The use and abuse of addictive drugs has occurred throughout many centuries. Only relatively recently have certain drugs under question become defined as "illicit." Many pregnant women use such medications without prior consideration to the adverse effects of these substances on their unborn children. The effects of chemicals, such as opiates, cocaine, nicotine, alcohol, and new recreational drugs, on fetal development have been seriously studied only in the last 40-50 years.
The difficulty in evaluating research in this area is enormous. Clear methods for differentiating drug use from drug abuse are not established. The question of whether the mere presence of the chemical in maternal serum results in fetal damage needs to be answered. Evaluating if the mother in question has told the whole truth about her drug use is difficult. Given the stigma of substance abuse during pregnancy, lack of disclosure by the mother to her health provider is common because such damaging information could ultimately lead to the separation of mother and child.
Many confounding factors may be recognized, such as the probability of polysubstance use and how this affects single-drug studies. Additionally, the fact that a mother has used an illicit drug (or even a legal substance such as alcohol or tobacco) intertwines with many other factors that can affect a child. Socioeconomic status, support systems, role of the father, lack of prenatal care, and the caregiving ability of the mother; all of these factors play tremendous roles in child development.
Mothers with a previous mental health admission, with a low skill level, with Aboriginal status, or who smoked during pregnancy were significantly more likely to have an infant with neonatal withdrawal syndrome. These infants were at greater risk of having substantiated child maltreatment allegation and for entering foster care.
These results show an important pathway into child maltreatment and the need for well-supported programs for women who use illicit drugs during pregnancy and long-term support after birth of the child.
In 2011, the American Academy of Pediatrics published a clinical report detailing the recommended guidelines for the management of neonatal drug withdrawal.[1]
Note that many states in the United States are decriminalizing marijuana use, for medical and nonmedical uses. An overall 9.8% of women self-report prepregnancy marijuana use, 4.2% during pregnancy, and 5.5% post pregnancy, primarily as a means of stress/anxiety relief or relief from vomiting or pain.[2]
Almost all drugs of abuse follow a similar mechanism of action in the adult brain; this mechanism alters the pathways for reward. Through complex neurochemical interactions, various chemicals act to increase dopaminergic pathways from the midbrain ventral tegmental area (VTA) to the nucleus accumbens (NAc) in the striatum. Additionally, the NAc provides a negative feedback loop to the VTA using the inhibitory monoamine gamma-aminobutyric acid (GABA). Blocking such a pathway also attenuates the reward mechanism in the adult brain.
Fetal alterations
Although the full spectrum of physical damage that drugs of abuse can cause cannot be documented, one thing is certain: the effect of maternal drug use on fetal brain development is the most critical and most studied effect. The two broad classes of fetal brain insult are as follows:
In the first 20 weeks of gestation, damage can occur during cytogenesis and cell migration.
In the second half of gestation, damage can occur during brain growth and differentiation.
Continuous abuse, especially during the first half of gestation, is likely to disrupt the complicated neural wiring and associative connections that allow the developing brain to learn and mature. Most drugs of abuse freely cross the placental barrier; however, damage to the fetus also can occur via indirect methods. In particular, the vasoconstrictive properties of cocaine have been discussed as a potential cause for the delivery of growth-retarded infants.
Through multiple mechanisms, all drugs of abuse can cause molecular and cellular changes that ultimately lead to changes in neural migration, cell structure, neurotransmitter dynamics, and overall brain formation. These alterations are likely associated with a whole range of behavioral and cognitive changes. Maternal polydrug use is likely to be far more damaging than use of any single drug.
Ethanol
Alcohol produces teratogenic effects associated with fetal alcohol syndrome (FAS) and its variations. The suggested pathway for teratogenicity involves a direct effect on the anterior neural tube and surrounding structures. This leads to decreased brain development as well as typical FAS facies. The continuum of clinical outcomes within this disorder is broad. From the most severe form (FAS) to milder forms, such as alcohol-related neurodevelopmental disorder (alcohol-related neurodevelopmental disorder [ARND]), issues of somatic growth, brain growth and development, and facial dysmorphisms can occur.
In animal models, evidence shows disruption in the hippocampus, cortical cytostructure, and neuronal migration. Changes in subsequent behavior in animal models reveal deficits in object permanence, increased distractibility, and delays in gross motor development.
Nicotine
Studies on in utero effects of nicotine have typically focused on low birth weight and smaller head circumference. Evidence suggests that nicotine causes more than 50% of all low birth weight babies.
Further studies on nicotine's effects on behavior and neurochemistry are eagerly anticipated.
Cocaine
Cocaine can freely cross the placental barrier. A widely held belief was that cocaine caused fetal hypoxia due to placental vasoconstriction.
Animal studies have shown disruptions in the neural and glial organization and migration.
Dopamine, serotonin, or both may mediate withdrawal from cocaine.
From a behavioral standpoint, cocaine has been shown to attenuate an animal's classic conditioning ability to noxious stimuli. Adult animal models of cocaine exposure tend to show a higher predisposition to self-administration for reward.
Opiates
In utero opioid exposure has consistently shown a decrease in nucleic acid synthesis and protein production in the brain, suggesting that overall brain growth is compromised. Effects on neurotransmitter concentrations and production have not been confirmed.
Behaviorally, prenatally exposed animals tend to show decreased exploration and increased response latency to noxious stimuli.
The definitions of maternal drug abuse and newborn withdrawal syndrome have been difficult to standardize (see Background). Therefore, documented disease prevalence varies tremendously. The prevalence of prenatally exposed newborns to one or more illicit drugs averages approximately 5.5%, with a range of 1.3-50%. Variations depend on the geographical detail (eg, local vs state) as well as the method of testing (eg, maternal history, urine testing, meconium testing, a combination of these tests).
In 1998, Lester reported that the Maternal Lifestyles Study (MLS), a multicenter clinical study, evaluated the effects of fetal exposure to opiates, cocaine, or both in the United States.[3] The overall exposure rate was 10%. Of these pregnancies, the rate of perinatal morbidity was higher than the nonexposed group but was less than 5% overall. Prematurity, lower growth parameters, compromised cognitive ability, and neurological symptoms were barely significant compared with nonexposed newborns.
The National Household Survey on Drug Abuse (NHSDA) reported that, from 1996-1998, 14.8% of pregnant women consumed alcohol.[4] During that same period, 2.8% of the surveyed women were reported to have used an illicit substance. Of those using illicit substances, two thirds were using marijuana, and one tenth were using cocaine.
Studies showed an increase in the incidence of neonatal abstinence syndrome between 2000 and 2009, from 1.20 cases to 3.39 cases per 1000 hospital births per year. As well, the cost of treating an infant with neonatal abstinence syndrome increased from an estimated average of $39,400 in 2000 to $53,400 in 2009.[5]
In a 2018 retrospective study (1999-2014), the national prevalence of opioid abuse in the United States increased by 333%, from 1.5 cases per 1,000 delivery hospitalizations to 6.5 per 1,000 delivery hospitalizations, an average annual increase of 0.4 per 1,000 delivery hospitalizations per year.[6]
In 2020, between 8-11% of pregnant women aged 15 to 44 used illicit drugs, tobacco products, or alcohol in the past month. Marijuana is the most commonly used illicit drug among pregnant women.[7] Nearly 1 in 12 newborns in the United States in 2020 experienced prenatal exposure to alcohol, opioids, marijuana, or cocaine.[8]
International data
Perinatal drug abuse and neonatal drug withdrawal is probably a recognized problem in neonatal and postnatal care in every country in the world.
O’Donnell and colleagues measured the birth prevalence of neonatal withdrawal syndrome over time, associated maternal characteristics, and child protection involvement.[9] This retrospective cohort study used linked health and child protection databases for all live births in Western Australia from 1980 to 2005. Maternal characteristics and mental health-related and assault-related medical history were assessed using logistic regression models. The study showed the birth prevalence of neonatal withdrawal syndrome increased from 0.97 cases per 10,000 live births to a high of 42.2 per 10,000 live births, plateauing after 2002.
Race-related demographics
The difficulty in assessing drug use confounds research into racial differences. Overall, cocaine use is higher among black women (5% of all black women) than white women (2% of all white women). Prevalence rates are lower among Asian and Pacific Islander women. The use of amphetamines, opioids, and cannabinoids appears to be equal between black and white women.
Sex-related demographics
By definition, perinatal drug abuse is a disease exclusively of pregnant women; however, several interesting epidemiological patterns emerge among mothers who abuse substances. These patterns include the following:
Genetics: Approximately 60% of mothers who abuse drugs describe a family history of substance abuse, particularly alcoholism. The closer the relative who abuses drugs, the higher the potential for the patient to be an abuser as well. Twin and adoption studies show a weaker genetic role in women than in men. Environmental factors may play a more dominant role for mothers who abuse substances. Patients who describe families of alcohol abuse also describe greater parental-marital conflicts and parent-child conflicts during their childhoods.
Sexual abuse and domestic violence: In a sample of 1099 women, Wilsnack et al reported that those with a history of being sexually abused in childhood were 2.5 times more likely to abuse substances and 3 times more likely to abuse alcohol than those who were not sexually abused.[10] In another study, Hien et al reported that 60% of women who abuse substances claimed to have an adult partner who committed domestic violence.[11] Likewise, many women report that their own drug use is initiated by their male partners.
Psychiatric comorbidity: A report from the National Institute of Mental Health (NIMH) Epidemiologic Catchment Area Survey showed that people who abuse substances were 4.5 times more likely to have a comorbid mental disorder than those individuals who do not abuse substances.[12] Of those with a lifetime alcohol or drug disorder, more than 50% were likely to have a comorbid psychiatric disorder. Females with comorbidities to their substance abuse were more likely than men to have affective and anxiety disorders. Also, comorbidity varies with the drug of abuse. People with opioid addictions tend to have a higher associated comorbidity of affective, anxiety, and personality disorders. Cocaine addiction tends to be associated with attention deficit hyperactivity disorder (ADHD).
Age-related demographics
Little data on the age stratification of substance abusing mothers are available. Research has focused on the adolescent mother. In particular, a link between adolescent pregnancy and substance use may be present.
If teenage pregnancy is believed to be a high-risk condition, then those individuals may be prone to other high-risk behaviors. Evidence does support a clustering of teen pregnancy with substance abuse, most notably abuse of cigarettes, alcohol, and marijuana. However, the statement that most pregnant and parenting teenagers abuse substances is a gross oversimplification. The literature supports that most pregnant teenagers do not use substances. Among those teenagers who do use substances, the amount used is far lower than the amount used by adult users who are pregnant.
Children with prenatal nicotine exposure exhibit appropriate catch-up growth but are known to have smaller lungs and, possibly, decreased ventilatory drive in response to carbon dioxide.
Children with prenatal amphetamine and cocaine exposure exhibit catch-up growth within 2 years of life.
Children with prenatal opiate exposure typically do not exhibit changes in growth parameters.
Infants exposed to buprenorphine have not exhibited significant differences in growth parameters compared to infants who have not been exposed.
Cognitive and developmental defects
Infants exposed to nicotine tend to score higher on auditory habituation but lower on the orientation cluster of the Brazelton Newborn Behavioral Assessment Scale (NBAS).
Infants exposed to alcohol may develop intellectual disability, which is one of the hallmarks of fetal alcohol syndrome (FAS). An apparent dose-dependent relationship is present, and FAS now accounts for approximately 33% of all intellectual disability. Milder cognitive effects include prolonged language delays and sleep dysfunction. Newborns exposed to alcohol also tend to be hypotonic.
Infants exposed to cocaine may exhibit fetal brain malformation resulting from changes in the homeostatic neurochemistry. Serious debate surrounds the actual deleterious effects of in utero cocaine exposure. Consequences previously described include altered behavior on NBAS scores (eg, poor state regulation, decreases in alertness and orientation, abnormal reflexes, tone and motor maturity), increased tone (described as hypertonic tetraparesis), electroencephalogram (EEG) changes, abnormal auditory brainstem responses,[13] and prolonged behavioral and language delays. However, data are inconsistent to prove that cocaine is solely responsible for these problems. Prenatal cocaine exposure can negatively affect the overall quality of maternal-child interaction during early childhood.[14] Research on this topic has been difficult, as confounding variables (eg, postnatal psychosocial issues, polydrug use in pregnancy) are difficult to control.
Prior conventional wisdom dictated that neurological morbidity was associated with cumulative postnatal risks preventing proper development. Prospective studies have shown no direct effect of cocaine exposure on development at age 3 years after correcting for race, parity, and socioeconomic status. However, data have also shown that infants exposed to cocaine may require more educational services than infants who are not exposed.[15, 16] The effect was magnified if the infants also had low birth weight or if they had low intelligence quotient (IQ).
A follow-up to the Maternal Lifestyle Study has shown that high exposure to cocaine, particularly with other drugs, is associated with behavioral issues in adolescence. However, protective factors such as beneficial bonding, community and family support, as well as stable home structure can attenuate the intensity of these behavioral issues.[17]
Infants exposed to opioids may have increased overall activity on NBAS testing. They tend to have difficulty being consoled. These infants also have been shown to have an early learning difficulty.[16]
Infants exposed in utero to methadone have been shown to have altered visual-evoked potentials, inferring a need for earlier visual assessments.[18]
Treatment length
Although length of treatment cannot always be correlated as a dose-dependent relationship with maternal use, data have suggested that, in mothers using high doses of methadone, for every daily dosage increase of 5.5 mg, an extra day in length of treatment time was added. Gestational age was not seen as significant.[19] However, data have also shown that infants born to mothers using methadone had increased length of treatment when concomitant benzodiazepine use or increased gestational age were associated. These findings were noted even when controlling for maternal methadone dose, concomitant use of tobacco or antidepressants, and trimester timing of initial dose.[20]
Several studies have compared the withdrawal effects of buprenorphine exposure with that of methadone exposure. In most cases, buprenorphine exposure was associated with decreased overall neonatal withdrawal treatment time and lower neonatal length of stay. Data on whether infants exposed to buprenorphine were more likely to require withdrawal treatment compared with infants exposed to methadone are conflicting.[21, 22, 23]
Morbidity/mortality
Neonatal withdrawal syndrome occurs in 60% of all fetuses exposed to drugs. Withdrawal syndromes for heroin, codeine, methadone, and meperidine have been extensively described. As more psychotropic medications are prescribed, more withdrawal syndromes are described. Heroin, cocaine, and amphetamine withdrawal usually occurs within the first 48 hours of life; however, a syndrome associated with intrauterine cocaine use has not been well defined. Methadone withdrawal can occur up to 2 weeks after birth but most likely occurs within the first 96 hours after birth. The syndrome is typically an autonomic multisystemic reaction, the symptoms of which are mostly neurological and may be prolonged.
Alcohol is the only drug of abuse that is well associated with other teratogenic effects. The classic triad of fetal alcohol syndrome (FAS) consists of growth retardation, physical anomalies (with characteristic facies), and CNS dysfunction. The risk of delivering a child with FAS increases with gravidity in mothers with alcoholism. Milder forms of FAS have also been described, representing a dose-dependent version of the entire syndrome. More severe aspects are associated with first trimester use of alcohol, especially in those women with a poor diet. At this time, a safe level of alcohol use during pregnancy is not known; therefore, the amount of alcohol that can be consumed without resulting in any part of the FAS spectrum is unknown.
Poor feeding is a common issue with withdrawing infants. Increasing evidence suggests that neurological alterations occur during withdrawal that prevent normal autonomic functions. Newborns, in particular, depend on their reflexive suck and swallow abilities, which may be significantly affected by intrauterine drug exposure.[24] As such, poor feeding alone can start a cascade of other diagnoses.
Complications
Perinatal complications include the following:
Incidence of medical and obstetric complications increases with in utero drug exposure. In particular, the incidence of premature delivery, abruptio placentae, breech presentation, and intrauterine growth retardation are significantly increased in mothers who are dependent on drugs. The doses of analgesia are typically higher to match the tolerance to drugs already being used.
In particular, cocaine use, with its vasoconstrictive properties, has been associated with an increase in vaginal bleeding, abruptio placentae, placenta previa, premature rupture of membranes, abortion, pneumothorax, pneumonia, malnutrition, and seizures.
Amphetamine use presents similarly to cocaine use and is related to an increased rate of abruptio placentae, maternal hypertension, and renal disease. Hypertension can often be confused with preeclampsia, leading to an increased cesarean delivery rate.
Opioid use has been shown to increase the rate of premature labor, premature rupture of membranes, breech presentation, antepartum hemorrhage, toxemia, anemia, uterine irritability, and infection (eg, HIV, hepatitis, syphilis).
Alcohol use has been associated with an increased rate of abruptio placentae. Complications for mothers who drink alcohol heavily can include increased spontaneous abortions and premature placental separation.
Cannabinoid use has been associated with an increased serum carboxyhemoglobin level. A slightly elevated incidence of precipitate labor, meconium staining, and dysfunctional labor occurs in mothers who use cannabinoids.
Maternal methadone use has been correlated with infant complications, such as prematurity, symmetrical growth retardation, and increased risk of neonatal abstinence syndrome (NAS), admission to the neonatal intensive care unit (NICU), small for gestational age (SGA), and major congenital anomalies.[25, 26]
Prematurity is accompanied by a host of medical complications including asphyxia, neonatorum, intracranial hemorrhage, respiratory distress syndrome, hypoglycemia, hypocalcemia, septicemia, and hyperbilirubinemia.
Although gross generalizations, the following growth characteristics may occur as a result of exposure to drugs:
Tobacco is described as perhaps the most common cause of low birth weight deliveries. Symmetric decreases are observed in all growth parameters, but these children exhibit appropriate catch-up growth.
Alcohol may cause symmetric decreases in all growth parameters. Data supports a synergistic effect in growth retardation with concomitant cocaine abuse.
Amphetamines and cocaine may cause symmetric decrease in all growth parameters. However, the growth-restricting effect of cocaine is more likely a result of maternal malnutrition. Likewise, growth retardation resulting from cocaine use tends to resolve with catch-up growth within 2 years after birth.
Opiate use may result in normal growth parameters. In particular, newborns exposed to methadone tend to have higher-than-expected growth parameters.
Government programs are available to help the prevention of perinatal drug use. Many have published documents that address support for pregnant women who abuse substances, addiction prevention, and treatment programs and guidelines for clinicians managing patients who abuse substances. These publications are available to primary care physicians and obstetricians and can be obtained free of charge from the Substance Abuse and Mental Health Administration (SAMHSA).
The following Internet sites provide guidelines for providers:
American Academy of Pediatrics
National Institute on Drug Abuse (NIDA)
Administration for Children and Families (ACYF) for programs on foster care, adoption, family support, Head Start, child abuse and neglect, and child welfare
Pregnancy actually offers an excellent opportunity for a mother to seek help and to change her life to protect another. However, given the large numbers of mothers who abuse drugs and whose use goes undetected by their obstetricians and pediatricians, the history-taking practice in prenatal settings must change if this part of the medical evaluation is to be useful.
Previous attempts at universal toxicology screens for women who are pregnant typically have uncovered one half of all women who abuse drugs. Urine toxicology in combination with a well-performed history is likely to have synergistic results in discovering mothers who abuse substances.
All too often, the wish to perform an efficient prenatal screening consists solely of asking whether the woman who is pregnant uses drugs. Such questioning carries such stigma and lack of empathy that it is likely to prevent a mother-to-be from admitting her habit of substance abuse. Questioning should be nonjudgmental (ie, ask in a neutral tone of voice), specific (ie, ask about each potential drug of abuse starting with the least innocuous to the most), and asked in succession with the other standard screening inquiries (eg, general medical condition, diet).
Although several perinatal complications have been thought to be highly associated with in utero drug use, none are pathognomonic. Multiple studies have reported an association of maternal cocaine and tobacco use and placental abruption.
Methadone is perhaps the most commonly seen medication in the withdrawing infant. Clinicians can be somewhat prepared to care for these infants because such information is made available during the prenatal visit. In assessing the history of the maternal methadone dose, one must consider a great deal of conflicting data concerning the predictability of withdrawal severity with maternal methadone concentrations. Whether the relationship between maternal methadone dose and severity of neonatal withdrawal is linear remains a subject of debate.[27, 28, 29, 30, 31] One study noted that infants who were conceived while the mother was on methadone had better drug treatment outcomes for withdrawal compared with infants who were only exposed in the third trimester.[32] Withdrawal severity was similar for both groups.
Buprenorphine has become a rapidly popular withdrawal treatment medication for pregnant women.[33, 34, 23, 22] As a partial opiate agonist, it has a ceiling effect in pleasurable effects and has shown increased compliance while also demonstrating lower transference through the placenta compared with methadone due to its greater molecular weight. As well, when compared with methadone use in utero to treat opioid dependence in the mother, buprenorphine use resulted in fewer infants requiring withdrawal treatment. In addition, of infants who did require treatment, those exposed to buprenorphine spent fewer days in the hospital compared with those exposed to methadone.[35]
The severity of newborn withdrawal from substances depends on the drugs and the frequency of use by the mother during pregnancy. Note the following:
Nonopiate drug withdrawal: Withdrawal syndromes that are related to individual nonopiate drugs have been difficult to study. The high prevalence of polydrug use prevents clinicians from witnessing the effects of isolated medications. At this time, little data supports a description of a cocaine-abstinence syndrome.
Alcohol withdrawal: Signs of alcohol withdrawal may include hyperactivity, crying, irritability, poor sucking, tremors, seizures, poor sleeping patterns, hyperphagia, and diaphoresis. Signs usually appear at birth and may continue until age 18 months. Withdrawal typically appears within 3-12 hours after delivery.
Barbiturate withdrawal: Signs may include irritability, severe tremors, hyperacusis, excessive crying, vasomotor instability, diarrhea, restlessness, increased tone, hyperphagia, vomiting, and disturbed sleep.
Marijuana withdrawal: For marijuana, a mild opiatelike withdrawal syndrome has been observed. Signs may include fine tremors, hyperacusis, and a prominent Moro reflex; however, these symptoms rarely require treatment.
Nicotine withdrawal: Mild signs are observed, including fine tremors and variations in tone; data have shown that maternal smoking was associated with subtle neonatal behaviors, such as poor self-regulation and an increased need for handling.[36] These behaviors are suggestive that neonatal withdrawal is possible for nicotine exposure in utero.
Acute narcotic withdrawal: This withdrawal usually begins 24-48 hours after birth, depending on the time of last dose. However, signs may not appear in the infant until 3-4 days after birth.
Methadone withdrawal: Symptoms typically appear within 48-72 hours but may not start until the infant is aged 3 weeks. This is particularly true for infants whose mothers took excessively higher doses. Conflicting data have emerged concerning withdrawal severity and higher in-utero methadone doses. Data have shown that coexposure with nicotine increases the severity and duration of the neonatal withdrawal.
Buprenorphine withdrawal: Symptoms typically occur within the first 72 hours. Typically, fewer postnatal complications are reported compared with methadone, but 10% of infants exposed to buprenorphine are delivered prematurely compared with 7% of infants who are not exposed.[23] A neurological follow-up study revealed no significant differences in infants who received buprenorphine compared with infants who did not at age 4 months. However, some studies have seen increased levels of jitteriness, jerky movements, and lower limb hypertonia as late as age 9 months. However, effects of polydrug use cannot be ruled out.[23] As many as 85% of infants exposed to buprenorphine have shown signs of neonatal withdrawal; however, the syndromes and duration of treatment appear to be milder in comparison with infants exposed to methadone. Data have also shown that buprenorphine concentration in meconium may be linearly related to the onset and frequency of neonatal abstinence syndrome (NAS).[33]
Opiate withdrawal: Signs of NAS include hyperirritability, gastrointestinal dysfunction, respiratory distress, and vague autonomic symptoms (eg, yawning, sneezing, mottling, fever). Tremors and jittery movements, high-pitched cries, increased muscle tone, and irritability are common. Normal reflexes may be exaggerated. Loose stools are common, leading to possible electrolyte imbalances and diaper dermatitis. Long-term symptoms have been difficult to study, but evidence supports that these children show hyperphagia, increased oral drive, sweating, hyperacusis, irregular sleep patterns, poor tolerance to environmental changes, and continued loose stools. NAS appears to be less severe if the mother has used opiates longer than one week prior to delivery.
Cocaine: Acute signs such as tremors, high-pitched cry, irritability, excess suck, hyperalertness, apnea, and tachycardia can be seen with the first 72 hours of life. However, because these signs can be seen before the typical half-life of a dose immediately prior to delivery, one can argue that these signs are more typical of intoxication, rather than withdrawal.
Amphetamines: Whether amphetamine use during pregnancy affects neonatal outcome remains unclear. Increasing evidence suggests that it is associated with an increased risk of prematurity and intrauterine growth restriction and the risk of congenital anomalies does not appear to be increased.[37, 38] As well, although several reports of neonatal amphetamine withdrawal are documented, each case involved polydrug use during the pregnancies.
Phencyclidine: Because the number of known phencyclidine use during pregnancies is limited, little is known of the neonatal consequences. Some studies have reported neurobehavioral abnormalities in the immediate neonatal period, such as hypertonicity, irritability, sleep problems, and temperature instability. However, as in many other observational reports, these typically include patients with polydrug use during the pregnancy.
Antidepressants: Perhaps no class of medications is more studied than the current generation of selective serotonin reuptake inhibitors (SSRI). Because of their widespread use, concern over possible fetal or infant effects have been well studied.[39] In general, no withdrawal syndrome has been associated with SSRIs. However, infants have been noted to show jitteriness, respiratory distress, and other neonatal complications. They are more commonly observed in newborns whose mothers were taking a short-acting SSRI such paroxetine (Paxil). Debate rises over whether these symptoms are actually withdrawal or, more likely, a drug intoxication effect. Of all SSRIs studied, intrapartum use of sertraline (Zoloft) has shown the safest neonatal clinical profile.
Generally, perinatal information is enough to provide clues about the mother and her history of drug abuse, as well as urine toxicology screening at the time of admission to the hospital for delivery. Based on the information obtained, clinicians also need to examine the infant and see if further investigation is clinically warranted in addition to sending urine and meconium or umbilical cord samples for toxicology screening.
Typically, a sepsis work-up is not routinely performed solely because of drug exposure; however, a thorough review of the perinatal history and examination of the newborn is warranted.
The following studies are indicated when assessing perinatal drug abuse and neonatal drug withdrawal:
Obtain serum glucose and calcium levels.
Obtain a complete blood cell (CBC) count with differential and platelets.
Consider blood culture and other cultures to rule out newborn sepsis.
Confirm maternal hepatitis status and treat accordingly.
Confirm human immunodeficiency virus (HIV) status.
The advent of umbilical cord testing has shown promise, as such tissue can be more readily sampled at the time of birth. There is a high correlation between this tissue sample with meconium specimens.[40]
Neonatal hair analysis may prove useful in confirming fetal drug exposure and possibly predicting neonatal withdrawal severity.[41] Hair analysis should be used in conjunction with urine and meconium analysis.
Toxicology screening
A maternal urine toxicological screen may be helpful in determining drug use. A urine screen only signifies recent use or heavy use of drugs. In general, the length of time that a drug is present in urine after use is as follows:
Marijuana: 7 days to 1 month in an adult, perhaps even longer in an infant
Cocaine: 24-28 hours in an adult, 72-96 hours in an infant
Heroin: 24 hours in an adult, 24-48 hours in an infant
Methadone: Up to 10 days in an infant
Neonatal toxicology screening should also include algorithms using meconium testing.[42] Meconium testing provides higher sensitivity than urine testing and is comparable to umbilical cord tissue samples.
In 1986, Finnegan et al created the Neonatal Abstinence Scoring System, which provides an objective measure of a newborn's symptom severity (see image below).[43]
View Image
Perinatal Drug Abuse and Neonatal Drug Withdrawal. Neonatal abstinence scoring form.
This system is currently used as a diagnostic tool and as a monitor for the response of a newborn with withdrawal to pharmacotherapy.
Each of the 21 different symptoms is scored depending on severity. All scores are then added. Scoring is performed in 4-hour intervals. If the newborn receives a score of 8 or greater, then scoring should occur every 2 hours. If the scores in the first 96 hours of life are consistently 8 or less, then scoring can be discontinued and pharmacotherapy is typically not needed.
If the maternal urine screen or history is positive for drug use, first assess the infant at 2 hours after birth. Scores should reflect the symptoms observed during the entire interval, not just at a single point. Scores involving sleep and behavior should reflect any changes during the test period. For instance, if the child was awakened for the examination, do not score against the child for diminished sleep.
A higher total score implies a more severe withdrawal syndrome. Likewise, as the child responds to treatment, use the scores to titrate the amount of pharmacotherapy needed.
Although the scoring system is primarily designed for withdrawal from opiates or CNS depressant drugs, it has been used for other drugs (eg, cocaine, amphetamines). Its efficacy in these situations is likely from a preponderance of polypharmacy use.
In a study that evaluated the brains of 118 newborns born to 118 mothers with marijuana, cocaine, and/or methadone maintenance and/or heroin use, there appeared to be anatomic abnormalities at similar sites among the three groups, including smaller volumes in the dorsal, medial, and ventral surfaces of the frontal lobe, as well as dose-related increases in volumes in the lateral temporal lobe, dorsal parietal lobe, and superior frontal gyrus.[44] Also similar among the drug exposures were dose-related increases in diffusion tensor measures of tissue organization, decreases in T2 relaxometry times, and increases in spectroscopy metabolite concentrations. The investigators indicated the findings suggest an association between prenatal drug exposure and measures of newborn brain tissue in patterns that may indicate such exposures accelerate normal fetal brain maturation as well as mediate associations of these drug exposure with poorer 12-month infant outcomes.[44]
Perhaps the most important aspect of medical care for the potentially withdrawing infant should be that all nurseries caring for such infants develop a care protocol addressing screening and treatment. Such plans minimize care variance and have the potential to prevent unnecessary withdrawal from occurring.[1]
Administer paregoric and phenobarbital for withdrawal of opiates and barbiturates, respectively (see Medication).
Naloxone should not be administered to any infant born to a mother who is known to be using narcotics (eg, opium, heroin, methadone, hydrocodone) because it may cause sudden symptoms of withdrawal, including seizures.
Treatment and medication primarily focus on opiate and cocaine withdrawal. Although understanding polydrug interactions is difficult, no specific treatment plan for amphetamine, marijuana, tobacco, or alcohol withdrawal is recognized (unless teratogenic effects are observed).
Controversy still remains over the proper choice of pharmacologic treatment. The mainstays of treatment include opioids (especially if specific prenatal opioid use was known) and phenobarbital. In meta-analyses, opioid therapy alone versus phenobarbital therapy alone showed no difference in treatment failure. However, those treated with opioid therapy alone had shorter lengths of stay in the hospital.
One study showed that combined use of opioid therapy and phenobarbital may reduce the overall length of hospital stay and durations of symptoms.[45]
As maternal buprenorphine use increases, the rationale for its use as a treatment for neonatal withdrawal becomes more evident. One study used buprenorphine sublingually (13.2 μg/kg/d, divided 3 times) in withdrawing neonates. A 30% reduction in treatment time and length of stay was noted compared with standard opiate treatment.[34]
Studies have also investigated the use of clonidine with or without opiate treatment for neonatal abstinence may be a worthy alternative.[28, 46, 47]
Until the child has been weaned off medication, or until the symptoms have abated (as confirmed by the Neonatal Abstinence Scoring System), the patient should be constantly monitored by newborn nursery staff. Vital signs should be checked, the Neonatal Abstinence Scoring System score should be obtained, seizure precautions should be taken, and frequent weight checks should be performed.
All medically treated newborns should constantly be monitored for cardiovascular, respiratory, and oxygen saturation changes.
In newborns with severe symptoms, intravenous fluids with electrolytes may be needed. Oral feedings may need to be withheld.
Hospital social services: A positive drug screen in a newborn of a mother without a prescription for the suspected drug warrants an investigation by the state child protection agency. The hospital social services staff can coordinate and supervise the interactions of staff, parents, and state services.
Occupational and physical therapy: Use of a team of therapists decreases the overall treatment time. Issues surrounding environmental stressors and patient contact can be addressed.
Many infants in this situation have difficulty establishing breastfeeding or bottle-feeding.
Although no consensus has been reached, a meta-analysis has demonstrated that, even when controlled for methadone or polydrug use, infants of drug-using women who were breastfed showed an overall lower need for abstinence treatment.[48]
Controversy has emerged regarding breastfeeding and maternal methadone use, particularly with the large dose increases seen in the last decade. In an American Academy of Pediatrics statement from 2001, breastfeeding has been encouraged, regardless of dosage. The impetus of this decision is based mostly on the minimal transfer of methadone through breast milk. Evidence has shown that regardless of maternal dose, methadone concentrations in breast milk were minimal, and neurobehavioral effects on the newborn were generally not seen.[49]
In addition, women who are adhering to buprenorphine maintenance treatment should be encouraged to breastfeed, as the amount of this medication being excreted in human milk is small.[50]
Withhold breastfeeding if other substances are suspected or if the mother is HIV positive.
Increased caloric intake
The newborn withdrawing from drugs has higher caloric demands. In addition to the catabolism resulting from withdrawal symptoms, these patients lose calories from vomiting, drooling, and diarrhea.
Consider provision of hypercaloric (100.42 J/oz) formula in frequent small feedings. The daily caloric goal should be 627.6-1046 J/kg/d.
The child's comfort is paramount. Being a newborn is extremely stressful in the first few weeks of life because every external stimulus is entirely new to the infant. Add the stress of the internal stimuli from drug withdrawal, and the usefulness of environmental control can be understood. With this in mind, consider that 40% of all withdrawing newborns can be treated symptomatically (without medication). Specific methods include the following:
Loose swaddling, as well as holding and slow rocking the infant, may be helpful.
Perform environmental controls emphasizing quiet zones, low lighting, and gentle handling. At Massachusetts General Hospital, a battery-operated vibrating box that clips to the bassinet is used often. The device creates a tactile "white noise" that allows the newborn withdrawing from drugs to focus away from multiple-environmental stimuli. Anecdotal evidence supports improved outcomes with its use.
Use a pacifier for excessive sucking.
Frequent diaper changes are necessary. Diaper dermatitis is common in infants who are withdrawing from narcotics and have loose stools. Proper skin care can minimize skin breakdown and associated discomfort.
Position the newborn to reduce aspiration. The guidelines of the American Academy of Pediatrics specifically discourage prone position sleeping for newborns. Some evidence suggests that placing babies in the left lateral position is more useful to decrease gastroesophageal reflux than placing babies in the right lateral or supine position. However, supine positioning is encouraged in infants preparing to be discharged home to avoid increasing the risk of sudden infant death syndrome.[51]
The following is indicated as part of further outpatient care in perinatal drug abuse and neonatal drug withdrawal:
Early intervention and developmental pediatrics: Any newborn who has been exposed to drugs is considered at risk for developmental and cognitive compromises. These children should have regular follow-up care with a team of child development specialists to quickly identify potential deficits.
State child protective services: In the event of court-imposed custody, children should be monitored through the foster family and adoption process.
General pediatrics: As with any newborn, perform regular follow-up care for immunizations, anticipatory guidance, and physical examinations.
Opiate substitutes and phenobarbital are the mainstays of treatment. Other sedatives such as diazepam have not been shown to be effective. Many studies have compared opiates with phenobarbital alone. In general, opiates have been most effective. However, considerable data have shown that a combination treatment of opiates and phenobarbital significantly decreases hospital stay and decreases withdrawal severity. The drawback is that total duration of treatment (mostly as an outpatient on phenobarbital) is increased.
Clinical Context:
Use a 1:25 dilution. When ordering such a medication, be sure to emphasize that a dilute solution of the deodorized tincture is needed in a 1:25 ratio. Without this emphasis, the pharmacy may deliver undiluted DTO (used for adults) or the camphorated tincture of opium (Paregoric), which contains 45% alcohol, camphor, anise oil, and benzoic acid.
Clinical Context:
Increasing data shows that, although this is similar in effect to DTO, it may be a safer alternative because the morphine elixir avoids the effects of alcohol extracts in DTO. Morphine elixir may allow for better weight gain compared with DTO, as well.
These are the treatment of choice for neonates known to be at risk of withdrawal from opiates. Morphine elixir is gaining more support over deodorized tincture of opium as the treatment of choice for a primarily opioid withdrawal syndrome.
Clinical Context:
Interferes with transmission of impulses from thalamus to cortex of brain. Used as a sedative. As above, this is perhaps best used in combination with an opiate analog in reducing withdrawal severity.
Although barbiturates also are available for neonatal withdrawal syndrome, their optimal use is limited to several clinical situations, including the following:
1. The newborn with a nonopiate withdrawal
2. The newborn with a known polydrug withdrawal
3. The newborn with abstinence-related seizures
4. The newborn who has already received the maximum safe level of deodorized tincture of opium (DTO)
Marvin Wang, MD, Clinical Instructor, Department of Pediatrics, Harvard Medical School; Co-director of Newborn Nurseries, Attending Physician, Department of Pediatrics, Massachusetts General Hospital,
Disclosure: Received research grant from: New England Pediatric Device Consortium.
Specialty Editors
Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
Brian S Carter, MD, FAAP, Professor of Pediatrics, University of Missouri-Kansas City School of Medicine; Attending Physician, Division of Neonatology, Children's Mercy Hospital and Clinics; Faculty, Children's Mercy Bioethics Center
Disclosure: Nothing to disclose.
Chief Editor
Dharmendra J Nimavat, MD, FAAP, Associate Professor of Clinical Pediatrics, Department of Pediatrics, Division of Neonatology, Southern Illinois University School of Medicine; Staff Neonatologist, Clinical Director, NICU Regional Perinatal Center, HSHS St John's Children's Hospital
Disclosure: Nothing to disclose.
Additional Contributors
Ted Rosenkrantz, MD, Professor, Departments of Pediatrics and Obstetrics/Gynecology, Division of Neonatal-Perinatal Medicine, University of Connecticut School of Medicine
US Department of Health and Human Services. 2020 National Survey on Drug Use and Health: Women. Substance Abuse and Mental Health Services Administration. July, 2022. Available at https://www.samhsa.gov/data/sites/default/files/reports/slides-2020-nsduh/2020NSDUHWomenSlides072522.pdf. Accessed: March 11, 2024.
Umer A. 1 in 12 infants are exposed to drugs prenatally. Clinical Advisor: Pediatrics. March 5, 2024. Available at https://www.clinicaladvisor.com/home/topics/pediatrics-information-center/1-in-12-infants-exposed-drugs-prenatally/. Accessed: March 5, 2024.
Wilsnack SC. Drinking, sexuality, and sexual dysfunction in women. In: Wilsnack SC, Beckman LJ, eds. Alcohol Problems in Women: Antecedents, Consequences, and Intervention. New York, NY: Guilford Press; 1984. 189-228.
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