Infants with Antenatal Exposure to Drugs



Infants with Antenatal Exposure to Drugs


Mark L. Hudak


Use or abuse of certain illicit and prescription drugs in the United States adversely affects public health in diverse ways and substantially increases overall health care expenditures. Selected antenatal drug exposures can produce significant short-term consequences or serious permanent long-term injuries in the child (Table 53-1). The US Department of Health and Human Services, through its annual National Survey on Drug Use and Health (NSDUH), extrapolates the annual use of illegal drugs (marijuana, cocaine, heroin, hallucinogens, methamphetamine, and inhalants) and the nonmedical use of prescription drugs (pain relievers, tranquillizers, sedatives, stimulants). The 2011 NSDUH found that 22.5 million Americans age 12 or older, or 8.7% of this population, admitted to one of more of these types of drug use within the past month of being surveyed. This percentage has remained relatively stable (7.9%-8.9%) from 2002 to 2011. Recent heavy or binge drinking and smoking, which also negatively impact public health but are not necessarily illegal activities, occur at significantly greater rates of 22.6% and 26.5%, respectively.95



Marijuana has consistently been the most commonly used illegal drug in the U.S. population age 12 or greater. In 2011, the NSDUH estimated 18.2 million (7.0%) past-month users of marijuana, followed by cocaine (1.4 million), hallucinogens (972,000), inhalants (600,000), methamphetamine (439,000), and heroin (281,000). Another 6.1 million (2.4%) used prescription drugs without a medical indication. The NSDUH found that 5.0% of pregnant women ages 15 to 44 admitted to such drug use in the past month, whereas only 2.6% reported binge or heavy drinking and 17.6% acknowledged recent smoking. Although this 5.0% rate is less than half of the 10.8% rate found among nonpregnant women in the same age range, it is still high and of special concern because of possible drug effects on the fetus. Furthermore, the 5.0% estimate most likely underestimates the true rate, because the percentage of pregnant women who report recent use of illegal drugs or the nonmedical use of prescription drugs on screening interviews can be substantially lower than the percentage determined by testing of biologic samples.


Antenatal drug exposure can have a host of effects on the developing fetus. Drugs act as teratogens (from the Greek, meaning “monster producing”) when time-dependent fetal exposures cause major morphologic abnormalities of the developing organ systems during the embryonic period (roughly the first 8 weeks of development) or when continued exposure during later fetal life results in minor morphologic abnormalities or physiologic defects. Thalidomide, a medication that became available in Europe in 1959 as an aid for sleeping and “morning sickness” in pregnant women, was distributed for use by physicians in the United States without formal federal approval and serves as the archetypal example of a teratogen. Use of this drug was linked to an epidemic of phocomelia in newborn infants, half of whom died in the first year of life. This tragedy shattered the illusion that the uterine environment sequestered the fetus from adverse effects due to drugs. As a result, Congress passed legislation that gave the FDA additional authority to regulate drug use in pregnant women.


Drugs can also have other direct and indirect effects on the fetus. Drugs can directly affect fetal growth and maturation; can alter levels of brain neurotransmitters or expression of neural receptors; and can disrupt normal brain morphogenesis throughout the continuum of neurogenesis, proliferation, migration, organization, and synaptogenesis. Examples of indirect effects include uteroplacental insufficiency caused by vasoconstriction of uterine or placental vessels and drug-induced alterations of maternal behavior that secondarily compromise maternal, and hence fetal, well-being. Poor nutrition, sexually transmitted diseases, exposure to violence, and inadequate access to health care can all result in maternal and fetal harm.


Near the time of birth, maternal drugs can produce signs of acute toxicity in the newborn infant, cause persistent abnormal neurobehavior, or result in signs of withdrawal. For some fetal drug exposures, long-term outcome studies suggest a quantifiable impact on internalizing and externalizing behaviors as well as on cognition, especially with respect to higher-level executive functioning.


The distinction between an acute or chronic drug effect and the signs of drug withdrawal is important but on occasion difficult to determine for certain. Signs of acute neonatal drug toxicity abate as the drug is eliminated from the infant. Signs of chronic drug effect on neurobehavior may remain static for a prolonged time independent of fluctuations in total body storage and blood or cerebral spinal fluid concentrations of drug. Alcohol can cause both acute toxic effects (depressed sensorium) and chronic effects (fetal alcohol syndrome) depending on whether the exposure occurred just prior to birth or for a sustained period of time during early gestation. Signs of neonatal withdrawal worsen as levels of the active drug moiety decrease owing to metabolism and excretion. Many intrauterine drug exposures have been associated with signs of neonatal withdrawal.51 The overwhelming majority of cases of neonatal withdrawal result from intrauterine opioid exposure. Antenatal fetal exposure to benzodiazepines and barbiturates is a less common cause of neonatal withdrawal.



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 optimal. The pediatrician also has an important role in screening adolescent females for high-risk behaviors and providing factual information about the consequences of unhealthy lifestyle choices in a nonjudgmental manner.


Women of childbearing age and their sexual partners should be counseled to discontinue use of illegal drugs before conception. Women addicted to illicit or prescription opioids should be encouraged to enroll in a supervised 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. 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 maternal benefit-to-fetal risk ratio. Often, however, limited data must guide informed 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.


The obstetric provider should conduct periodic SBIRT (screening; brief intervention; referral to treatment) procedures for each pregnant woman under care.6 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 Adapted to Include Drugs (CAGE-AID),19 4P,23 and CRAFFT,63 have been validated. The four CAGE-AID questions are listed in Box 53-1. If two or more yes responses are obtained, this screen has a 70% sensitivity to identify use of illegal drugs or abuse 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.



Box 53-1   CAGE Questions Adapted to Include Drugs (CAGE-AID)




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, although the clinician should understand the limitations of such testing. 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 what 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 secondhand exposure.


A flexible and nonjudgmental approach to the care of women who use illicit drugs or abuse prescription drugs should be adopted, and all community resources for education (e.g., community support groups) and treatment (e.g., rehabilitation centers) should be incorporated. The goals of the provider are to establish a trusting relationship with the women so that they continue regular prenatal care, to reduce harm to the women and their fetuses without necessarily requiring cessation of the drug (e.g., in the case of a pregnant mother on opioid maintenance therapy), to recognize and treat potential co-morbidities, and to counsel about the possible maternal and fetal effects of drug use. In particular, because catastrophic obstetric complications can accompany the use of certain drugs, these pregnant women should be educated about the signs of antepartum hemorrhage, premature rupture of membranes, premature labor onset, 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 co-morbidity. Emergency room visits and hospital admissions may afford the only windows of opportunity to evaluate such a patient and then 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 drug testing assays do not identify all infants with significant antenatal exposure to drugs. Newborn caregivers should be knowledgeable about patterns of illicit drug use or prescription drug abuse in their community. Guidelines for neonatal biologic testing at birth for exposure to illicit drugs are commonly based on associated conditions, such as self-reporting of alcohol or drug use, inadequate or no prenatal care, presence of 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 many exposed infants. For these reasons, some have advocated testing all newborns for antenatal drug exposures. In 2013, most hospitals in the Cincinnati, Ohio, area implemented a policy of universal newborn drug screening.84



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.9 However, marijuana remains in the body tissues of chronic users for as long as 30 days and 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. The American Academy of Pediatrics considers maternal marijuana use to be a relative contraindication to breastfeeding.


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.13



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 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.92 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. It is thought that abrupt discontinuation of an exogenous opioid and the resultant decline in the concentration of opioid-bound receptors leads to a supranormal release of noradrenaline that in turn produces the autonomic and behavioral signs and symptoms characteristic of withdrawal.


Opioids are small molecular weight and variably lipophilic compounds 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 and exhibits a mean half-life of approximately one day (versus only 15 to 30 minutes for heroin) to produce a sustained effect.


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 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. Infants exposed prenatally to opioids have less risk of respiratory distress syndrome and hyperbilirubinemia. 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.


Maternal opioid detoxification is generally not recommended because of concerns about a possible increased risk of fetal distress and fetal loss during withdrawal,82 but in selected cases in which a mother is highly motivated and does not have access to a supervised opioid maintenance program, inpatient detoxification may be the only alternative to continued abuse of illicit drugs. Maintenance programs with 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 prevent fetal stress. Other benefits from this once-controversial treatment are optimization of prenatal care and general maternal physical and mental health as well as anticipation of potential withdrawal signs 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 with heroin exposure. These issues have encouraged the development of other opioids as alternative treatments to methadone.


Buprenorphine is a semisynthetic opioid with mixed µ-opioid receptor agonist and 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.


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 are categorized by the FDA as class C pregnancy drugs. 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.56 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.




Growth


The preponderance of evidence suggests that opioids have a mild independent effect on fetal growth, but many confounders exist. Birth weight percentiles of babies born to mothers who adhere to methadone maintenance therapy are greater than those of babies born to heroin addicts.57 Some studies suggest that buprenorphine-exposed fetuses demonstrate better growth than fetuses exposed to methadone. Analysis of data in the NIH-sponsored Maternal Lifestyles Study revealed that opioid-exposed infants born at or after 33 weeks’ gestation had lower birth weight after controlling for other potential confounders.8 However, opioids do not affect long-term growth.90



Neonatal Neurobehavior/Withdrawal


Prevalence


Neonatal abstinence syndrome (NAS) is the term that encompasses the constellation of clinical signs associated with opioid withdrawal. Signs of withdrawal develop in 55% to 94% of neonates exposed to opioids in utero. The incidence of NAS has increased dramatically in the past decade. A review of national hospital discharge records from 2000 to 2009 found that the incidence of NAS among newborns discharged after birth increased from 1.20 to 3.39 per 1000 hospital births per year and correlated with an increase in maternal opioid use from 1.19 to 5.63 hospital births per year.79 These data are consistent with the experience of a single obstetric clinic in which chronic use of narcotic prescriptions (use for ≥1 intrapartum month) among pregnant women rose fivefold from 1998 to 2008.60



Epidemiology


The distribution of specific opioids that cause NAS likely varies substantially from region to region. In areas such as Appalachia and rural New England that have witnessed disproportionate increases in the rate of NAS, anecdotal data have pointed to the diversion and nonmedical use of prescription opioids (e.g., oxycodone and hydrocodone) as a key driver of the epidemic. Beginning in January 2013, the state of Tennessee implemented mandatory reporting of infants with NAS. Preliminary data from January to August 2013 detailed in Table 53-1 support this supposition and demonstrate that pregnant women commonly access multiple sources of opioids.97


How do pregnant women access these potent drugs? The 2011 NSDUH reported that 66% of the population that is dependent or addicted to pain relievers acquired drugs at no cost or purchased drugs from relatives or friends (80% of whom had residual opioid drug that had been prescribed by a single physician), 18% used drugs remaining from a prior physician prescription, and the remaining 16% obtained them through theft, dealer purchase, multiple physician prescriptions, or purchase through the internet.95



Risk Factors


The clinical presentation of NAS varies with the opioid, maternal drug history (including timing of the most recent use of drug prior to delivery), maternal metabolism, net transfer of drug across the placenta, placental metabolism, infant metabolism and excretion, genetics, environmental care, and other factors. Maternal use of other drugs such as cocaine, barbiturates, hypnotics-sedatives, and cigarettes27 may influence the severity and duration of NAS.


Studies have found either a correlation30,32,33,46,73,78,85,94 or no correlation14,18,29,64,72,89 between maternal methadone dose and the incidence and severity of NAS. However, there were substantial variations in the mean and range of daily methadone dose among the populations. Studies that found no correlation tended to include infants born to mothers who had been prescribed higher doses of methadone (50-200 mg/day), whereas those who did note a relationship between maternal dose and NAS sequelae reported lower maternal doses (e.g., less than 50 mg/day) or included women undergoing partial detoxification.30 So there may be a threshold dose above which nearly all infants will exhibit signs of withdrawal. There is also significant interindividual variability in maternal methadone metabolism35 that can result in different cumulative fetal exposure in mothers on equivalent methadone regimens.


A recent study in babies with NAS has correlated the presence of certain single-nucleotide polymorphisms of the opioid receptor (OPRM1) and the catechol-O-methyltransferase (COMT) genes with shorter lengths of hospital stay and less severe signs of withdrawal as measured by the need for pharmacologic treatment.101 These findings are consistent with studies that have linked these same single-nucleotide polymorphisms to the risk of opioid addiction in adults.



Clinical Presentation


Because opioid receptors are concentrated in the CNS and the gastrointestinal tract, the predominant signs and symptoms of pure opioid withdrawal reflect CNS irritability, excessive autonomic activity, and gastrointestinal tract dysfunction (Table 53-2). Excess environmental stimuli and hunger will exacerbate the perceived severity of NAS. Methadone and buprenorphine may produce slightly different patterns of signs of withdrawal. Abnormal motor findings (tremors, hyperactive Moro reflex) are more common in methadone-exposed infants, whereas buprenorphine-exposed infants are more likely to demonstrate autonomic and gastrointestinal signs (nasal stuffiness, sneezing, loose stools).42



Because of differences in drug half-lives, the onset of signs attributable to neonatal withdrawal from heroin may be present at birth or begin within 24 hours of birth, whereas withdrawal of an infant of a mother on a daily methadone maintenance program typically commences around 24 to 72 hours of age.105 For both opioids, evidence of withdrawal is occasionally delayed beyond 7 days of age.58 A consensus has developed that buprenorphine-exposed infants experience a slightly later onset and less severe signs of NAS compared to infants withdrawing from heroin or methadone,68 but outliers do exist, and some buprenorphine-exposed infants undergo severe withdrawal.59,65,88 If more than 1 week has elapsed between the last maternal opioid use and delivery of the infant, the incidence of neonatal withdrawal is relatively low.93 In the acute phase, seizures of unknown etiology and long-term significance have been reported in 2% to 11% of infants withdrawing from opioids;47,58,105 however, abnormal electroencephalograms (EEGs) without overt seizure activity have been reported in greater than 30% of neonates.80,99 Subacute signs of opioid withdrawal may last up to 6 months.31


Preterm infants have been described as being at lower risk of drug withdrawal with less severe and/or prolonged courses. Infants born at less than 35 weeks’ gestation whose mothers received methadone maintenance had significantly lower total and CNS abstinence scores than did term infants of mothers receiving similar methadone dosages.33 Lower gestational age has correlated with a lower risk of neonatal withdrawal.71 The apparent decreased severity of signs in preterm infants may relate to developmental immaturity of the CNS that minimizes expression of motor signs, differences in total drug exposure, or lower fat depots of drug. Alternatively, the clinical evaluation of the severity of abstinence may be more difficult in preterm infants, because scoring tools to describe withdrawal were largely developed in term or late preterm infants.39,70

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