Perinatal Drug Abuse and Neonatal Drug Withdrawal

Etiology

Opioids are the most commonly abused drugs and are associated with significant neonatal complications. Poly-drug abuse is extremely common. Various other drugs identified used illicitly are nicotine, cocaine, heroin, benzodiazepines, amphetamines, and selective serotonin reuptake inhibitors (SSRIs).

Epidemiology

Based on 2013 data, 5.4% of pregnant women aged 15 to 44 years were using illicit drugs. However, the rate was higher in women aged 18 to 25. Though maternal substance use disorders are equally common in different socioeconomic classes and races, they more common in younger, unmarried women and women with lower educational status.[1][2]

In last two decades, the incidence of opioid use has increased almost five times. Simultaneously, the incidence of neonatal abstinence syndrome has increased from 1.2 to 3.4 per 1000 live births per year. There has been a significant increase in hospital costs associated with the care of opioid-addicted women and their newborns who remain hospitalized for several weeks for management of their withdrawal signs.[3]

Pathophysiology

Clinical presentation of an infant with withdrawal symptoms depends on the type of drugs used, timing, and amount of last maternal use, along with genetic factors that have not been completely evaluated. Pathophysiology of drug withdrawal is a complex biological phenomenon and seems to involve cerebral alterations in levels of norepinephrine, serotonin, and dopamine. The exact molecular mechanisms remain poorly understood.[4]

Some studies have linked genetic variations of mu opioid receptor and catechol-o-methyl transferase enzyme to the need and length of pharmacotherapy in neonates with prenatal opioid exposure.[5]

The incidence and severity of withdrawal remain low in premature infants. This can be explained by decreased exposure, decreased morphine clearance due to functional immaturity and decreased receptors.[4]

History and Physical

The majority of newborns exhibiting signs of withdrawal will have a maternal history of drug use before and during pregnancy. The timing of withdrawal depends on the most recent history of the drug dose and the half-life of that drug. For example, in infants exposed to short-acting substances like heroin, withdrawal signs can be seen within the first 24 hours. However, for long-acting agents like methadone and buprenorphine, the withdrawal signs may be seen 1 to 3 days after birth. Occasionally, withdrawal signs may be delayed until five days of age or later. As a result, opioid-exposed infants should be observed in the hospital for at least 5 to 7 days with close follow-up care in place.

The classic signs of withdrawal include[6][4][7]:

• High-pitched excessive cry
• Tremors and irritability
• Poor sleep
• Increased tone
• Exaggerated Moro reflex
• Poorly coordinated feeding, vomiting, and failure to thrive
• Loose stools and perianal excoriation
• Sweating, sneezing, fever, mottling, temperature instability
• Tachypnea and tachycardia
• Seizures

The timing of the onset of withdrawal signs, along with the type and severity of signs, has a wide variability. The pathophysiology of this variability is not well understood but may be related to a variety of factors, such as:

• Type and dosages of the maternal drugs
• Concomitant use of other opioid and non-opioid drugs
• Maternal factors such as nutritional status, infections, and psychiatric conditions
• Genetic factors
• Prematurity and other comorbid infant morbidities
• Breastfeeding preferences
• Environmental factors like availability of infant handlers, excessive stimulation including noise and light levels

Evaluation

Prenatal maternal history and urine drug screening form the basis of evaluation. Identification of drug or its metabolite can be performed on maternal and/or neonatal urine specimens. Neonatal meconium can also be used for this purpose. Tests have been developed to identify drugs from neonatal hair and umbilical cord tissue.[4][7]

However, all these tests have limitations. Urine drug screening has low sensitivity and is positive only in infants with recent exposures. Meconium testing has high sensitivity and specificity, but the test is time-consuming and likely be done at reference laboratories only. Also, the presence of the drug in meconium may not be indicative of recent exposure, since meconium testing has a longer window of detection. Occasionally, meconium may not be passed for several days. Testing the neonatal hair for drugs has difficulties due to a small amount of drug in the hair and a slow rate of growth.

Despite limited clinical utility, such assays may be helpful in cases where an infant exhibits signs of withdrawal and mother denies substance use.

Treatment / Management

A multidisciplinary approach provides optimal care for the infant and the mother. Various disciplines, including occupational and physical therapy, social services, and child life, should be included in patient care in addition to physicians and nursing staff. Appropriate post-discharge planning and follow-up care are as important as services during the hospital stay.[6][4][7](B3)

Each unit taking care of drug-withdrawing infants should have a standardized policy for the management of neonatal abstinence syndrome. Adherence to a standardized policy has been shown to reduce the length of hospital stay for these infants.

Management during hospital stays includes supportive care with pharmacological and nonpharmacological interventions.

The goal of nonpharmacological interventions is to reduce the need for pharmacotherapy. These interventions should be individualized based on each infant's behavioral patterns. TThey 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 excoriation.

Breastfeeding should be encouraged in women who are on stable maintenance regimens such as methadone, suboxone, and similar drugs. Breastfeeding increases mother-infant bonding and encourages maternal participation in infant care. Studies have shown that breastfeeding reduces the need for treatment in opioid-exposed infants[8]. These women should be abstinent from illicit drugs, should have received appropriate prenatal care, and should not have medical contraindications to breastfeeding like HIV. Breastfeeding should be discouraged for mothers who had used illicit drugs in the recent period before delivery, had a lack of adequate prenatal care, and had comorbid conditions like HIV.(B2)

The goal of pharmacotherapy is to provide short-term relief in symptoms of drug 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 commonly used. Older opioids such as tinctures of opium and paregoric are no longer used.[4][7](B3)

Some infants with severe withdrawal may need a second medication. Again, data is limited on the ideal choice of a second agent. Clonidine and phenobarbital are the most commonly used additional choices. Phenobarbital is the drug of choice for nonopiate withdrawal.

Different scoring systems, such as the Lipsitz tool, the Finnegan Neonatal Abstinence scoring system, and others, have been used to guide initiation, titration, and weaning of opioid therapy. These scoring systems are based on the presence and severity of clinical signs. All these scoring systems involve monitoring for withdrawal signs starting at birth and assessment every three to four hours during the entire hospitalization. Although the Finnegan scoring system is the most widely used, there is no data to support the use of one system over the other.

Once an infant has been completely weaned off from pharmacotherapy and stable for at least 24 hours, the infant can be discharged from the hospital. Some units discharge infants needing multiple medications after they are weaned off opioid medications. They are then discharged with a prescription of the second line agent they have been on, to be later weaned off by the pediatrician on close follow-up.

Differential Diagnosis

Due to the similarity in presentation, clinical signs of drug withdrawal should be differentiated from conditions like[7]:

• Sepsis that presents with temperature instability, irritability
• Hypoxic ischemic encephalopathy presenting with tone abnormalities, irritability, and seizures
• Metabolic abnormalities like hypocalcemia and hypoglycemia
• Endocrine disorders like hyperthyroidism presenting with temperature instability, irritability, and loose stools