exposed to methadone during pregnancy. Conversely, compared to pregnant people treated with buprenorphine, those who were randomized to methadone had a higher study completion rate, with 33% vs. 18% of pregnant people in the buprenorphine and methadone arms, respectively, discontinuing therapy during pregnancy.

Other studies also have demonstrated that, compared to pregnant people who received MAT with buprenorphine, those who received methadone MAT were more likely to experience fewer drug relapses and to remain in treatment for a longer period of time.¹⁰ Methadone is known to prolong the QT interval, so patients receiving methadone ideally should have electrocardiograms performed prior to starting and during therapy. If the QTc interval is noted to be > 450 msec to 499 msec, caution should be exercised, and if ≥ 500 msec, methadone should not be used.⁶ A buprenorphine-naloxone combination historically has been used for pregnant persons even though there is a lack of safety and efficacy data to support its use in pregnant persons with OUD.¹¹ The use of buprenorphine-naloxone drug combination during pregnancy likely will increase when additional safety data are accumulated.

Opioid Receptor Agonist Therapy

Although buprenorphine and methadone are the recommended MAT for pregnant persons with OUD, some pregnant people may want to, or be motivated to, use an opioid receptor antagonist for therapy. Extended-release injectable naltrexone (XR-NTX), administered once monthly, is a newer opioid antagonist that was approved by the Food and Drug Administration (FDA) in 2006.¹² Evidence to date points to its efficacy. Use of XR-NTX eliminates the need for daily MAT (since it is administered monthly) and is associated with a four-fold decrease in tolerance and withdrawal associated with methadone and buprenorphine.¹³

Although some treatment facilities use XR-NTX to treat OUD in pregnant people, there still are limited data about its safety. ACOG recommends that if a woman is stable on XR-NTX before becoming pregnant, the decision about whether to continue treatment with XR-NTX during pregnancy should be made after a thorough discussion between the patient and their healthcare provider that carefully balances the limited safety data with the potential risk of relapse with treatment discontinuation.⁴ A recent survey among pregnant people enrolled in a comprehensive substance use treatment program demonstrated a strong interest in considering XR-NTX antagonist therapy during pregnancy.¹⁴

During labor, a maintenance opioid agonist dose with buprenorphine or methadone should be continued and additional pain relief should be provided as needed to pregnant persons who are using methadone or buprenorphine. Although pain relief using epidural or spinal analgesia is recommended, opioid agonist-antagonist-like pentazocine, nalbuphine, and butorphanol are contraindicated because they can trigger severe withdrawal in pregnant people receiving opioid agonists.⁴ During the postpartum period, nonsteroidal anti-inflammatory medications and acetaminophen should be administered as first-line therapy for pain following a regular vaginal birth or cesarean delivery, unless contraindicated. When non-opioid alternatives are ineffective at controlling severe pain, a brief course of low-dose opioids may be tried. Patients should be counseled about the pros and cons of opioids, including their potential for abuse.

Other Concerns

It is critical to understand that NAS is a potential complication of exposure to MAT. Healthcare professionals should not refrain from providing MAT because of concerns about NAS alone. Working closely with the pediatric care team can make sure that babies delivered to mothers who used opioids while pregnant are checked for NAS, given the proper care, and directed to necessary programs.

Studies have shown that breastfeeding can shorten hospital stays and eliminate the need for morphine treatment in newborns, despite the fact that rates of breastfeeding often are low among postpartum people with OUD.¹⁵ Encouraging postpartum people to breastfeed to reduce NAS symptoms and strengthen parent-child relationships is encouraged, unless there are significant medical complications that preclude breastfeeding, such as galactosemia and maternal HIV infection. The American Academy of Pediatrics recommends breastfeeding for women taking methadone and buprenorphine regardless of maternal dose, since transfer of these medications into breast milk is minimal.⁴

REFERENCES

1. Gomes T, Tadrous M, Mamdani MM, et al. The burden of opioid-related mortality in the United States. JAMA Netw Open 2018;1:e180217.
2. Guille C, Simpson AN, Douglas E, et al. Treatment of opioid use disorder in pregnant women via telemedicine: A nonrandomized controlled trial. JAMA Netw Open 2020;3:e1920177.
3. Azuine RE, Ji Y, Chang HY, et al. Prenatal risk factors and perinatal and postnatal outcomes associated with maternal opioid exposure in an urban, low-income, multiethnic US population. JAMA Netw Open 2019;2:e196405.
4. [No authors listed]. Committee Opinion No. 711: Opioid use and opioid use disorder in pregnancy. Obstet Gynecol 2017;130:e81-e94.
5. Brookmeyer KA, Haderxhanaj LT, Hogben M, Leichliter J. Sexual risk behaviors and STDs among persons who inject drugs: A national study. Prev Med 2019;126:105779.
6. Ecker J, Abuhamad A, Hill W, et al. Substance use disorders in pregnancy: Clinical, ethical, and research imperatives of the opioid epidemic: A report of a joint workshop of the Society for Maternal-Fetal Medicine, American College of Obstetricians and Gynecologists, and American Society of Addiction Medicine. Am J Obstet Gynecol 2019;221:B5-B28.
7. Reddy UM, Davis JM, Ren Z, Greene MF. Opioid use in pregnancy, neonatal abstinence syndrome, and childhood outcomes: Executive summary of a joint workshop by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, American College of Obstetricians and Gynecologists, American Academy of Pediatrics, Society for Maternal-Fetal Medicine, Centers for Disease Control and Prevention, and the March of Dimes Foundation. Obstet Gynecol 2017;130:10-28.
8. Shulman M, Wai JM, Nunes EV. Buprenorphine treatment for opioid use disorder: An overview. CNS Drugs 2019;33:567-580.
9. Jones HE, Fischer G, Heil SH, et al. Maternal Opioid Treatment: Human Experimental Research (MOTHER) — approach, issues and lessons learned. Addiction 2012;107 Suppl 1(0 1):28-35.
10. Chou R, Fanciullo GJ, Fine PG, et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain 2009;10:113-130.
11. Link HM, Jones H, Miller L, et al. Buprenorphine-naloxone use in pregnancy: A systematic review and metaanalysis. Am J Obstet Gynecol MFM 2020;2:100179.
12. Kjome KL, Moeller FG. Long-acting injectable naltrexone for the management of patients with opioid dependence. Subst Abuse 2011;5:1-9.
13. Towers CV, Katz E, Weitz B, Visconti K. Use of naltrexone in treating opioid use disorder in pregnancy. Am J Obstet Gynecol 2020;222:83.e1-83.e8.
14. Jones HE. Acceptance of naltrexone by pregnant women enrolled in comprehensive drug addiction treatment: An initial survey. Am J Addict 2012;21:199-201.
15. Jones HE, Kaltenbach K, Heil SH, et al. Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Engl J Med 2010;363:2320-2331.