#93093: Management of Opioid Dependency During Pregnancy

In recent decades, opioid use disorder (OUD) has become a global public health emergency, with trends in opioid prescribing for women in their reproductive years, in particular, continuing to be a major health concern [1,2]. Estimates show that nearly 1 in 6 women of reproductive age (15 to 44 years of age) are prescribed opioids, and women are prescribed opioid medications for pain and for various medical ailments more often than men, causing complications such as insomnia, gastrointestinal side effects, tolerance, and dependence. The most common indication for opioid prescriptions for women is chronic pain management, but opioids may also be prescribed following surgery (e.g., cesarean section, hysterectomy) [2]. Oxycodone, hydrocodone, and codeine are among the most prescribed opioids, and each carries a risk for misuse [1]. The synthetic opioid pain reliever fentanyl is available by prescription but has gained traction in recent years as a common illicit street drug [18]. While opioids can be an effective analgesic, properties of these medications may cause patients to continue to seek the drug when the prescription runs out, thus contributing to misuse of opioids and the cycle of the opioid epidemic.

An extension of the opioid misuse epidemic is the public health issue of infants who are exposed to opioids in utero and who exhibit withdrawal symptoms at birth, known as neonatal opioid withdrawal syndrome (NOWS), or previously under the umbrella term of neonatal abstinence syndrome (NAS) [1,2]. Local, national, and international reports from neonatal intensive care units (NICUs) have brought awareness to the issue of opioid use and misuse in women. The epidemic has affected cities and small towns alike and involves people of all races and ethnicities. As a result, more research has been conducted and programs have been established to heighten awareness of the relationship between opioid use, misuse, and dependence and maternal/fetal health. The U.S. Food and Drug Administration (FDA) require boxed warnings be available for all patients on all immediate- and extended-release opioid pain medications due to the potential for "addiction, abuse, and misuse, which can lead to overdose and death" [3]. In addition, the FDA requires labeling that if an opioid (immediate- or extended-release) is required for an extended period of time in a pregnant woman, the patient must be advised of risk of NOWS, which may be life-threatening if not recognized and treated. It is also advised that management by neonatology experts be available at delivery [3].

It is important to note that universal definitions regarding opioid abuse, misuse, and dependency are lacking; however, the text revised fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5-TR), uses the term "opioid use disorder" to include misuse and abuse of or dependence on opioids. Previous editions of the DSM differentiated between the two categories. The DSM-5-TR combines abuse and dependence into a single disorder, measured on a continuum from mild to severe. In this course, opioid use disorder (OUD) and opioid dependence will be used interchangeably.

This course will highlight the biologic effects of OUD in women and fetuses. There will be an in-depth examination of the available pharmacologic treatments for the treatment of OUD during pregnancy, also known collectively as medications for opioid use disorder (MOUD) (previously medication-assisted treatment, or MAT), and the effects of treatment on the fetus. Lastly, there will be information regarding the long-term effects of in-utero exposure to opioids for the child.

According to the Centers for Disease Control and Prevention (CDC), women are prescribed opioids at higher doses and for longer periods of time than men [4]. While men continue to be more likely to die of prescription pain medication overdose, this gap is closing. In fact, since 1999, the percentage increase in deaths was more than 400% among women, compared with 265% in men [4].

Women between 25 and 54 years of age are most likely to be prescribed opioid pain medications, and 7 out of 10 prescription drug deaths among women involve opioids [4]. This may be due in part to the greater incidence of chronic pain syndromes in this patient population. Women who present with chronic pain are more likely than men to be diagnosed with two or more pain conditions and to be diagnosed with migraine headache, irritable bowel syndrome, fibromyalgia, arthritis, and low back, joint, or neck pain [5]. Studies have shown that men and women experience different side effects and responses to analgesic medications, which may be influenced by physiologic differences and/or social and psychologic factors. It has also been hypothesized that women may feel more pressure than men to maintain their familial roles as caretaker, spouse, mother, and/or provider despite pain, making their main objective when seeking medical intervention to cease pain and continue activities without interruption rather than seeking a curative, though more disruptive, option [6]. As a result, women may be prescribed opioid medications for a longer duration compared to men, and the duration and amount can lead to dependence. Female opioid abusers are also more likely to abuse other prescription medications, making drug-drug interactions a concern [5].

Opioids are defined broadly as all compounds related to opium—both natural products and synthetic derivatives. Opioids affect many body systems and share the following physiologic effects [5]:

Potential side effects of opioid use include nausea, vomiting, constipation, dilation of the pupils, impaired ability to swallow, and an itchy feeling on the skin [7]. Women may suffer from secondary amenorrhea, defined as absence of menstruation for three or more months as a result of opioid use [7]. Because amenorrhea is relatively common, women may be unaware of their pregnancy and continue to use or abuse opioids, which can be harmful to the mother as well as the fetus. Other possible adverse effects of opioid use include sedation, cough suppression, dry mouth, and miosis.

Between 2010 and 2017, identification of OUD among pregnant women increased 131% at time of delivery. Recent estimates have shown that 7% of pregnant patients use prescription opioid pain relievers during pregnancy; of those, 1 in 5 reported misuse (defined as obtaining the drug without a prescription or using them for a reason not indicated) [1]. In addition, it has been shown that women who use opioids long-term before pregnancy tend to continue to use during pregnancy, and nearly 9 of 10 pregnancies among women with OUD are unintended [2]. Women who become pregnant while using opioids may be hesitant to obtain appropriate prenatal care for many reasons, including [1,2,11]:

All patients taking opioids who can become pregnant should be advised of the warning signs of a possible pregnancy, including nausea while not in active withdrawal, tender breasts, sensitivity to unusual smells, and extreme fatigue, and should be instructed to seek immediate medical attention if any of these symptoms are observed [11]. For pregnant patients, actively using opioids is associated with an increased risk for obstetric and gynecologic complications such as pre-eclampsia, communicable infections (e.g., hepatitis C, human immunodeficiency virus [HIV]), low-birth-weight infants, stillbirths, pre-eclampsia, excessive bleeding, miscarriages, small head circumference in offspring, preterm deliveries, and even death [12; 13].

If pregnancy is suspected, a test should be administered. If positive, the immediate focus of care is on the health and safety of the mother and the fetus. The healthcare team may include community workers, a harm-reduction counselor, a chemical dependency counselor, and medical personnel (e.g., obstetrician/gynecologist, primary care physician, nurse practitioner) [14]. If a woman is under a physician's care for chronic pain and there is suspicion of pregnancy, the physician should assess the patient's medical condition prior to changing or refilling the patient's prescription. The potential risks of withdrawal and the short-and long-term effects on the fetus (e.g., developmental and congenital disabilities) should be included in patient education.

According to the World Health Organization, pregnant women dependent on opioids should be encouraged to use opioid maintenance treatment whenever available rather than to attempt opioid detoxification.

(https://www.who.int/publications/i/item/9789241548731 Last Accessed: December 14, 2023)

Strength of Recommendation/Level of Evidence: Strong/Very Low

In MOUD, methadone, buprenorphine, and buprenorphine/naloxone are used to avoid withdrawal symptoms in non-pregnant patients with OUD. Methadone and buprenorphine are rated pregnancy category C, meaning animal studies have shown an adverse effect on the fetus in the absence of human studies, but the potential benefits may warrant use in pregnant women despite the risks. Studies conducted through the SAMHSA have shown that naloxone can interfere with skeletal development and increase fetal mortality. Therefore, it is recommended that women taking buprenorphine/naloxone prior to becoming pregnant should be transferred to buprenorphine alone for the duration of the pregnancy. Overall, methadone and buprenorphine are the preferred medications used to stabilize the mother and fetus during pregnancy, and promising research has shown that neurological development in children of mothers who used MOUD is similar to those unexposed [9,10,29].

Infants who have been exposed to opioids run a higher risk (30% to 80%) of developing NOWS, which can appear within 72 hours to 14 days after birth for methadone (resolving in several days to weeks) and within 12 to 48 hours after birth for buprenorphine (peak: 72 to 96 hours; resolving in seven days) [17,20]. NOWS can also occur or be exacerbated in infants exposed or co-exposed to nicotine, benzodiazepines, and/or selective serotonin reuptake inhibitors in utero [17,20,21].

After delivery, the neonate should be assessed immediately for NOWS, the signs of which are generally apparent with routine newborn assessment and Apgar scores. Apgar scores are based on assessment of five categories (heart rate, respiratory effort, muscle tone, reflex irritability, and color) and are administered to all infants regardless of opioid exposure; however, special attention should be paid to possible signs of withdrawal in exposed infants [11]. The scores in each Apgar domain range from 0 to 2, with a maximum possible score of 10. The average score is 8 to 10, which indicates the infant does not need immediate attention. If the score is less than 8, the system affected is identified and appropriate medical procedures are initiated. If a third assessment at 10 minutes after birth does not show improvement, transfer to the NICU is warranted. Infants with acute NOWS usually have an Apgar score less than 8; however, there have been instances in which an infant's Apgar score is within normal range at birth but then deteriorates and begins to show signs of NOWS within 3 to 12 hours [11]. Comparison studies have found no significant differences in Apgar scores at birth of infants exposed to buprenorphine compared to those exposed to methadone [22].

The signs of NOWS are a result of the effects of opioid withdrawal on the infant's neurologic, gastrointestinal, and autonomic systems [12]. Neurologically, the clinical signs of NOWS include irritability; staying awake for long periods of time/sleeping in short intervals; high-pitched crying and inconsolability; seizures; sneezing; stiff arms, legs, and back; and body tremors with or without a Moro reflex [13,29]. NOWS may also compromise the infant's gastrointestinal system, resulting in vomiting, diarrhea, dehydration, and inadequate weight gain. High fever is common, and regulating the body temperature can be difficult. Elevations in respiration and blood pressure can occur [13]. Infants often appear uncomfortable and restless, even after being fed or swaddled.

If signs of NOWS are present, the infant should be taken to the NICU for further assessment and to determine the amount of opioid replacement (e.g., morphine) necessary to stabilize the patient, reverse the syndrome, and reduce the complications of withdrawal, if indicated. Additional medications (e.g., phenobarbital for seizures) may be required to control symptoms.

Several assessment tools are available and recommended to help determine the severity of NOWS (or NAS), including the Finnegan Neonatal Abstinence Scoring System, the Lipsitz Neonatal Drug-Withdrawal Scoring System, the Neonatal Withdrawal Inventory, the Neonatal Narcotic Withdrawal Index, and the Withdrawal Assessment Tool–Version 1 (WAT-1) [13,17,20,26]. The Finnegan Neonatal Abstinence Scoring System is a 31-item scale that will quantify the severity of NAS/NOWS in order to help guide treatment decisions. The tool may be administered every four hours, and if an infant receives a score of 8 or more points, or the total for three consecutive scores is greater than 23, pharmacotherapy is indicated. In response to the complexity of the Finnegan tool, a shorter modified version is available (the Finnegan Neonatal Abstinence Syndrome Scale—Short Form) and is recommended by the American Academy of Pediatrics [24]. The Lipsitz Neonatal Drug-Withdrawal Scoring System consists of 11 items, and a score of 4 or greater is an indication that opioid therapy should be started. The Neonatal Withdrawal Inventory is an 8-point checklist of NAS/NOWS symptoms, with a 4-point behavioral distress scale. The Neonatal Narcotic Withdrawal Index is comprised of six items, for a possible maximum score of 12 points. A score of 5 or more on this index should prompt pharmacologic intervention [13]. Finally, the WAT-1 is administered to infants experiencing NAS/NOWS who have been exposed to opioids and benzodiazepines for an extended period (including throughout a pregnancy) [20]. With this tool, pharmacotherapy is recommended for patients who score 10 or more points. However, the relative efficacy of these scores has not been definitively proven [23].

Specific neonatal assessments for opioid withdrawal continue to be developed and are becoming more specific to NOWS sequelae. One such tool is the Maternal Opioid Treatment: Human Experimental Research (MOTHER) Neonatal Abstinence Measure (based on the Finnegan scoring system), which includes the addition of common central nervous system, gastrointestinal tract, and autonomic clinical signs. Another simplified tool to assist in quick assessment is the Eat, Sleep, Console (ESC) measure, which is guided by the infant's clinical signs of withdrawal through evaluation of an infant's ability to eat ≥1 oz or breastfeed well, sleep undisturbed ≥1 hour, and be consoled [13]. More research is required to prove the relative efficacy of these scales in screening for NOWS.

If indicated, opioid treatment should be initiated and the infant should be reassessed every three hours. Treatment with other sedatives (e.g., benzodiazepines, clonidine) has been effective, but 83% of physicians in the United States use an opioid (morphine or methadone) to treat NOWS [23]. The dose of replacement opioid varies according to the severity of symptoms and degree of exposure; the average initial dose of morphine sulfate is 0.05 mg/kg every three hours [5]. If there is no improvement after three hours, the dose may be increased to 0.08 mg/kg, then again to a maximum of 0.1 mg/kg every four hours if necessary. Stabilization may take up to 48 hours. After 24 to 48 hours of a constant morphine dose, a gradual weaning can begin. Even after morphine is discontinued, the infant should be monitored hourly for 48 hours. If signs of NOWS reappear, the original dose should be restarted and the same procedure followed until successful. After this, discharge plans may be implemented [13,24].

After NOWS has resolved and the infant is stabilized, the interdisciplinary team, together with the mother or caregiver, should work to create a discharge plan that will be conducive to the health and safety of the infant and the mother. It is important that infants continue to be physically supported and monitored for any signs of digression [13].

Opioid use disorder has become a global public health emergency. Women (particularly in their reproductive years) are prescribed prescription opioids more often than men for a variety of conditions. While opioids can be an effective analgesic, properties of these medications may cause patients to continue to seek the drug when the prescription runs out, thus contributing to misuse of opioids and the cycle of the opioid epidemic. An extension of the opioid misuse epidemic is the public health issue of infants who are exposed to opioids in utero and who are at risk of experiencing symptoms of NOWS. Proper use of MOUD during pregnancy, thorough assessment at birth, and treatment of neonates with NOWS will ensure best outcomes for both parent and infant. Discharge planning includes education for caregiver(s), information on breastfeeding, and referrals for follow-up and specialty care, if indicated. As a member of the interdisciplinary healthcare team, compassionate management and treating the whole person will increase positive outcomes for this sensitive population and future generations.