Opioid use disorder: Overview of treatment during pregnancy

INTRODUCTION — Opioid use disorder (OUD) may involve heroin, diverted or misused prescription opioids, or other morphine-like drugs (eg, fentanyl). OUD during pregnancy is associated with substantial maternal, fetal, and neonatal risks. These risks are related to repeated opioid exposure (eg, risk of overdose) as well as factors associated with opioid use (eg, smoking, poor nutrition, needle sharing, unstable lifestyle).

Medication for OUD (MOUD) is recommended for pregnant patients and should be accompanied by close supportive clinical follow-up. The goal is to prevent maternal, obstetric, and neonatal complications associated with OUD, provide an entry into recovery, facilitate prenatal care, and help patients avoid the myriad risks from the unstable lifestyle associated with substance use (eg, drug-related criminal activity, housing instability, intimate partner violence, infectious disease) [1-3]. While methadone has been the standard choice for MOUD during pregnancy since the 1970s, buprenorphine is increasingly used because neonatal withdrawal (also known as neonatal abstinence syndrome) appears to be less severe when the pregnant patient is treated with buprenorphine as opposed to methadone [4]. Continuous use of either treatment during pregnancy appears to reduce the odds of preterm birth compared with discontinuing opioid agonist treatment [5].

This topic will provide an overview of the management of OUD in pregnant and postpartum patients. Administration of methadone and buprenorphine pharmacotherapy, as well as fetal/neonatal effects, are discussed separately (see "Opioid use disorder: Pharmacotherapy with methadone and buprenorphine during pregnancy"). General issues related to prevalence, screening, complications, and care of the pregnant patient with OUD are also discussed separately. (See "Substance use during pregnancy: Screening and prenatal care" and "Substance use during pregnancy: Overview of selected drugs", section on 'Opioids'.)

MOUD OR MEDICALLY ASSISTED WITHDRAWAL? — Treatment with either methadone or buprenorphine plus psychosocial treatment is the preferred approach to treatment of OUD during pregnancy given the many benefits of medication for OUD (MOUD) (table 1) [6-13]. Either methadone or buprenorphine is provided throughout pregnancy and the postpartum period to prevent withdrawal symptoms and reduce or eliminate cravings. The medication may be continued for years beyond the postpartum period; the duration of therapy in nonpregnant individuals is reviewed separately (see "Opioid use disorder: Treatment overview"). Psychosocial interventions, such as addiction counseling, peer support groups, and/or structured, multimodal care, are provided concurrently to support the patient in recovery and reduce the risk of relapse. (See "Opioid use disorder: Psychosocial management".)

Medically assisted opioid withdrawal followed by psychosocial treatment is an alternative, but it is not recommended because a high proportion of patients return to using opioids [14-21]. In medically assisted opioid withdrawal, methadone or buprenorphine is provided to prevent withdrawal symptoms and reduce or eliminate cravings, but the dose is then gradually reduced to the lowest dose that prevents withdrawal symptoms and then reduced further until the medication can be discontinued. Following withdrawal, psychosocial interventions should be provided to support the patient and reduce the risk of relapse. The American Society of Addiction Medicine does not consider medically assisted withdrawal to be a standalone treatment for OUD. (See 'Medically assisted opioid withdrawal' below.)

These two approaches have never been compared in a randomized trial involving pregnant patients. The process of medically assisted withdrawal is no longer thought to be associated with adverse fetal outcomes [22,23]. However, in nonpregnant patients treated for OUD, pharmacotherapy has had greater efficacy in reducing recidivism and maintaining abstinence compared with medically assisted withdrawal followed by nonpharmacologic psychosocial treatment [24,25].

CANDIDATES FOR MOUD — All pregnant patients with OUD, as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (table 2), are candidates for medication for OUD (MOUD). The duration of OUD is not a criterion for eligibility if continuation of, or return to, illicit opioid use is likely during pregnancy. (See "Substance use disorders: Clinical assessment", section on 'Assessment/Diagnosis'.)

Candidates for treatment should be referred to a clinician with training and familiarity with MOUD and/or to an OUD treatment program. Barriers to treatment include lack of health insurance or resources to self-pay, incarceration, transportation and childcare needs, guilt about the effect of drugs on the fetus, and fear of legal consequences, including loss of custody of children.

Treatment programs that are oriented to abstinence only and do not utilize or understand MOUD should be avoided.

METHADONE OR BUPRENORPHINE? — Programs in the United States that treat OUD during pregnancy use either methadone or buprenorphine for first-line therapy. Buprenorphine is available as a monoproduct or in combination with naloxone, an opioid antagonist [26,27]. (See "Opioid use disorder: Pharmacotherapy with methadone and buprenorphine during pregnancy", section on 'Use of combined buprenorphine and naloxone formulation'.)

The overall pros and cons of the two medications for pharmacotherapy are summarized in the table (table 3). The Substance Abuse and Mental Health Services Administration (SAMHSA) has also published a table of decision considerations when selecting methadone or buprenorphine for pregnant patients (table 4).

The American College of Obstetricians and Gynecologists (ACOG) and other major medical organizations [10,11,28] have concluded that the available evidence supports the use of either methadone or buprenorphine as a potential first-line medication for pregnant patients with OUD who are new to treatment [2,29]. As a result of the ACOG opinion and increasing data suggesting decreased severity of neonatal withdrawal with buprenorphine use, use of buprenorphine in pregnancy has increased [30,31]. However, the improvement in neonatal outcome may be related to differences in baseline characteristics between patients who are offered methadone versus buprenorphine treatment.

Our approach — We consider the following factors when counseling patients about their options; the choice of medication (methadone versus buprenorphine) is a shared decision.

●Program availability – A list of local opioid treatment programs can be found online. In many areas of the country, need for treatment greatly exceeds capacity. Regulations for dispensing methadone are different from and more restrictive than those for dispensing buprenorphine. (See "Opioid use disorder: Pharmacotherapy with methadone and buprenorphine during pregnancy", section on 'Provider' and "Opioid use disorder: Pharmacotherapy with methadone and buprenorphine during pregnancy", section on 'Provider'.)

●Availability of comprehensive treatment – Successful treatment with medication for OUD (MOUD) depends upon a comprehensive, multidisciplinary, coordinated approach to care [32,33]. Most pregnant patients will benefit from opioid treatment programs that offer all of the following at a single site: MOUD; psychiatry and social worker services; individual and group counseling; case management; and prenatal care, including health and parenting counseling. Opioid treatment programs that specialize in care of pregnant individuals generally provide all of these services on-site, in contrast to an office-based setting where a clinician prescribes buprenorphine and the only requirement is a "capacity to refer" the patient for counseling [34].

●Patient preference – Methadone generally has to be dispensed to the patient on a daily basis by a registered opioid treatment program. Buprenorphine can also be provided by an opioid treatment program but can also be prescribed in an office-based setting. Patients can receive a prescription for up to 30 days of buprenorphine, fill the prescription at a pharmacy, and take the medication as prescribed on their own.

The office setting allows more privacy and convenience since patients do not come in daily for treatment. For some patients, geographic and economic limitations (eg, childcare, transportation costs) are barriers to attending an opioid treatment program on a daily basis. Although office settings are convenient, less frequent clinical contact can also be disadvantageous and may make an office-based setting less suitable for some individuals.

●Maternal and perinatal outcome – Both methadone and buprenorphine are effective MOUD, and neither appears to be teratogenic [35]. For the pregnant person, buprenorphine may pose a lower risk of overdose mortality than methadone because of the "ceiling effect" [36,37], but does not appear to reduce the risk of severe maternal complications compared with methadone [38]. (See "Opioid use disorder: Pharmacotherapy with methadone and buprenorphine during pregnancy", section on 'Pharmacology'.)

For the newborn, in utero exposure to buprenorphine rather than methadone has been associated with a lower risk of preterm birth, higher birth weight, larger head circumference, neonatal abstinence syndrome (NAS; discussed below), and possibly less severe NAS [35,39-41]. Severity of NAS, although important to consider, is not necessarily the most important factor in choosing MOUD during pregnancy because NAS, when properly identified and managed, has not been associated with long-term harm. (See "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Management and outcomes".)

●Neonatal abstinence syndrome (NAS) – The landmark Maternal Opioid Treatment: Human Experimental Research (MOTHER) trial is the largest randomized trial comparing pregnancy outcome among pregnant patients with OUD randomly assigned to treatment with methadone or buprenorphine at eight international sites [39]. Compared with methadone, buprenorphine resulted in significantly [42]:

•Lower doses of morphine for treatment of NAS (mean total 1.1 versus 10.4 mg)

•Shorter duration of treatment for NAS (4.1 versus 9.9 days)

•Shorter neonatal hospital stay (10.0 versus 17.5 days)

However, there were several limitations to this trial, such as its small size (175 pregnancies) and a statistically nonsignificant but markedly higher attrition rate from the buprenorphine treatment arm than from the methadone arm (33 versus 18 percent), which may have been due to the buprenorphine dosing protocol. The usual maximum dose of sublingual buprenorphine (32 mg daily) may not have been sufficient to prevent symptoms of withdrawal in some pregnant patients (usually those requiring >140 mg methadone daily).

A large cohort study of a Medicaid dataset also reported benefits associated with use of buprenorphine. This study included over 13,000 pregnant persons exposed to buprenorphine and over 6000 exposed to methadone who had a live birth [38]. Compared with methadone, buprenorphine was associated with:

•A nearly 30 percent reduction in NAS (52 versus 69 percent; aRR 0.73, 95% CI 0.71-0.75) in those exposed in the 30 days before delivery

•A 40 percent reduction in preterm birth

•A 25 percent reduction in small for gestational age newborn

•A 45 percent reduction in low birth weight

•Similar risks for severe maternal complications (defined as potentially life-threatening conditions caused or aggravated by pregnancy [eg, organ failure, myocardial infarction, coma, delirium, cerebrovascular disorder, pulmonary edema or embolism, sepsis, shock, disseminated intravascular coagulation])

Key strengths of this study include the large sample size and adjustment for known confounders, including the use of a propensity-score analysis for early, late, and within 30 days before delivery exposure windows to balance all measured covariates among the exposure groups. Sensitivity analyses to address possible misclassification bias and unmeasured confounding resulted in similar findings.

●Maternal treatment retention – Ultimately, the best treatment option is the one that maximizes retention in treatment and prenatal care while minimizing recidivism. An analysis of data from three randomized trials [39,43,44] found no difference between methadone and buprenorphine for maternal retention in treatment [45]. However, each of the three trials also reported lower rates of opioid use during pregnancy among participants assigned to methadone. Thus, although use of buprenorphine may lower neonatal resource utilization (eg, days in neonatal intensive care) and cost [39], it may not achieve the primary objective of effective MOUD for all patients. Of note, in males and nonpregnant females, methadone maintenance is associated with greater treatment retention than buprenorphine [25,46]. (See "Opioid use disorder: Pharmacologic management" and "Opioid use disorder: Treatment overview".)

Although a meta-analysis that included these randomized trials and additional cohort studies noted that pregnant patients treated with buprenorphine were less likely to use opioids near delivery than those treated with methadone (RR 0.44, 95% CI 0.28-0.70), it is likely that differences in patient characteristics between the two treatment groups accounted for this finding [40].

Other pharmacotherapy

●Naltrexone – Naltrexone (an opioid antagonist) is available in oral, injectable, and implantable forms (implant not approved in the United States). There is a paucity of high-quality prospective data with regard to its use in pregnancy.

•Data from a small, retrospective cohort study including 68 naltrexone-exposed neonates reported outcomes comparable to using methadone or buprenorphine in pregnancy, except that urogenital anomalies appeared to be more frequent in naltrexone-exposed fetuses. The authors did not state if these anomalies occurred with first-trimester exposure [47].

•In the largest study, which prospectively compared 121 patients with naltrexone medication-assisted treatment with 109 patients with methadone or buprenorphine medication-assisted treatment, naltrexone was well tolerated by both mother and fetus, and no neonates who were exposed to the drug in utero up to delivery experienced symptoms of neonatal abstinence syndrome [48]. Blood levels were similar in cord and maternal blood and were not detected if naltrexone was discontinued >60 hours before delivery. There were no congenital anomalies reported in the 23 infants with first-trimester exposure.

•In a retrospective cohort study comparing six pregnant patients on naltrexone with 13 matched controls on buprenorphine, the rate of neonatal opioid withdrawal syndrome (NOWS) was less in the naltrexone group (0 versus 92 percent in the buprenorphine group), which resulted in reductions in neonatal treatment for NOWS and length of stay [49]. There were no significant differences in congenital anomalies, birthweight, head circumference, or Apgar scores.

If naltrexone is maintained until delivery, opioids are not likely to be effective for intrapartum and postpartum pain control. Expert panelists of the Substance Abuse and Mental Health Services Administration disagreed regarding continuing naltrexone use during pregnancy [50]. A joint workshop of the Society for Maternal-Fetal Medicine, ACOG, and American Society of Addiction Medicine concluded that data are insufficient to support the initiation of naltrexone therapy in pregnancy, but it may be continued for those patients who already are taking this medication after discussion of the risks of discontinuing naltrexone (eg, risk of relapse) and the limitations of data of its use in pregnancy [12]. One (ER) of the three authors of this topic uses naltrexone in their clinical practice in select cases.

●Kratom – Kratom, an herb with opioid- and stimulant-like properties, should not be used in patients withdrawing from opioids. Pregnant patients have used kratom for self-treatment for OUD [51]. There is little published evidence of efficacy and increasing numbers of reports of lethal overdose and other adverse effects. A systematic review of six case reports of Kratom exposure in pregnancy found neonatal withdrawal and maternal withdrawal requiring treatment in five of six of the cases [52]. Maternal outcomes were not reported in one of the cases [52].

Buprenorphine has been used in pregnancy to treat kratom use disorder [51]. (See "Opioid withdrawal: Medically supervised withdrawal during treatment for opioid use disorder", section on 'Kratom'.)

PRETREATMENT MATERNAL EVALUATION — A thorough medical, psychosocial, and physical assessment should be performed, given the prevalence of concomitant medical disorders, the socially and environmentally complex lives of individuals with OUD, and their frequent lack of consistent medical care [53,54]. Care should be empathetic and nonjudgmental, with a focus on building a strong patient-provider relationship [55,56]. This may reduce negative interactions and improve patient satisfaction.

Confidentiality — There are special considerations with regard to confidentiality when treating patients with OUD or other substance use disorders. For example, programs or providers in the United States are prevented from disclosing information identifying a patient as having a substance use disorder without written consent from the patient [57]. Clinicians should be familiar with local laws and regulations.

History — A detailed and accurate medical and obstetric history can usually be obtained if the questions are asked in a direct and nonjudgmental way (see "Opioid use disorder: Epidemiology, clinical features, health consequences, screening, and assessment", section on 'Assessment'). The following four areas are of particular concern in this population.

●Social history – In one report, 83 percent of pregnant patients entering methadone treatment programs came from households in which the parents used substances, 67 percent had been victims of sexual assault, and 60 percent had been physically assaulted [32]. Adverse childhood events such as physical, emotional, and sexual abuse or neglect are strongly associated with substance use disorder. One large retrospective cohort study found that people with a history of five or more adverse childhood events were 7 to 10 times more likely to report illicit drug use and addiction [58]. (See "Intimate partner violence: Diagnosis and screening" and "Intimate partner violence: Intervention and patient management" and "Evaluation and management of adult and adolescent sexual assault victims in the emergency department".)

●Depression – We agree with the American College of Obstetricians and Gynecologists' recommendation for screening for depression and other behavioral health conditions [2], as co-occurring mental health conditions are common (50 to 65 percent) [59,60]. Among pregnant patients enrolled in a methadone treatment program, 30 percent had moderate-to-severe depression, and 40 percent reported postpartum depression [61]. (See "Prenatal care: Second and third trimesters", section on 'Mental health screening'.)

●Tobacco use – Approximately 80 to 90 percent of pregnant patients with OUD also smoke cigarettes [14,62-65]. The combination of tobacco and methadone delays the onset of neonatal abstinence syndrome and increases the severity of neonatal withdrawal [66-68]. In addition, tobacco use has multiple adverse effects on maternal health and pregnancy outcome. For all of these reasons, and others, smoking cessation is recommended. (See "Cigarette and tobacco products in pregnancy: Impact on pregnancy and the neonate" and "Tobacco and nicotine use in pregnancy: Cessation strategies and treatment options".)

●Illicit substances or alcohol – It is common for patients who use opioids during pregnancy to use more than one illicit substance or misuse alcohol [69]. Polysubstance use is associated with an increased risk of preterm birth. As an example, a retrospective cohort study including 258 neonates born to patients with OUD treated with methadone reported the rates of preterm birth among those using 0, 1, 2, or ≥3 substances (alcohol or illicit drugs) in addition to methadone were approximately 24, 26, 48, and 65 percent, respectively [70].

Polysubstance use can also affect medication for OUD (MOUD), depending on the substance and interaction. For example, barbiturates induce methadone metabolism, while benzodiazepines like diazepam may act synergistically, causing excessive sedation [71-74]. Chronic alcohol use may lower methadone levels through induction of hepatic enzymes, while acute consumption can accentuate methadone effects. (See "Alcohol intake and pregnancy".)

Physical examination — Important aspects of the physical examination are listed in the table (table 5) and reviewed in detail separately. (See "Opioid use disorder: Epidemiology, clinical features, health consequences, screening, and assessment", section on 'Physical examination'.)

Laboratory tests — Routine prenatal laboratory tests are performed. (See "Prenatal care: Initial assessment", section on 'Laboratory tests'.)

Laboratory tests of specific significance in this population include:

●Urine toxicology screening to monitor for continued substance use. Toxicology screening is performed serially; the frequency during treatment is described separately. (See "Opioid use disorder: Pharmacotherapy with methadone and buprenorphine during pregnancy", section on 'Role of urine drug testing'.)

●Screening for tuberculosis. (See "Tuberculosis disease (active tuberculosis) in pregnancy".)

●Screening for sexually transmitted infections at the first prenatal visit and repeated in the third trimester in patients who remain at increased risk. (See "Prenatal care: Second and third trimesters", section on 'Screen for sexually transmitted infections'.)

•HIV counseling and testing using an opt-out approach (ie, testing will be done routinely unless a patient explicitly refuses). (See "HIV and women", section on 'HIV and pregnancy'.)

•Hepatitis B and C and liver chemistry tests (eg, hepatitis B surface antigen, anti-hepatitis C virus antibodies, aspartate aminotransferase [AST], alanine aminotransferase [ALT]).

Hepatitis B vaccination is recommended for patients with negative serology. (See "Immunizations during pregnancy", section on 'Hepatitis B'.)

•Chlamydia, gonorrhea, syphilis, and Trichomonas vaginalis (in settings where the prevalence is high). (See "Screening for sexually transmitted infections".)

Imaging — One or two ultrasound examinations before 22+0 weeks of gestation are performed routinely during pregnancy because early ultrasound estimation is superior to pregnancy dating based on the last menstrual period or physical examination, and also provides information about fetal development. Females who have been using nonprescribed opioids frequently have irregular menses, so ultrasound is essential to establish gestational age. (See "Overview of ultrasound examination in obstetrics and gynecology", section on 'Obstetric sonography'.)

For patients who present for prenatal care late in pregnancy, ultrasound still provides useful information, but it is less accurate for estimating the date of delivery. (See "Prenatal assessment of gestational age, date of delivery, and fetal weight".)

INDUCTION AND MAINTENANCE METHADONE AND BUPRENORPHINE DOSING — Issues related to administration of methadone and buprenorphine in pregnant and postpartum patients, including dosing and side effects, are reviewed in detail separately. (See "Opioid use disorder: Pharmacotherapy with methadone and buprenorphine during pregnancy".)

PRENATAL CARE — Coordination of care between obstetric providers and the other providers (eg, addiction medicine, psychiatry, primary care, pediatrics, social service) is important. Routine aspects of prenatal care are discussed in detail separately. In general, a history of OUD per se, whether receiving medication for OUD (MOUD) or not, does not alter the frequency of prenatal care visits. (See "Prenatal care: Initial assessment" and "Prenatal care: Second and third trimesters" and "Prenatal care: Patient education, health promotion, and safety of commonly used drugs".)

Obstetric providers should be aware of the reporting requirements related to OUD within their community/state/country [75,76].

Antenatal fetal monitoring — The optimal method of fetal assessment during initial patient stabilization and initiation of pharmacotherapy ("induction") is unknown; no data are available to support any protocol. In our practice, we perform a daily nonstress test in pregnancies >24 weeks of gestation admitted for inpatient stabilization during induction of pharmacotherapy. Abnormal results are managed according to standard obstetric protocols, with consideration of the effect of opioids on fetal biophysical parameters (discussed below) (see "Overview of antepartum fetal assessment", section on 'Management of pregnancies with abnormal test results'). Hospital admission is not mandatory for patients beginning MOUD, though admission is not uncommon for coordination of care. Daily nonstress testing is not performed in patients who undergo induction on MOUD as outpatients.

After the initial period of stabilization and initiation of MOUD, we believe continued antepartum fetal testing (nonstress test, biophysical profile [BPP]) does not improve pregnancy outcome in patients who consistently demonstrate good adherence by negative urine toxicology screens and have no standard indications for fetal surveillance. However, for patients with evidence of ongoing substance use or those who have other indications for fetal surveillance (eg, preeclampsia, fetal growth restriction), weekly or twice weekly testing during the third trimester is reasonable, as these pregnancies are probably at higher risk of abnormal fetal testing warranting intervention. (See "Overview of antepartum fetal assessment", section on 'Indications for fetal assessment'.)

Opioids, like other central nervous system depressants, can affect the fetal heart rate, resulting in decreased variability and fewer accelerations [77]. To reduce the chances of nonreactive nonstress test or a low BPP score related to opioids, we suggest delaying the test until at least four to six hours after MOUD is consumed, if possible. If daily fetal monitoring is performed, we suggest performing the test just before consuming the dose.

●Effect of methadone on fetal biophysical parameters – Methadone use decreases fetal heart rate reactivity (higher frequency of nonreactive nonstress tests), increases time to achieve a reactive nonstress test [78-81] and increases time to complete the BPP score [79,82]. Reductions have been observed in [83-85]:

•Fetal baseline heart rate

•Fetal heart rate variability

•Number of heart rate accelerations

•Fetal breathing movements

•Fetal movement

In a study of 16 pregnancies between 28 and 40 weeks in patients on methadone, scores for the modified BPP were the same before and after methadone dosing in 75 percent of the pregnancies, but it took on average 16 minutes longer to complete the modified BPP after methadone dosing (mean time 20 minutes) [79]. Others have also reported minimal impact of the BPP score [81].

●Effect of buprenorphine on fetal biophysical parameters – In studies evaluating fetal neurobehavior during periods of peak and trough buprenorphine concentration, buprenorphine was associated with reductions in fetal heart rate, heart rate variability, and heart rate accelerations [86,87]. However, these effects are less pronounced than those seen with methadone and may not significantly affect interpretation of tests of fetal well-being.

Patients treated with buprenorphine tend to have greater fetal heart rate variability; more accelerations; better coupling between fetal movement and heart rate in early gestation (24 to 28 weeks); and longer, more frequent movements in later gestation (32 to 36 weeks) than those treated with methadone [86]. The suppressive effects of buprenorphine are most notable in later gestation (>32 weeks) and at higher doses (>13 mg) [87]. Compared with fetal testing postmethadone dosing, postbuprenorphine dosing nonstress tests are more likely to be reactive (adjusted odds ratio [OR] 0.13, 95% CI 0.04-0.48) and BPP scores are likely to be higher (8.7 versus 8.2; p<0.02) [81].

Assessment for growth restriction — There is no consistent effect of MOUD on fetal growth. Because several studies have demonstrated an association between OUD and low birth weight, particularly in untreated patients [88], we and others perform ultrasound assessment of fetal growth in the third trimester, between 28 and 32 weeks [89-91]. Impaired fetal growth is more likely to be a concern in those patients with ongoing substance use. Regardless, if there is a clinical suspicion of fetal growth restriction (eg, lagging fundal height), an ultrasound examination is indicated, and management is the same as for any pregnancy complicated by impaired fetal growth. (See "Fetal growth restriction: Evaluation".)

LABOR AND DELIVERY

Intrapartum methadone and buprenorphine dosing — The patient's usual oral methadone or buprenorphine dose is continued intrapartum (during labor or before scheduled cesarean birth) to prevent withdrawal. (See "Opioid use disorder: Pharmacotherapy with methadone and buprenorphine during pregnancy", section on 'Intrapartum and postpartum methadone dosing' and "Opioid use disorder: Pharmacotherapy with methadone and buprenorphine during pregnancy", section on 'Intrapartum and postpartum buprenorphine dosing'.)

Labor and delivery management — Initial evaluation of any patient with OUD on the labor and delivery unit should include a medication history (including medication for OUD (MOUD) dose verification); inquiry about use of opioids, alcohol, and tobacco; urine toxicology; and testing for sexually transmitted infections (which may include rapid HIV testing), if not already performed in the third trimester. (See 'Laboratory tests' above.)

Most patients on the labor unit have an intravenous (IV) line or IV access placed early in labor in case of an emergency (eg, hemorrhage, nonreassuring fetal tracing). This is particularly important in this population because peripheral access may be difficult due to sclerosed veins, scars, and cellulitis.

Routine aspects of labor and delivery management are reviewed separately. (See "Labor and delivery: Management of the normal first stage".)

Analgesia and anesthesia — Neuraxial anesthesia is a common approach to pain management during labor and delivery in the general obstetric population and a good option for patients on MOUD [12]. Buprenorphine and methadone do not interfere with regional or local anesthetics. The goal of peripartum pain management is to provide adequate analgesia while avoiding both overmedication and withdrawal. The following are important principles to keep in mind:

●Health care professionals concerned about drug-seeking behavior and overmedication may make the erroneous assumption that the daily maintenance dose of methadone or buprenorphine alone provides analgesia. Although pharmacotherapy for OUD provides analgesia, long-term opioid exposure leads to tolerance (increasing amount of drug to achieve the same response) and opioid-induced hyperalgesia (increased sensitivity to pain) [56,92]. Patients who report acute pain with objective findings are less likely to be exhibiting drug-seeking behavior.

●There is no evidence that exposure to opioid analgesics in the setting of acute pain increases rates of relapse in patients with OUD [93].

●Efforts to achieve adequate pain control in patients with OUD should be similar to that in patients without such disorders, and include both pharmacologic (nonopioid and opioid) and nonpharmacologic approaches.

●Acute intrapartum pain should not be treated with additional doses of methadone or buprenorphine.

●Higher than usual opioid analgesic doses may be required because tight binding to the mu-opioid receptor blocks the analgesic effects of full opioid agonists; opioid cross-tolerance to anesthetics and other depressants occurs, a result of chronic receptor stimulation [94]; and patients have increased pain sensitivity.

●Although acceptable pain control can be achieved in clinical practice without clinically important central nervous system or respiratory depression, patients should be closely monitored because significant depression, though unlikely, is possible. Sedatives, opioids (including intrathecal), and general anesthetics should be administered cautiously since these drugs can potentiate the central nervous system depressant and analgesic effects of pharmacotherapy of OUD.

●In the absence of neuraxial analgesia, opioids, such as morphine, can be used safely in early labor. For labor pain, we give 6 to 10 mg of morphine IV to patients dilated less than 6 cm. Alternatively, patient-controlled analgesia (PCA) can be used, but neonatal depression should be anticipated if IV or PCA opioids are used throughout labor. Promethazine 25 mg IV is commonly given to laboring patients in conjunction with morphine. However, this combination in patients also taking buprenorphine, methadone, or nonprescribed opioids can increase the potential for respiratory depression, so treatment with opioids alone or dose modification with close maternal monitoring is recommended.

●Opioid antagonists or agonist-antagonists can precipitate acute withdrawal and should be avoided [95,96]. Examples of these drugs are nalbuphine hydrochloride, pentazocine, butorphanol tartrate, and naloxone. If any of these drugs are given inadvertently, withdrawal can be reversed with any full opioid agonist [96].

(See "Obstetric anesthesia for patients with opioid use disorder or opioid tolerance".)

POSTPARTUM CARE

Continue MOUD — Continuing MOUD postpartum is important to support retention in treatment of OUD and prevent return to use.

Overdose is a leading cause of pregnancy-related deaths in the year following delivery [97]. In a population-based study of individuals with Medicaid insurance in the United States from 2006 to 2013, individuals with OUD had higher incidences of both postpartum opioid overdose death (118 versus 5.4 per 100,000 deliveries) and all-cause postpartum death (316 versus 51.1 per 100,000 deliveries) compared with the general obstetric population in this database [98]. Postpartum use of MOUD was associated with a 60 percent reduction in the odds of opioid overdose death (odds ratio [OR] 0.4, 95% CI 0.1-0.9). However, MOUD is often discontinued. A study using data from the Massachusetts Department of Public Health found MOUD discontinuation in 36 percent of patients and <4 months of treatment increased the likelihood of postpartum discontinuation [99,100]. In another study, treatment dropout was related to ongoing use of illicit substances, particularly benzodiazepines [101].

Given the substantial obstacles present in the postpartum period (eg, postpartum mood disorders, stress of newborn care, child protective services involvement), a plan should be in place to ensure that the patient receives adequate MOUD and does not delay follow-up with their OUD treatment provider. This is particularly important for patients newly engaged in treatment.

Postpartum methadone and buprenorphine dosing — The patient's usual oral methadone or buprenorphine dose is continued postpartum to prevent withdrawal. Dosing is discussed in more detail separately. (See "Opioid use disorder: Pharmacotherapy with methadone and buprenorphine during pregnancy", section on 'Intrapartum and postpartum methadone dosing' and "Opioid use disorder: Pharmacotherapy with methadone and buprenorphine during pregnancy", section on 'Intrapartum and postpartum buprenorphine dosing'.)

Pain management — Postpartum pain should be managed using a multimodal approach that starts with nonopioid analgesia, when possible, in addition to standard postpartum pain control measures and MOUD [12]. Persistent pain despite these measures may be treated with opioids (eg, fentanyl, hydromorphone).

The goal of postpartum pain control is subjective pain relief without excessive side effects. Patients should be informed that while individual experience varies, antenatal opioid use may interfere with postpartum pain control and increase postpartum opioid requirements, particularly after cesarean birth. Opioid requirements may be 30 to 100 percent higher than those in opioid-naïve patients; sometimes even greater increases are required [95,102]. Significant interpatient variability in opioid dose requirements makes it impossible to precisely predict the opioid dose necessary to control postpartum pain [56,95]. The additional difficulty of continued opioid use may prevent providers from having a full appreciation of a patient's total opioid dose [55]. Smoking is very common in individuals with OUD and is associated with increased postoperative narcotic requirements [103]. Psychologic conditions, which are also prevalent in this population, independently predict poor pain control [92,95,104]. As with antepartum pain management, tight binding to the mu-opioid receptor, cross tolerance, and opioid-induced hyperalgesia result in increased pain and the need for higher than usual doses of opioid analgesics. Management of acute pain is more challenging in patients taking buprenorphine than those taking methadone because of its higher affinity for the mu-opioid receptor.

Specific approaches to pain management after vaginal and cesarean birth are reviewed separately. (See "Obstetric anesthesia for patients with opioid use disorder or opioid tolerance", section on 'Postpartum analgesia'.)

Postpartum monitoring and counseling

●Frequent maternal follow-up for recovery support, relapse prevention, and assessment of other preexisting mental health disorders is important after delivery. Patients should be seen in the office and/or contacted by phone multiple times, ideally over the first year postpartum. They are at particularly high risk of relapse postpartum due to multiple stressors, including changes in insurance coverage and access to care, demands of newborn care, exacerbation of underlying mental health conditions, and the stress of involvement of child protective services and the threat of losing custody of the child [105]. Large, population-based retrospective cohort studies of the general obstetric population have reported high rates of overdose 7 to 12 months after delivery [106,107]. Risk factors for postpartum overdose included maternal diagnosis of OUD and prior non-fatal overdose [107]. Longer duration of MOUD during pregnancy appears to increase the chances of MOUD continuation postpartum and appears to protect against overdose [13,100].

The Alliance for Innovation on Maternal Health Program (AIM) has developed a maternal safety bundle on obstetric care of patients with OUD. The bundle includes recommendations for breastfeeding and lactation support for all patients on pharmacotherapy; provides immediate postpartum, long-acting reversible contraception (LARC) when desired; and facilitates referrals to providers (eg, social work, psychiatry, and infectious disease) for management of comorbid conditions. It is important to ensure a "warm hand off" (ie, direct introduction of the client to the behavioral health provider) to the clinician who will coordinate care going forward after the birth [108].

●If a comorbid mental health disorder has been diagnosed, follow-up with an appropriate provider should be arranged. Postpartum screening for depression is recommended for all patients. (See "Postpartum unipolar major depression: Epidemiology, clinical features, assessment, and diagnosis", section on 'Screening'.)

●Postpartum contraceptive counseling is particularly important in this population due to a high rate of unplanned pregnancy [109]. The option of an immediate postpartum contraceptive (eg, LARC) should be discussed prior to hospital discharge. (See "Contraception: Postpartum counseling and methods".)

●Provide information on neonatal abstinence syndrome and newborn care. (See "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Management and outcomes".)

●Involve appropriate partners (eg, social workers, case managers, peer recovery coaches) to assist patients and families in the development of a plan of safe care for mother and infant [110]. Families should be referred to programs providing perinatal and infant health services, where available.

●Breastfeeding should be encouraged, with lactation support. (See "Opioid use disorder: Pharmacotherapy with methadone and buprenorphine during pregnancy", section on 'Breastfeeding' and "Opioid use disorder: Pharmacotherapy with methadone and buprenorphine during pregnancy", section on 'Breastfeeding'.)

MEDICALLY ASSISTED OPIOID WITHDRAWAL

Overview — Medically assisted opioid withdrawal (also called medically supervised opioid withdrawal, detoxification, or medical withdrawal) followed by psychosocial (nonmedication) treatment, although possible, should be used rarely due to the high percentage of recidivism: A systematic review found that relapse rates varied from 0 to 100 percent across studies depending on whether data from participants who did not complete detoxification or who were lost to follow-up were included in analyses [22]. The overall quality of the evidence was fair to poor, and few studies followed patients past delivery. Although historically concerns have been raised that medically assisted withdrawal could lead to fetal demise based on one case report [111] and the results of serial amniocentesis for amniotic fluid catecholamines, thought to be indicative of fetal stress [112], the systematic review did not find higher rates of fetal demise in patients undergoing medically assisted withdrawal.

For patients declining medication for OUD (MOUD), medically assisted withdrawal may be offered, but requires a thorough discussion about the risks of relapse and the need for consistent psychosocial support during and following the withdrawal process [12]. For patients initially declining MOUD, the process of medically assisted opioid withdrawal presents an opportunity to reconsider and switch to MOUD, particularly with a longer tapering schedule. In one study, 42 percent of patients undergoing a seven-day methadone taper transitioned to methadone treatment versus 11 percent undergoing a three-day taper [8].

Candidates — Indications for medically assisted opioid withdrawal during pregnancy include inability or declining to participate in long-term MOUD, patient request, and/or when MOUD is unavailable [6].

Procedure — Medically assisted opioid withdrawal should only be undertaken at a center familiar with this procedure in pregnancy and after obtaining informed consent. Candidates should undergo an ultrasound examination to look for preexisting signs of fetuses at risk for adverse outcome, such as oligohydramnios or fetal growth restriction, which would preclude medically assisted withdrawal [14,113].

Patients not on methadone should be admitted for methadone initiation and stabilization, after which the methadone dose can be slowly tapered at a rate of up to 20 percent every three days. A more gradual approach of lowering the dose 2 to 5 mg every 6 to 16 days has also been used [71,112]. Patients already taking methadone can be tapered to 20 mg per day as outpatients and then admitted for further tapering and discontinuation of the drug. A detailed description of the procedure in nonpregnant patients is available separately. We would avoid accelerated protocols during pregnancy as safety is unknown. (See "Opioid withdrawal: Medically supervised withdrawal during treatment for opioid use disorder".)

Buprenorphine can also be used for medically assisted opioid withdrawal. Hospital admission is not a requirement if the patient can be cared for by a buprenorphine provider. Before beginning buprenorphine, it is important to remember that it requires 12 to 24 hours of abstention from short-acting opioids and 48 to 72 hours abstention from methadone, and the patient should have mild to moderate opioid withdrawal with documentation of objective signs of withdrawal. For patients who cannot achieve this interval of abstention, methadone may be a better option. Alternatively, utilizing a microdosing protocol for buprenorphine may be effective for these patients [114]. We generally recommend not switching patients already on methadone to buprenorphine, as this will precipitate withdrawal. However, in shared decision-making with the patient, if this transition is desired, it may be achieved with a microdosing protocol, although microdosing for this purpose has only been studied outside of pregnancy [115,116].

We have no experience with use of other drugs for this purpose in pregnancy, and would specifically avoid lofexidine or tizanidine because they can significantly lower blood pressure.

Medically assisted opioid withdrawal can take place in any trimester, although most authorities avoid the procedure in the first and late third trimester. If the reason for medical withdrawal is prevention of neonatal withdrawal, the medical withdrawal treatment should be completed two months before delivery [117]. We suggest daily nonstress tests during the withdrawal process for pregnancies in the late second and third trimester.

Pregnancy outcome — The best evidence suggests that there is no increased risk of harm to the fetus [23,113,118,119], although miscarriages, preterm births, meconium passage, stillbirths, and elevated amniotic fluid epinephrine and norepinephrine levels have been reported in case reports [111,112]. Systematic reviews have reported that fetal loss and preterm birth rates were similar among patients who did and did not undergo medically assisted withdrawal [22,23]. A detailed illustrative example is described below:

●One large series of outcomes of medical withdrawal in 301 patients in Tennessee divided them into four groups: group 1 (involuntary because of incarceration; n = 108), group 2 (five to eight days of inpatient detoxification with an outpatient behavioral health follow-up; n = 23), group 3 (five to eight days of inpatient detoxification without an outpatient behavioral health follow-up; n = 77), and group 4 (8 to 16 weeks of outpatient detoxification with an outpatient behavioral health follow-up; n = 93) [119]. Major findings were:

•Two fetal deaths occurred, both to patients in group 1. The first occurred in the setting of abruption at 18 weeks, 8 weeks after detoxification, and the second occurred at 34 weeks in the setting of congenital anomalies and hydrops, following detoxification at 12 weeks. In both cases, urine drug screening was negative at the time of demise.

•Relapse occurred in 17 to 23 percent of patients in groups 1, 2, and 4, and 74 percent of patients in group 3.

•31 percent of infants were treated for neonatal abstinence syndrome, and all were delivered of mothers with evidence of relapse (eg, maternal admission, positive urine drug screening, meconium in amniotic fluid).

The authors could not assess the incidence of fetal distress because fetal monitoring was not routinely performed during opioid withdrawal.

There are no long-term follow-up studies of children born to mothers who underwent opioid withdrawal during pregnancy.

We agree with the American College of Obstetricians and Gynecologists' recommendation for additional research to assess the safety, efficacy, and long-term outcomes of medically assisted withdrawal [2].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Opioid use disorder and withdrawal" and "Society guideline links: Substance misuse in pregnancy".)

SUMMARY AND RECOMMENDATIONS

●Candidates for MOUD – Pregnant individuals with opioid use disorder (OUD) should be offered medication for OUD (MOUD). (See 'Candidates for MOUD' above.) MOUD is preferable to medical withdrawal followed by medication-free psychosocial treatment because medical withdrawal is associated with a high percentage of recidivism. (See 'MOUD or medically assisted withdrawal?' above and 'Medically assisted opioid withdrawal' above.)

●Options for MOUD – For pregnant individuals who are identified as candidates for MOUD, we consider several factors when counseling about options (table 3); the choice of medication (methadone versus buprenorphine) is a shared decision. (See 'Our approach' above.)

●Pretreatment evaluation – Pretreatment maternal evaluation in patients with OUD should include a detailed psychosocial history, screening for sexually transmitted and other infections, and sonographic examination of the pregnancy. (See 'Pretreatment maternal evaluation' above.)

●Pregnancy management

•Fetal monitoring – After initial stabilization and initiation of pharmacotherapy, we do not obtain outpatient antepartum fetal testing (nonstress test, biophysical profile) in patients who consistently demonstrate good compliance by negative urine toxicology screens and have no standard indications for fetal surveillance. However, for patients with evidence of ongoing substance use, or patients who have other indications for fetal surveillance (eg, preeclampsia, fetal growth restriction), weekly or twice weekly testing during the third trimester is reasonable. (See 'Antenatal fetal monitoring' above.)

•Monitoring fetal growth – There is no consistent effect of MOUD on fetal growth; however, we perform an ultrasound to assess fetal growth between 28 and 32 weeks of gestation. Growth is more likely to be a concern in those patients with ongoing illicit drug use. If there is a clinical suspicion of fetal growth restriction (eg, lagging fundal height), an ultrasound examination is indicated and management is the same as for any pregnancy complicated by impaired fetal growth. (See 'Assessment for growth restriction' above.)

●Pain management – Neuraxial anesthesia is a common approach to pain management during labor and delivery in the general obstetric population and a good option for patients on MOUD. Pain control in patients with OUD is similar to that in patients without this disorder and include both pharmacologic (nonopioid and opioid) and nonpharmacologic approaches; however, mixed agonist and antagonist opioid analgesics, such as pentazocine, nalbuphine, and butorphanol, should not be administered, as they may displace methadone from the mu receptor and precipitate acute withdrawal. Acute intrapartum and postpartum pain should not be treated with additional doses of methadone or buprenorphine. (See 'Analgesia and anesthesia' above and 'Pain management' above.)

●Postpartum care – Patients are at particularly high risk of relapse to opioid use postpartum due to multiple stressors. Close monitoring and continuing MOUD postpartum are important to support retention in treatment of OUD and prevent return to use. As in all postpartum patients, screening for depression and offering postpartum contraception is important. (See 'Postpartum monitoring and counseling' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Susan M Weiner, PhD, MSN, RNC, CNS, who contributed to earlier versions of this topic review.