Prenatal and Perinatal Infants

Maternal substance use during pregnancy results in direct exposure to the growing fetus due to shared placental circulation. Determining substance-specific adverse effects on the fetus from in-utero exposure is complex. ^, Dose, duration of use, type of substance, timing of exposure during gestation, polysubstance exposure, maternal health factors, and genetic predisposition to disease have overlapping effects and pose challenges for interpreting outcome studies of in utero exposure. Expanding into the postnatal period, family issues such as co-occurrence of substance misuse and interpersonal violence, psychosocial stressors in the family, social determinants of health, and community/environmental factors add to the complexity of the issue.

Longitudinal studies comparing outcomes in children who were substance exposed versus unexposed during pregnancy while controlling for confounding factors have identified adverse effects that are subtle but measurable. ^, Children who were substance-exposed during pregnancy may go on to develop disruptive behaviors, ^, and be more likely to be rated as having trouble with attention compared to those not exposed. The prenatally exposed child may demonstrate decrease in long-term trajectory of growth in length and head circumference as well as impaired intellectual and academic achievement. Prenatal exposure to alcohol has the most causal direct adverse impact on growth, cognition, behavior, language, and achievement throughout life.

While prenatal exposure to drugs may increase the risk of problematic behaviors, protective factors at individual, family, and societal levels may attenuate some of the detrimental effects. The quality of the relationships and home environment of the child demonstrates a consistent protective effect on outcome, ^{, ,} underscoring the importance of utilizing the discovery of maternal/parental substance misuse as an opportunity to engage with the parents in assessing/referring for treatment and supportive services.

Postnatal Infants and Young Children

Due to relatively small volume of distribution, higher resting respiratory rates, and developmental traits, infants and young children are at greater risk for exposure and toxicity compared with older children and adults. Toddlers spend more time indoors crawling and contacting surfaces where there may be drug residue and hand-to-mouth behaviors are common, increasing the risks for accidental ingestions.

Children may be exposed passively by inhalation, accidental ingestion, or may be given drugs intentionally. Differentiating accidental from intentional/abusive drug consumption is challenging. Parents may inappropriately administer over-the-counter medications, such as diphenhydramine, prescription substances not intended for the child, illicit drugs, such as tetrahydrocannabinol (THC), or alcohol to quiet or calm an irritable child. Alternatively, a child may accidently ingest various formulations of drugs and have similar symptoms to that of a child who was given the drug intentionally. Substance use while breastfeeding will also result in substance exposure to the infant.

Young children living with caregivers who have problematic substance use are at risk for injuries due to insufficient supervision. Examples include injuries due to falls, near-drowning, suffocation due to overlay, and injuries sustained during motor vehicle crashes when present in a car being driving by an intoxicated caregiver. Injuries can also take the form of intentional/abusive injury ^, when a caregiver administers excessive physical punishment, especially in response to routine childhood issues such as toileting or crying, or if the caregiver has impaired impulse/anger control related to substance misuse. Caregivers incapacitated by substance use may experience difficulties providing needed care to their children, placing them at risk for physical and medical neglect. ^, This includes providing basic needs such as hygiene, nutrition, shelter, and nurturing, as well seeking care in a timely manner when a child shows signs of illness or injury. Children residing in homes with caregivers using substances are more likely to be rated as having signs of anxiety and depression. Older children in the family will often take on the role of parent to attempt to cover the unmet needs of their siblings in these settings.

Prenatal Substance Exposure

Exposure to substances during the prenatal period may be identified by history obtained during pregnancy or after delivery, or after birth if the infant manifests symptoms of withdrawal. Neonatal opioid withdrawal syndrome (NOWS) has a structured assessment, scoring, and treatment approach. However, other substances such as methamphetamine and benzodiazepines can also manifest with physiologic withdrawal symptoms. Evidence-based scoring and treatment pathways for nonopioid withdrawal are lacking.

When prenatal care history is lacking or when infants have symptoms suggestive of withdrawal, drug testing for the infant could be considered if the results will assist in management of the patient’s health and safety. Depending on state and institutional laws/policies, separate informed consent may be needed for both maternal and newborn drug testing. If drug testing of the newborn is being performed as part of the medical care plan, consent may be covered under the institution’s general consent to treat. The indication for testing should be documented in the patient’s medical record and results and plan of care should be discussed with the parent(s).

Given that evidence suggests that infants born to caregivers with problematic substance use are at greater risk for additional CPS intervention in the first year of life, ^, discharge planning from the nursery should emphasize a warm hand-off with a primary care medical home and should consider referral for in-home supportive care via a nurse visitation program or advocacy partnership program. ^, The management of NOWS is transitioning to a more comprehensive care approach with parent involvement as opposed to focusing solely on the management of physiologic signs of withdrawal. While drug use to include marijuana is discouraged during breastfeeding, ^, breastfeeding while being monitored and supported as part of a substance use disorder treatment plan can be safely achieved.

Since parental substance use can interfere with the healthy mother-infant attachment and bonding, direct involvement by parents with activities such as providing feeds and basic care should be encouraged when appropriate and safe for the newborn’s clinical condition. For newborns being treated for NOWS, transition from care in the neonatal intensive care unit to a room-in setting with the parent(s) has been found to be a safe and effective method to decrease length of stay and maximize opportunities for early parent-child bonding. Safe sleep practices should be modeled and reinforced during the nursery stay. Additional injury prevention topics such as car seat safety and reviewing appropriate steps for managing infant crying should be discussed as part of discharge planning.

Postnatal Substance Exposure

Emergent clinical presentations outside of the newborn period include infants/children with acute toxicity or injury due to exposure to drug manufacturing materials and children with a toxidrome due to symptomatic systemic exposure. These children may present with sudden onset of respiratory depression, seizures, or lethargy with or without a history of ingestion. They may have dermal or mucosal injury from exposure to caustic substances. Rapid assessment and stabilization using standard principles of advanced life support protocols should be followed. Administration of naloxone to the unresponsive patient may be appropriate; in addition, the child’s response to naloxone may assist in medical assessment and management. Drug testing should be considered for any child with sudden onset of altered mental status. Pediatric clinicians should be aware of the drugs included on in-house, rapid immunoassay screening tests and consider including more comprehensive urine testing panels that include prescription and over the counter drugs when clinically indicated.

Children found in environments where there are caustic substances, explosions, or fires may require hazardous materials intervention which includes on-scene decontamination, and emergency medical assessment of issues such as problems with breathing and injuries such as burns. Care should be taken by first-responders to wear appropriate personal protective equipment to minimize primary and second-hand exposure.

Most children found in environments with evidence of drug manufacture or packaging will present nonemergently and do not need decontamination. The initial assessment should include a history from the child (if verbal) with screens for abuse, neglect, and other adverse childhood events including intimate partner violence, developmental assessment, inspection of all body surfaces including intraoral and anogenital, documentation of all findings, plots of weights/heights/head circumference, and identification of any unmet medical needs. Follow-up appointments should be considered for age-appropriate dental health assessment as well as referral for assessment for the potential need for trauma-focused mental health services. Laboratory and radiographic evaluation should be considered if there are findings suggestive of physical abuse, ^, history or symptoms of sexual abuse. ^, or indications of malnutrition/failure to thrive. Consulting a child abuse pediatrician should be considered if the pediatric clinician is not familiar with standard protocols for the assessment and diagnosis of child maltreatment.

Universal periodic screening for caregiver substance use as well as adverse childhood experiences is recommended for pediatric clinicians. ^, While these topics are typically well-received by parents when interacting with trusted medical professionals, screening and subsequent following up on items that need attention are time-consuming endeavors. Partnerships with nurse educators, community health workers, social work, or other support staff can be helpful. Databanks mapped to the community level for accessing resources for social determinants of health and substance abuse treatment are available online. ^, Take-home naloxone is a consideration to prevent adverse effects of accidental opioid ingestions in homes where others are undergoing medication-assisted opioid treatment programs. Basic home safety advice of keeping all medications in a locked space should be reinforced.

Drug Testing Modalities and Interpretation

There should be a clear medical or safety indication established prior to drug testing. Confirmatory testing of a positive screening test should be ordered if the result of the test could be used as part of contested proceedings. The clinician should be familiar with the point-of-care testing panels used at their hospital/clinic and should consult the laboratory to clarify whether confirmatory testing will be done automatically or will need to be specifically ordered. Consultation with a clinical toxicologist should be considered for challenging and complex cases.

Timing of Drug Exposure

Urine, blood, and saliva detect more recent exposures; urine is the preferred testing medium in children with acute symptoms as both the primary drug and metabolites are detectable on a more consistent basis compared to blood. Exposures involving alcohol, acetaminophen, tri-cyclic antidepressants and therapeutic drug monitoring are best analyzed via blood sample. If the initial urine screen is negative and drug exposure is still suspected, the clinician should consider sending an extended or “comprehensive” drug panel to identify substances not detected in most initial screens such as synthetic opioids, over-the-counter medications, and common prescription drugs. Results for extended drug screens are generally not available same-day, so while a positive result may be helpful in the ongoing evaluation of the safety of the child’s environment, it may not be helpful in acute medical management. The frequency and intensity of drug use/exposure can impact the time of detection of drugs in the urine and blood. Tetrahydrocannabinol is a notable exception as it is lipophilic as opposed to water-soluble and therefore can be detected in urine longer than a few days.

Meconium, umbilical cord tissue, hair, and nails are matrices that can indicate both recent and remote exposure. Meconium and umbilical cord are unique to neonates. Hair is the most common matrix for remote exposure testing in infants and older children. Nail collection is uncommon in children due to the sample size/weight needed for testing typically being more than could be collected in a child. For neonates, meconium and umbilical cord tissue can reflect maternal substance use back to approximately the middle of the second trimester. If hair testing is performed in a neonate, results could reflect exposure back to the start of the third trimester when hair growth begins in-utero. Typically, infants will shed newborn hair between 4 and 8 months of age. Hair growth averages 0.5 inches/month after 1 year of age, but several factors can lead to periods of asynchronous growth.

Levels of Detection

Screening tests have a defined cutoff value and do not report the presence of drug down to “0” level. These cutoff levels have historically been set by the Department of Health and Human Services for the purpose of detecting active drug use during workplace drug testing. If the same levels of detection are used when testing for passive exposure, the result could represent a false negative. Confirmatory tests that identify the specific drug in the specimen through mass spectroscopy methodology typically display the cutoff level for the test as well as the quantitative level for the drug if it was detected in the sample. A quantified level may be useful in cases of therapeutic drug monitoring (known timing of expected peak and trough drug levels based on dosing) or to test for risk for toxicity following ingestions with substances such as acetaminophen. Quantified levels are typically not helpful when reported on tests reflecting a longer duration of potential exposure (meconium, umbilical cord, hair, and nails) as intensity, duration, and frequency of exposure is typically unknown. Short-interval (3–6 months) follow-up testing using hair and nails should not be used to prove that the child is no longer being exposed as these matrices do not have steady-state growth or predictable clearance rates.

Adulterants (inhibitor substances) are sometimes added to urine samples in an attempt to mask a drug. This could include liquid drain cleaner, chlorine bleach, liquid soap, ammonia, hydrogen peroxide, lemon juice, and eye drop solution. Most of these adulterants target cannabinoids. Of note, the adult may add adulterant to their child’s urine. Some drug screens can specifically detect adulterants. In addition, some infant wipes will yield a false-positive initial screen for cannabinoids (which will be negative on confirmatory testing).

Laboratory Methodology

Knowledge of whether a reference laboratory testing methodology includes prewashing for hair drug test samples is vital for interpretation of the test results. Prewashing of the sample removes drug residue adherent to the outer surface of the hair prior to testing. Positive results on samples that were prewashed likely indicate systemic exposure (ingestion, inhalation, injection, et al.) as the test will identify drug that was in the bloodstream, taken up by the capillary bed of the hair follicle, and then present in the shaft of the hair as it grows out with time. If the sample was not prewashed, the results could include both environmental (drug residue present on the external shaft of the hair) and systemic exposure. ^, Inhibitor substances applied to hair, such as dyes, relaxing agents, and bleaching, can affect results, as does the frequency of washing. The quality and color of hair can also modify results; light colored hair tends to be thinner and more porous, and hair with more melanin may absorb a higher concentration of drug. Hair grows at approximately 0.5 inches per month in children and adults with individual variability. Most reference laboratories test the first 1.5 inches of hair that was closest to the scalp estimating 3 months of exposure. The 3-month window of potential exposure represents an estimate due to individual variability in hair growth. It should not be applied to infants since the initial shedding of neonatal hair may not occur until 6 to 8 months of age.

False-Positive/Negative Results and Other Potential Interpretation Pitfalls

With an immunoassay screening test, the highest positive predictive values are for cannabinoids and cocaine; these substances are most likely to be confirmed on follow- up testing. The lowest positive predictive values are for opiates and amphetamines. Reference tables are available listing common causes for false-positive and negative immunoassay tests. However, the only conclusive method to determine if a positive immunoassay test represents a true or false-positive is to submit the sample for confirmatory testing using mass spectroscopy methodology.

A negative drug screen in the setting of a child with symptoms that are concerning for acute ingestion may indicate that drug was present but at a level below the cutoff value set for the test, adulterants were added, or the ingested drug was not included in the testing panel. The opiate/opioid class of drugs poses a particular risk for misinterpretation of screening test results. Most opioid screening panels are designed to detect drugs derived from natural opiates (morphine and codeine) and some semisynthetic opioids (heroin and hydrocodone). A history of prescribed use of a synthetic opioid as part of a treatment program should not be accepted as reason for a positive screening test for opioids unless there is a specific result line for the synthetic opioid in question. See Table 1 for differentiation of opiates, semisynthetic opioids, and synthetic opioids.

Metabolites

Quantitative drug test reports typically list the drug name and the relevant metabolites that are included in the testing methodology. For hair drug tests that do not employ pretest sample washing methodology, caution should be taken to applying the presence of metabolites in differentiating between environmental and systemic exposure For example, one of the by-products of cocaine metabolism is benzoylecgonine (BE). Finding BE in a hair test sample might be used to suggest that some component of the exposure resulted in systemic uptake of cocaine via inhalation, injection or absorption following ingestion. However, BE is produced by hydrolysis of cocaine which can occur enzymatically (inside of the body) or nonenzymatically when exposed to air and moisture. Also, testing of illicit drugs seized by law enforcement commonly reveal impurities compared to what was expected. Therefore, even though amphetamine could be present in a hair test sample due to hepatic metabolism of methamphetamine, it could have also been present as an environmental contaminant on the surface of the hair shaft.