As the United States experiences an opioid crisis, how are pregnant individuals impacted?
Opioid use and opioid use disorder have profoundly impacted the United States over the past 2 decades. The opioid crisis began with the overprescribing of prescription opioids and has had distinct subsequent waves, followed first by heroin and more recently by synthetic opioids including illicitly manufactured fentanyl.1-3 Overdose rates have continued to rise with more than 100,000 people dying from overdose in 2022.4
The ages associated with the highest prevalence of substance use and development of use disorder overlap, especially during the earlier years of pregnancy potential. Hence, opioid use, use disorder, and overdose in pregnancy and postpartum have increased in parallel with the opioid crisis, and overdose is a leading cause of pregnancy-associated deaths.2 Most adults in the United States have used substances; however, only a minority of people develop a use disorder.5 Risk factors for development of substance use disorder include a younger age of first use, substance availability in both the household and the neighborhood, preexisting mental illness, and, especially for women, gender-based violence, including childhood sexual abuse, that leads to trauma.6,7
Although medications for opioid use disorder (MOUDs) have been available for more than 50 years, most pregnant women with OUD receive no treatment because of inadequate access, ambivalence, and fear of stigma and discrimination.8-10 As obstetricians and gynecologists, we are uniquely positioned at routine and episodic periods along the reproductive health life course. By integrating OUD assessment and treatment into prenatal and postpartum care, we can directly address the opioid crisis and interrupt the generational cycle of addiction.11
In this manuscript, we will review how to assess and treat OUD, with an emphasis on medication, the birthing hospitalization, and postpartum.
Stigma and language
Stigma is the process by which people are “marked” by a perceived differentness of deviation from social norms.12 Stigma is often expressed in language and experienced by people as discrimination. A large body of evidence documents how common stigmatizing beliefs are among health care providers and how the experience of health care discrimination negatively impacts care.13-17 Pregnant women who use drugs experience compounded stigmas (of substance use, pregnancy, treatment) and consequentially may be legitimately fearful to disclose their use despite desiring treatment.
Responsibility of ensuring patient safety rests upon the provider. Therefore, it is important that providers interact with patients in a nonjudgmental way and provide support to patients who are at a variety of entry points of change18 (Table 1).19 Harm reduction, beyond MOUD, should be explored with all patients and includes naloxone and syringe services and safer injection practices if appropriate.20
Screening is the primary means by which substance use is identified clinically, whether the patient is pregnant or not.21 Screening should be distinguished from testing. Screening is characterized by a series of questions or use of a validated tool, such as a questionnaire.21 See Box 1 for examples of validated screening tools.22 Testing is the examination of a biological specimen (such as urine) for the presence of drug metabolites or parent compounds. Although universal screening is recommended for all pregnant women by the American College of Obstetricians and Gynecologists, drug testing is not.23
“Presumptive tests” utilize ELISA technology and are the most common test used. Although they render results rapidly, providers should be aware that the information quality obtained from a presumptive test is poor because of both false-positive and false-negative results. Definitive tests use the technology of liquid or gas chromatography–mass spectrometry and provide quantified results and exact substance identification.24 Definitive tests are more expensive and take days to report. In addition, the window of detection varies by substances and for many is typically fewer than 3 days.25 The primary symptoms of addiction are behaviors, and a positive drug test cannot identify a substance use disorder, much less parenting competence, even when a positive result is confirmed.21 Finally, professional society recommendations are unanimous: Drug testing, if done, requires informed written patient consent.
Assessment for substance use should be performed via validated screening instrument. A positive screen should be followed by diagnostic assessment. The Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) diagnostic criteria should be used to diagnose OUD (Table 2).26 To meet criteria for OUD, 2 or more affirmative responses to the criteria are required.27
After confirmation of OUD, treatment should be offered. The standard of care for OUD rests on medications. Methadone and buprenorphine are the safest and most effective MOUDs in pregnancy. There are less data for naltrexone in pregnancy. These 3 medications differ in pharmacology: Methadone is a full opioid receptor agonist, buprenorphine is a partial agonist, and naltrexone is an opioid antagonist28 (Figure). The μ-opioid receptor is the primary site of action and is responsible for many of the favorable aspects of opioids, namely euphoria, analgesia, and stress coping. However, MOUD also exerts activity on both δ- and κ-opioid receptors, which are important to understand in terms of potential medication adverse effects. δ-Receptor activation leads to anxiolysis and positive affect, whereas κ activation is associated with dysphoria, stress, and negative affect.29 Methadone is a full agonist at the μ, δ, and κ receptors; buprenorphine is a partial μ agonist and a δ and κ antagonist; and naltrexone is an antagonist at the μ, δ, and κ receptors.30
Opioids are addictive, in part because they are both positively and negatively reinforcing. These dual characteristics lead to neuroadaptations that follow chronic use, causing a patient to develop tolerance, experience withdrawal when the substance is not used, and experience cravings. MOUD works first by treating opioid withdrawal and then by controlling drug cravings, which interrupts negative reinforcement. MOUD also works by establishing an “opioid blockade” (blocks the effect of other opioids if used), which interrupts positive reinforcement and establishes a cross-tolerance. Collectively, these features are associated with decreased mortality and reduced substance use.31
Behavioral therapy can be an important dimension of recovery for many people. However, the overall literature on OUD treatment demonstrates little to no additional benefit of behavioral therapies such as group counseling vs medication. Therefore, providers should support behavioral therapy but not insist upon it—and certainly not withhold medication for counseling nonadherence. Some patients may be reluctant or resistant to initiate MOUD because of prior negative experiences with medication or because of mistrust or family/peer pressure. Engagement in prenatal care, even in the context of continued substance use, improves birth outcomes, and providers should utilize a harm reduction framework, in which the provider not only “meets the patient where they are,” but also “helps them get where they want to go.”32
Methadone is among the most federally regulated medications in the United States; it cannot be prescribed for OUD but can be administered directly to patients in the outpatient setting from a federally licensed opioid treatment program (OTP). Methadone can also be initiated or continued in a hospital. Methadone does not require withdrawal for initiation.33 Because of its differential metabolism between individuals, initiation is often slower than for buprenorphine. However, pregnancy is a rapid metabolic state, and more rapid protocols have been suggested.34
Buprenorphine is less regulated and, hence, more easily integrated into prenatal care settings. The US Drug Enforcement Administration “X-waiver,” which had previously limited who could prescribe buprenorphine, was recently removed. Buprenorphine can now be prescribed by any provider with prescribing authority.35 This regulatory change should increase access to buprenorphine both for medication initiation and continuation.
Buprenorphine is a partial agonist; therefore, the patient needs to be withdrawn before medication initiation. If not, buprenorphine can precipitate withdrawal.33 Although there is concern that fentanyl might lead to a greater likelihood of precipitated withdrawal, population health data to support this are lacking, and the likelihood of precipitated withdrawal can be lessened with microdosing or cross-tapering protocols (Box 2).Buprenorphine is available in 2 formulations: sublingual films or tablets and a monthly extended release.33 Although the initial literature recommended the use of the buprenorphine monoproduct in pregnancy, subsequent research has concluded that the combination product of buprenorphine plus naloxone is as safe and effective.36
Naltrexone is an opioid receptor antagonist and hence requires a week of opioid abstinence prior to initiation to avoid precipitated withdrawal. Naltrexone can be prescribed by anyone with prescribing authority and comes in both oral and extended-release formulations.33 The existing literature on naltrexone in pregnancy is limited to case series. There are less data on the safety and effectiveness of naltrexone compared with buprenorphine or methadone, so its use is not recommended.24 See Table 3 for a comparison of medications.37
Opioid withdrawal and buprenorphine initiation
Withdrawal is the inverse of dependence and occurs following cessation of opioid use or administration of either a partial or a full opioid antagonist. Chronic opioid use leads to dependence on sympathetic and parasympathetic control by the exogenous opioid, and withdrawal, consequentially, leads to noradrenergic imbalance seen in the increase of norepinephrine from the locus coeruleus, which leads to the typical symptoms of withdrawal: irritability, abdominal cramps, nausea/vomiting, diarrhea, increased blood pressure and pulse rate, lacrimation, rhinorrhea, yawning, and pupil dilation.34 Withdrawal can be clinically measured using the Clinical Opiate Withdrawal Scale and should be assessed at every visit, especially early in treatment and in pregnancy.
Because buprenorphine is a partial agonist, withdrawal may be precipitated if the medication is initiated too early. Standard buprenorphine initiation protocols begin medication administration when the Clinical Opiate Withdrawal Scale score is at least 8.38 However, microdosing or cross-tapering protocols can be started before the patient has experienced withdrawal.39 These protocols begin with low-dose buprenorphine administration (typically 0.5 mg), below the threshold of precipitated withdrawal (Box 2). Table 4 describes a standard buprenorphine initiation protocol.40
MOUD care continuity
Following stabilization on MOUD, patients should be assessed at clinic visits for withdrawal, cravings, and other substance use. Both metabolic and physiologic changes of pregnancy can lead to more rapid metabolism of both methadone and buprenorphine. Hence, some patients who had previously been stable on a medication dose may present with increased drug cravings or even withdrawal symptoms. In this circumstance, providers should consider split dosing (twice daily, 3 times daily, or even 4 times daily) before dose increases, especially if the symptoms occur hours after medication administration. Split dosing increases the pharmacokinetic area under the curve by minimizing peaks and troughs and encourages a more optimal steady state. For methadone, split dosing provided by the OTP in the form of take-home bottles should be considered and fully discussed with the patient.24
The birthing hospitalization
The birthing hospitalization can be a period of increased stress for pregnant women with OUD. For those with untreated OUD, the birthing hospitalization can be an opportunity for assessment and MOUD initiation. Any of the screening instruments discussed in Box 1 are recommended, and positive screens should be followed by diagnosis and medication initiation.
Drug testing during the birthing hospitalization is not recommended by professional societies because of the limitations of testing. Drug tests should only be ordered if the provider can properly interpret the results and the results will impact clinical care.20 Clear clinical indications for drug testing should be documented and informed consent obtained. The American Society of Addiction Medicine is clear that if the results of a drug test impact “major clinical or nonclinical” decisions in care, then definitive, not presumptive, tests are required.41
For pregnant women with treated OUD, medication should be continued throughout the hospitalization. Query of the prescription drug monitoring program is required to confirm buprenorphine dose if it isn’t documented in the patient’s medical record. Methadone is not reported in prescription drug monitoring programs, so providers may need to call the opioid treatment program to confirm the dose. Providers should note that OTPs open early (by 6 AM) and often are closed by the afternoon and on Sundays.
MOUD does not provide analgesia, and individuals with OUD may need more analgesia compared with individuals without OUD. Analgesic goals should be developed in partnership with the patient, and overall multimodal therapies are preferred. Regional analgesia should be prioritized, including early epidural. Nonpharmacologic management (such as mindfulness), nonopioid pharmacology (such as acetaminophen or ketamine), and opioids (both systemic and regional) can be utilized.42
Some infants exposed in utero to opioids develop withdrawal (termed neonatal abstinence syndrome or neonatal opioid withdrawal syndrome).43 There is no relationship between maternal MOUD dose and newborn withdrawal.44 Risks of developing newborn withdrawal are complex and include both the intrauterine and the postpartum care environment. For example, the number of cigarettes per day and exposure to benzodiazepines and gabapentin are associated with increased severity and duration of newborn withdrawal.43
Breastfeeding, breast milk, and skin-to-skin contact all reduce the severity and duration of withdrawal. Many birthing hospitals have moved away from automatic placement in the neonatal intensive care unit for infants at risk of withdrawal and initiated programs such as “Eat, Sleep, Console” because placement in the neonatal intensive care unit worsens withdrawal and leads to more medication, longer lengths of stay, and increased costs of care.43
The Child Abuse Prevention Treatment Act requires that any infants born “affected by” substance exposure be reported to child welfare. Although state laws vary, the federal statute is clear that drug testing is not required and that drug exposure alone is not an indication for a report.45 The clinical definition of opioid withdrawal in the newborn was recently standardized. Of note: A diagnosis of neonatal abstinence syndrome does not require drug testing and “does not imply harm, nor should it be used to assess child social welfare risk or status.”45 Finally, providers should be aware that the Child Abuse Prevention Treatment Act is likely to be reauthorized in the 2023-2024 congressional session and that reporting requirements are likely to change.
Discharge opioid prescribing should be determined primarily by obstetric indications. Opioid agonists can provide analgesia to people receiving MOUD. Untreated or undertreated pain is likely a greater risk factor for return to use among postpartum women with OUD than opioid exposure through analgesic prescription. However, some patients may wish to avoid opioids. Hence, person-centered care is key, along with multimodal pain management and short-term postpartum follow-up.46
Postpartum OUD care
The postpartum period is a time of increased vulnerability for women with OUD. Discontinuities in health care including MOUD and child welfare involvement are both common and associated with return to use, overdose, and maternal death.47 Continuation of care postpartum by either the obstetrician-gynecologist or addiction medicine provider is critical, and the standard single 6-week postpartum visit is likely insufficient for women with OUD. Shorter-term and more frequent follow-up are needed to assess medication adherence and mood and allow opportunities for early intervention if problems develop.47
The importance of naloxone
Naloxone is a short-acting opioid antagonist with high affinity for the μ-opioid receptor. It is highly effective in reversing an overdose through the displacement of other opioids at the μ receptor. Anyone who uses opioids (prescribed, MOUD, or untreated OUD) and anyone who may witness an overdose (such as friends and families of people who use opioids) should receive naloxone and know how to use it.43 This is particularly important postpartum because overdose is a leading cause of maternal death in the United States and timely administration of naloxone saves lives.2
Naloxone can be prescribed, distributed directly often through local public health agencies, or obtained from a pharmacy under a regional standing order. The FDA recently approved naloxone for OTC sale. Naloxone has a short half-life, and its effect begins to wear off within 10 minutes. People can be reversed with naloxone and then slip back into overdose again. Therefore, multiple doses are often needed, and patients and families should also be advised to call 911 following an overdose event.
Obstetricians and gynecologists provide care at integral points in the lives of reproductive-aged women. Therefore, we are well positioned to assess, diagnose, and initiate treatment for OUD in pregnancy and through the postpartum period. Methadone and buprenorphine are the safest and most effective medications for OUD in pregnancy. Utilizing the key fundamental principles of OUD management, providers will be better prepared to confidently introduce this lifesaving treatment into their practice repertoire.