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]:

Because many oral prescription opioids have half-lives of 24 to 36 hours, users often use at least daily to avoid withdrawal symptoms. Early symptoms and signs experienced during withdrawal include [5,8]:

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].

Unlike methadone doses, which can increase up to 80 mg, the dosage for buprenorphine is one 4–16 mg tablet per day in the induction period, with a maximum of 24–32 mg per day by the end of the pregnancy. The lower dosage results from the longer half-life (24 to 60 hours, compared to 24 to 36 hours for methadone) [10].

Even in a supervised environment, opioid use during pregnancy can have negative effects on the fetus, and there is a significant risk of congenital birth defects. Infants born to mothers who used opioids during pregnancy may develop [29,31]:

Methadone has been the criterion standard for opioid maintenance and avoidance of withdrawal during medically managed detoxification since the 1960s, and it remains the preferred option for the management of pregnant women dependent on opioids [9,10]. As noted, methadone has been classified as pregnancy category C by the FDA because there is a lack of human studies. Although not approved by the FDA for OUD in pregnancy, patients who have been administered methadone properly, under medical supervision, have been found less likely to use other illicit drugs that could harm the fetus [15,16].

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].

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].

Most infants with NOWS are in the NICU for an average of 19 days (range: 7 to 32 days), and it is important to ensure that the child is discharged to a stable home. It should be noted that infants who remain in the same room as their mothers have shorter length of stays and are more likely to be discharged home [24,27]. The discharge plan should include the infant's pediatrician, who will have access to the infant's record and a knowledge of any pharmacotherapy given and the length of stay in the hospital. Along with the pediatrician, the plan should include other members of the interdisciplinary team, including the mother's obstetrician/gynecologist, social workers, chemical dependency counselors, and supportive family members or friends [19]. Referral to additional specialty providers, as indicated, is critical at this point for both mother and baby to ensure minimal long-term negative health and cognitive consequences.