Infants of Substance-Using Mothers

Prenatal and Perinatal Considerations

Prevention of drug effects on the fetus and newborn must begin with preconceptional education of women of childbearing age, their families, and their physicians. Because teenage females who become pregnant are more likely to have engaged in risky behaviors such as illicit drug use, alcohol, and smoking than their nonpregnant peers, early education about drug effects on a fetus and newborn that begins at home and is reinforced in elementary and middle school curricula is important. The pediatrician also has an important role in screening adolescent females for high-risk behaviors and providing factual information in a nonjudgmental manner about the consequences of unhealthy lifestyle choices.

Women of childbearing age and their sexual partners should be counseled to discontinue use of illegal nonopioid drugs before conception. Women with an illicit or prescription opioid use disorder should be encouraged to enroll in a supervised opioid maintenance treatment program. Women who are pregnant should be counseled to seek prenatal care as soon as possible and to abstain completely from use of any illegal drugs and from use of other prescription drugs that are not medically indicated. If a pregnant woman requires new or continued treatment for a medical or mental health condition, her physician should choose the drug class or the specific medication within the drug class that might be expected to confer the highest fetomaternal benefit-to-risk ratio. Often, however, limited data are available to guide decisions. Nonetheless, the pregnant woman should be given the most current evidence-based information about possible short- and long-term consequences to the fetus of any drugs that she uses or that might be recommended for use. Consistent with guidelines from the Centers of Disease Control and Prevention, new opioid prescriptions for pain should be considered only when other medications such as ibuprofen are inadequate. If opioids are required, only immediate-release, short-acting opioids should be prescribed, at the lowest dose and with shortest duration necessary. Concomitant use of opioids and benzodiazepines is contraindicated. These recommendations are particularly critical in women of childbearing age where both a woman and her fetus could be affected by injudicious prescription of opioids. The obstetric provider should conduct periodic SBIRT ( s creening by interview; b rief i ntervention; r eferral to t reatment) procedures for each pregnant woman under care. A short screening interview can help to determine whether a pregnant woman is likely to be engaged in surreptitious drug use. Several short questionnaires, including CAGE questions a dapted to i nclude d rugs (CAGE-AID), 4P, and CRAFFT, have been validated. The four CAGE-AID questions are listed in Box 46.1 . If two or more yes responses are obtained, this screen has a 70% sensitivity to identify use of illegal drugs or misuse of prescription drugs. A brief intervention consisting of short, focused education and referral to appropriate treatment can be performed for those women who admit to a problem.

If a pregnant woman admits to or is suspected to be engaged in such drug use, she should be asked to provide informed consent for biologic testing. Urine testing is preferred, and positive tests should be confirmed with mass spectrometry/gas chromatography. The clinician should be aware of limitations of testing. Tests vary widely with respect to which specific drugs are assayed. Threshold detection levels are set to avoid false positives, but levels that fall below the threshold owing to low dose exposure or a long interval between the most recent exposure and testing will provide a false negative result. Positive results may result from legitimate use of prescription drugs or in some cases from intense secondhand exposure.

A flexible and nonjudgmental approach to the care of women who abuse illicit drugs or misuse prescription drugs should be adopted, and appropriate community resources for education (e.g., community support groups) and treatment (e.g., rehabilitation centers) should be incorporated into the care plan. The goals of the provider are to establish a trusting relationship with each woman so that she continues regular prenatal care to reduce harm to the woman and her fetus without necessarily counseling cessation of the drug (e.g., in the case of a pregnant mother in an opioid maintenance program), to recognize and treat potential comorbidities, and to counsel about the possible maternal and fetal effects of the use of other drugs. In particular, because catastrophic obstetric complications can accompany the use of certain drugs, the pregnant woman should be educated about the signs of antepartum hemorrhage, premature rupture of membranes, premature onset of labor, and meconium-stained amniotic fluid so that prompt diagnosis and treatment can ensue.

Owing to guilt or to fear of legal action (incarceration, initiation of child welfare proceedings), a pregnant woman with illicit drug use may not have sought prenatal care before presenting with an obstetric complication, the onset of labor, or a medical comorbidity. The legal consequences to a woman abusing illicit drugs or misusing prescription opioids varies among states. Some states have passed punitive legislation whereas others have worked to encourage prenatal access to comprehensive care and treatment without legal repercussions. Emergency room visits and hospital admissions may afford the only windows of opportunity to evaluate such a patient and then to refer her for appropriate multidisciplinary treatment. During obstetric-related hospitalizations, providers can counsel a woman about the prevention of future drug-exposed pregnancies, sexually transmitted diseases, and HIV infection.

Neonatal Considerations

Providers who care for infants during the initial birth hospitalization should understand that maternal self-reporting, restricted implementation of screening procedures, and maternal drug tests do not identify all infants with significant antenatal exposure to drugs. Newborn caregivers should be knowledgeable about patterns of illicit drug abuse or the misuse of prescription drugs in their community. Guidelines for neonatal biologic testing at birth for exposure to illicit drugs are commonly based on associated conditions, such as maternal self-reporting of alcohol or drug use, inadequate or no prenatal care, presence of certain sexually transmitted maternal diseases, premature onset of labor, abruptio placentae, intrauterine growth restriction, congenital malformations, and overt signs of neonatal withdrawal. However, restricting testing of mothers and infants based on these or similar criteria will fail to detect all exposed infants. For these reasons, some have advocated for universal drug testing of all pregnant women or newborns. In 2013, most hospitals in the Cincinnati, Ohio, area implemented a policy of universal maternal testing but allowed the mother to opt out. A study at one Cincinnati hospital showed that this approach did identify substance-exposed infants that conventional screening procedures would have missed.

Marijuana (Cannabinoids)

Whereas the principal active cannabinoid in marijuana (δ-9-tetrahydrocannabinol) readily crosses the placenta, a major metabolite (11-nor-9-carboxytetrahydrocannabinol) remains sequestered in the maternal circulation. However, marijuana remains in the body tissues of chronic users for as long as 30 days and so can result in prolonged fetal exposure.

Marijuana does not independently affect somatic fetal growth and results in no known congenital anomalies. If marijuana affects newborn neurobehavior, the effects are subtle. Newborns have not demonstrated signs of withdrawal secondary to marijuana exposure. No study has discerned an independent effect of prenatal marijuana exposure on childhood growth through adolescence. Multiple studies have suggested that prenatal marijuana exposure exerts long-term effects on behavior (inattention and impulsivity), problem-solving skills, and underachievement in reading and spelling, but not on IQ or language. However, some preparations of marijuana (and synthetic cannabinoids) available today are much more potent than in the past, so that the results of existing studies that evaluated long-term outcomes of fetal exposure to lower potency marijuana may not accurately reflect current risk.

The American Academy of Pediatrics considers maternal marijuana use to be a relative contraindication to breastfeeding. The American College of Obstetrics and Gynecology also discourages marijuana use by lactating mothers.

Opioids

Opioids are a class of chemical compounds that activate µ-opioid (but also κ- and δ-opioid) receptors primarily in the central nervous system (CNS) to produce supraspinal analgesia. The term opiate refers to a subclass of alkaloid opioids. Naturally occurring opioids are present in the opium poppy (e.g., morphine) and occur endogenously (e.g., enkephalins, endorphins, endomorphins). Opioids can be synthetic (e.g., methadone and fentanyl are synthesized from nonopioid precursors) or semisynthetic (e.g., heroin and buprenorphine, which represent modifications of natural opioid compounds) in origin. Other acute effects of opioids include sedation, euphoria, miosis, respiratory depression, and decreased gastrointestinal motility. Prolonged use results in physical and psychologic dependence. As a class of drugs, opioids demonstrate a narrow therapeutic index within a given patient. However, the observed range in dose that achieves a similar therapeutic effect in a large population is fairly wide because of genetic differences in pharmacokinetics and pharmacodynamics. Opioids acutely inhibit the release of noradrenaline at synaptic terminals. The synthetic opioid methadone exerts secondary effects by acting as an n -methyl-d-aspartate receptor antagonist to block the actions of glutamate, the primary excitatory neurotransmitter in the CNS. In patients who are chronically exposed to some opioids, tolerance can develop, because over time the rate of noradrenaline release increases toward normal. The molecular mechanisms that result in substance abuse disorder and produce signs and symptoms of withdrawal are complex and incompletely understood.

Opioids are variably lipophilic compounds of low molecular weight that cross both blood–brain and placental barriers. Because heroin is more lipophilic than morphine, it crosses the blood–brain barrier more rapidly and causes a greater euphoric “high.” Methadone is well-absorbed orally; it has a mean half-life of approximately 1 day so that it produces a sustained effect compared to heroin that has a much shorter half-life of 15-30 minutes.

Opioid use in pregnant women carries risks for the mother, fetus, and newborn. Intravenous injection of heroin exposes the mother and her fetus to potential drug overdose, to a greater risk of acute bacterial endocarditis, and, owing to contaminated needles, to serious viral infections (e.g., hepatitis B and C, HIV/AIDS). Other direct and indirect prenatal complications of heroin use include extrauterine pregnancies owing to salpingo-oophoritis, premature labor, premature rupture of membranes, antepartum hemorrhage, fetal demise, and low birth weight. Mothers who use heroin experience rapid fluctuations in opioid concentration because of its short half-life so that the fetus may also suffer intermittent withdrawal effects. Therapeutic opioid maintenance therapy employs an opioid with a long half-life to minimize fluctuations between peak and trough fetal drug levels. A more stable maternal opioid level reduces overall fetal stress.

Maternal opioid detoxification is generally not recommended because of concerns about a possible increased risk of fetal distress and fetal loss during withdrawal as well as a high rate of maternal recidivism. In situations where a mother does not have access to a supervised opioid maintenance program, the American College of Obstetricians and Gynecologists has stated that medically supervised detoxification may be considered. Opioid maintenance therapy with daily methadone (a full µ-opioid agonist and a Food and Drug Administration [FDA] Schedule II controlled drug) for pregnant women can sustain opioid concentrations in the mother and fetus in ranges that minimize opioid craving, suppress abstinence symptomatology, block heroin-induced euphoria, and minimize fetal stress. Other benefits from this once-controversial treatment are optimization of prenatal care and general maternal physical and mental health as well as preparation for potential signs of withdrawal in the newborn infant. Disadvantages of methadone include greater difficulty in achieving successful detoxification after delivery and a more severe and prolonged course of neonatal abstinence syndrome (NAS) compared, for instance, with heroin exposure. These issues have encouraged the development of other opioids as alternative treatments to methadone.

Buprenorphine is a semisynthetic opioid with partial µ-opioid agonist and kappa-opioid antagonist properties that was first introduced in France in 1996 as an alternative to methadone. This drug demonstrates high receptor affinity and low intrinsic activity compared with other opioids. In adults, buprenorphine evokes fewer autonomic signs and symptoms of opioid withdrawal following abrupt discontinuation. In contrast to methadone, which is typically dispensed on a daily basis by methadone clinics, obstetricians who receive special training can dispense buprenorphine for a week or more. In late 2017, the Food and Drug Administration approved an intramuscular preparation of buprenorphine (RBP-6000) that can be dosed once a month. Benefits of this preparation include convenient monthly dosing and the elimination of any possibility of drug diversion.

Subsequent to the Drug Addiction Treatment Act of 2000 that allowed office-based treatment of addiction using FDA Schedule III-V drugs, buprenorphine was approved by the FDA in 2002 as a Schedule III controlled drug for the treatment of opioid dependence. Neither methadone nor buprenorphine is approved for use in pregnant women, and both were categorized by the FDA as class C pregnancy drugs (i.e., animal reproduction studies have shown an adverse effect on the fetus, and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks). Nonetheless, buprenorphine, either alone (Subutex) or in combination with naloxone (Suboxone), has been used both as a first-line treatment for heroin addiction and as a replacement drug for methadone. Results from the MOTHER (Maternal Opioid Treatment: Human Experimental Research) study suggest that newborns experience some benefits when mothers are maintained on buprenorphine rather than on methadone. Buprenorphine-exposed infants demonstrated shorter hospital stays (10 vs. 17.5 days) and treatment durations for NAS (4.1 vs. 9.9 days) and required a lower cumulative dose of morphine (1.1 vs. 10.4 mg) compared with infants born to mothers on methadone maintenance. Nonetheless, it is not currently recommended that mothers already on a successful methadone maintenance regimen switch to buprenorphine until it can be shown that this transition does not result in a higher than expected rate of nonadherence to treatment.