Substance Use in Pregnancy and Neonatal Withdrawal Syndromes

Etiology

Opioids are the most commonly used substances and are associated with significant neonatal complications. Poly-substance use is widespread. Other substances commonly used include nicotine, alcohol, cocaine, benzodiazepines, amphetamines, and selective serotonin reuptake inhibitors.

The use of marijuana during pregnancy has emerged as an increasing concern, particularly in light of its growing legalization and usage, prompting inquiries regarding its potential effects on newborns. Research suggests that prenatal exposure to marijuana may be associated with hyperactivity and persistent difficulties in memory and learning during childhood.[3]

According to a recent article, prenatal exposure to prescription opioids for more than 30 days is associated with an increased risk of neonatal opioid withdrawal syndrome, regardless of when the exposure occurred. Opioid exposure during the third trimester was linked to neonatal opioid withdrawal syndrome, no matter how long the exposure lasted.[4]

Epidemiology

In recent decades, the incidence of opioid use disorder has increased significantly.[5][6] Between 1999 and 2014, the national rate of opioid use disorder rose by 333%, increasing from 1.5 to 6.5 cases per 1000 delivery hospitalizations.[7] Although substance use disorders during pregnancy occur across all socioeconomic and racial groups, they are more prevalent among younger, unmarried individuals and those with lower educational status.[8][9].

The incidence of neonatal abstinence syndrome in the United States rose by 82% between 2010 and 2017, increasing from 4.0 to 7.3 per 1000 birth hospitalizations.[10] The most significant increases were observed among low-income, non-Hispanic White populations. Hospital costs associated with the care of individuals with opioid-related conditions have significantly increased, as these newborns often require several weeks of hospitalization to manage withdrawal symptoms.[11][12]

Pathophysiology

The pathophysiology of substance withdrawal is a complex biological process involving cerebral alterations in norepinephrine, serotonin, and dopamine levels. The exact molecular mechanisms remain poorly understood.[13] Research has suggested that genetic differences in the µ-opioid receptor (OPRM1) and catechol-O-methyltransferase (COMT) genes may influence the requirement for pharmacological treatment and the duration of hospital stay in newborns exposed to opioids before birth.[14] The incidence and severity of withdrawal remain low in premature infants, possibly due to shorter overall exposure time or the incomplete development of neurological pathways affected by substance exposure during fetal development.[15]

History and Physical

Most newborns who show signs of withdrawal have been exposed to substance use by the birthing parent during and before pregnancy. The timing and intensity of neonatal symptoms can be influenced by several factors, including the type of substance exposure, the timing of the most recent dose, the total amount ingested, and concurrent exposure to other substances. For example, in infants exposed to short-acting substances such as heroin, withdrawal signs can be observed within the first 24 hours. However, for long-acting agents such as methadone and buprenorphine, the withdrawal signs may be observed 1 to 3 days after birth. Occasionally, withdrawal signs may be delayed until 5 days of age or later. Preterm infants often exhibit milder or fewer symptoms of neonatal abstinence syndrome compared to those born at full term.[16] 

Classic signs of neonatal withdrawal include a range of neurological, gastrointestinal, and autonomic symptoms.

Neurological and Behavioral Symptoms

• High-pitched, excessive crying
• Tremors
• Irritability
• Poor sleep
• Increased muscle tone
• Exaggerated Moro reflex
• Seizures

Feeding and Gastrointestinal Disturbances

• Poorly coordinated feeding
• Vomiting
• Failure to thrive
• Loose stools
• Perianal excoriation

Autonomic and Other Systemic Signs

• Sweating
• Sneezing
• Fever
• Mottling
• Temperature instability
• Tachypnea
• Tachycardia [13][17][18]

The timing of onset, type, and severity of withdrawal symptoms in newborns can vary significantly. The pathophysiology behind this variability is not fully understood but is likely influenced by multiple factors, as follows:

• Type and dosage of substances used during pregnancy
• Concurrent use of other opioid and nonopioid substances
• Parental factors, such as nutritional status, infections, and mental health conditions
• Genetic predisposition
• Prematurity and other coexisting infant health conditions
• Breastfeeding practices and preferences
• Environmental factors, including the availability of consistent infant caregivers and levels of sensory stimulation, such as noise and light exposure

Evaluation

The evaluation of neonatal abstinence syndrome necessitates a comprehensive approach that includes maternal history, toxicology screening, and systematic observation of the infant's clinical manifestations. Identification of substances and metabolites can be performed on maternal or neonatal urine specimens. Neonatal meconium can also be used for this purpose. Tests have also been developed to identify substances from neonatal hair and umbilical cord tissue.[13][18] However, all these tests have limitations.

Urine toxicology screening in newborns has low sensitivity and typically detects only recent substance exposure. In contrast, meconium testing offers higher sensitivity and specificity, reflecting exposure over a longer period. However, meconium testing is time-consuming, may require referral to specialized laboratories, and delayed passage of meconium can limit timely testing. Additionally, the presence of substances in meconium may not indicate recent exposure. Neonatal hair analysis can also be used to detect prenatal substance exposure; however, it is limited by the slow rate of hair growth and the low concentrations of substances, making interpretation challenging.

Several assessment tools are available to evaluate the severity of neonatal withdrawal symptoms and guide treatment decisions. The Finnegan Neonatal Abstinence Scoring System is the most widely used tool for assessing 21 signs of withdrawal, including tremors, feeding difficulties, and irritability.[19] More recently, the Eat, Sleep, Console method has gained traction due to its focus on the infant's functional well-being and responsiveness to nonpharmacological care.[20] Other tools, such as the Modified Finnegan and Lipsitz Scales, are used in specific settings to provide more streamlined assessments. Regardless of the tool selected, it is essential to implement standardized protocols and ensure that staff conducting newborn assessments are adequately trained.

Treatment / Management

A multidisciplinary approach provides optimal care for the infant and the family. Various disciplines, including occupational and physical therapy, social services, and child life, should be integrated into patient care alongside clinicians and nursing staff. Appropriate post-discharge planning and follow-up care are as important as the services provided during the hospital stay.[13][17][18](B3)

Each unit taking care of infants with neonatal abstinence syndrome should have a standardized policy for managing neonatal abstinence syndrome. Strict adherence to a standardized policy has been shown to reduce the length of hospital stay for these infants. Management during hospital stays involves supportive care incorporating both pharmacological and nonpharmacological interventions.

The goal of nonpharmacological interventions is to reduce the need for pharmacotherapy. These interventions should be tailored to each infant's behavioral patterns. Strategies include appropriate swaddling, positioning, and rocking; reducing auditory and visual stimulation; providing small but frequent feedings; offering nutritional support; and managing associated morbidities, such as loose stools and perianal excoriations. Infants diagnosed with neonatal abstinence syndrome are at an increased risk of experiencing suboptimal growth during the neonatal period. Therefore, close monitoring of caloric intake and weight gain is essential.[21]

Breastfeeding is encouraged for individuals on stable medication-assisted treatment regimens, such as methadone or buprenorphine (Suboxone), according to guidelines from the Academy of Breastfeeding Medicine.[22] Breastfeeding promotes parent-infant bonding, enhances parental engagement in newborn care, and has been associated with a reduced need for pharmacological treatment in opioid-exposed infants.[23] Candidates for breastfeeding should be engaged in a supervised treatment program, abstinent from illicit substance use during the period leading up to delivery, have received appropriate prenatal care, and have no medical contraindications to breastfeeding. Conversely, breastfeeding is generally discouraged in cases of recent illicit substance use, inadequate prenatal care, or comorbid conditions that may pose risks to the infant.(B2)

The goal of pharmacotherapy is to provide short-term relief from symptoms of substance withdrawal. Opioid therapy is the preferred therapy based on available studies. The current literature does not establish an optimal opioid agent. However, morphine is the most commonly used medication. Methadone and buprenorphine are also widely used. Older opioids such as tinctures of opium and paregoric are no longer used.[24]

Some infants with severe withdrawal may need a second medication; however, data on the ideal choice of a second agent are limited. The most frequently utilized adjunctive options are clonidine and phenobarbital. Phenobarbital demonstrates greater efficacy in neonates with prenatal exposure to both opioids and benzodiazepines. However, its potential adverse effects, including oversedation, uncertain long-term neurodevelopmental outcomes, and significant alcohol content, necessitate careful consideration.[25](A1)

Infants may be discharged from the hospital once they have been fully weaned off pharmacological treatment and have remained clinically stable for at least 24 hours. In some settings, infants who require multiple medications are discharged after completing opioid weaning, while continuing a second-line agent at home. In such cases, a prescription for the remaining medication is provided at discharge, and the weaning process is completed under the supervision of a pediatrician with close outpatient follow-up.

Differential Diagnosis

Due to overlapping clinical features, signs of substance withdrawal in newborns should be carefully differentiated from other conditions with similar presentations, as follows:

• Sepsis, which may present with temperature instability and irritability
• Hypoxic-ischemic encephalopathy, characterized by abnormal muscle tone, irritability, and seizures
• Metabolic disturbances, such as hypoglycemia or hypocalcemia
• Endocrine disorders, including hyperthyroidism, which may cause temperature instability, irritability, and loose stools [18]

Prognosis

Determining the long-term neurodevelopmental outcomes of neonatal abstinence syndrome is challenging due to the numerous confounding environmental and social factors associated with individuals who use substances. A recent meta-analysis indicated that neonatal abstinence syndrome is associated with future instances of child abuse, mental health issues, vision impairments, and poor academic performance.[26] Early intervention programs and close follow-up care are essential for optimizing outcomes in these infants. Environmental factors, including the quality of postnatal care and family support, play significant roles in shaping the long-term prognosis of children affected by neonatal abstinence syndrome.

Complications

Neonatal abstinence syndrome can lead to a range of potential complications, including congenital birth defects, premature birth, low birth weight, microcephaly, seizures, hyperbilirubinemia, sudden infant death syndrome, and developmental and behavioral disorders.