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Infants with prenatal substance use exposure

Infants with prenatal substance use exposure
Author:
Lauren M Jansson, MD
Section Editor:
Joseph A Garcia-Prats, MD
Deputy Editor:
Laurie Wilkie, MD, MS
Literature review current through: Dec 2022. | This topic last updated: Apr 01, 2022.

INTRODUCTION — Substance use disorder during pregnancy is a potentially serious problem for both the mother/caregiver and the newborn infant. For the offspring, there can be both short-term and long-term consequences based on the specific substance(s) of exposure as well as environmental and other factors related to the maternal substance use disorder, particularly if maternal treatment and other needs are not met.

The clinical features and management of neonates born to people with substance use disorders will be reviewed here. Substance use disorder during pregnancy is discussed separately. In addition, there are separate topics that discuss the effects and management of prenatal exposure of nicotine, alcohol, and opioids on the newborn. (See "Cigarette and tobacco products in pregnancy: Impact on pregnancy and the neonate" and "Substance use during pregnancy: Screening and prenatal care" and "Alcohol intake and pregnancy" and "Neonatal abstinence syndrome".)

TERMINOLOGY AND DEFINITION — The term substance exposure encompasses all of the following different substances, all of which can have consequences for the infant and developing child:

Licit substances (not requiring a prescription) – Tobacco/nicotine, alcohol, cannabis (in some locations)

Prescription drug use or misuse – Opioids/painkillers, sedative/hypnotics, stimulants, psychotropic medications used for psychiatric comorbidities

Illicit drugs – Stimulants, including cocaine and amphetamines (methylenedioxymethamphetamine [MDMA, "ecstasy"]); heroin; hallucinogens; cannabis (in some locations)

Drugs used to treat maternal opioid use disorder (methadone, buprenorphine, buprenorphine-naloxone)

In addition, terminology continues to evolve for infants prenatally exposed to opioids. Neonatal abstinence syndrome (NAS) describes the syndrome of withdrawal in neonates who are exposed to opioids and other substances in utero; neonatal opioid withdrawal syndrome (NOWS) can also be used to describe the withdrawal syndrome of in utero opioid exposure only. In this discussion, we will use the term NAS to encompass withdrawal related to opioids and other substances. (See "Neonatal abstinence syndrome".)

EPIDEMIOLOGY — In the United States, substance use disorder during pregnancy has increased and is more common in younger people. As a result, the rate of newborns exposed to substances and/or drugs has increased. In particular, opioid use/misuse [1] and cannabis use have increased in the United States [2]. Cannabis is the most commonly used illicit substance during pregnancy [3] and increasing legalization is likely to explain why more people are using cannabis during pregnancy and lactation [4]. (See "Substance use during pregnancy: Screening and prenatal care".)

Many pregnant and postpartum people use more than one substance [5-8]. In particular, mothers/caregivers who used illicit drugs during pregnancy are more likely to concurrently smoke cigarettes and consume alcohol. Polysubstance use presents an increased challenge because of the increased risk for preterm birth and potentiated NAS spectrum presentation [9,10].

DIAGNOSTIC EVALUATION

Overview — Identification of substance use disorder during pregnancy is important, both to provide specialized obstetric and substance use disorder treatment during pregnancy and after delivery and to identify risk factors for the pregnant person, the pregnancy, and the offspring. Routine universal obstetrical screening by confidential interview for use and misuse of licit and/or illicit substances is the mainstay of identifying people in need of treatment for substance use disorder. For substance-using people who are not identified as having a substance use disorder during pregnancy, identification of withdrawal in the newborn can be diagnostic for maternal substance use disorder. (See "Substance use during pregnancy: Screening and prenatal care", section on 'Screening for substance use'.)

Maternal screening — Screening for substance use/misuse is a part of complete routine obstetric care and all pregnant people should be asked about their use of licit substances, illicit drugs, and prescription medications including those used to treat maternal opioid use disorder. Additionally, pregnant people should be asked about their past history of substance use disorder, including treatment, as well as violence exposure/trauma, psychiatric history, symptoms of anxiety/depression, and medications. Use of a standardized validated screening assessment tool is recommended. Screenings should be performed at multiple points during pregnancy, with the goal of engaging pregnant people in appropriate care. (See "Substance use during pregnancy: Screening and prenatal care", section on 'Screening tools'.)

Maternal screening is often complicated by fear of stigmatization as a substance user and/or initiation of children's protective services intervention. Intervention and referral for treatment for pregnant people with any substance use disorder are part of the multidisciplinary approach that should occur in the absence of pejorative/punitive attitudes and criminal sanctions [11]. Identification of a maternal substance use disorder does not necessarily imply that the mother/caregiver has harmed the fetus, nor should it be used for purposes of stigmatization or for child removal. Health care providers should be aware of state requirement for reporting substance use; decisions to report should be made in conjunction with social services providers based on the mother/caregiver's available support/treatment structure and not on the presence of substance use alone [12].

Biologic testing for substance use/misuse during pregnancy is discussed in detail separately. (See "Alcohol intake and pregnancy" and "Substance use during pregnancy: Screening and prenatal care".)

Neonatal assessment — The neonatal assessment is focused on identifying the substance-exposed infant who is at risk for symptoms of withdrawal to ensure that nonpharmacologic measures and potential administration of pharmacologic treatment for the infant are appropriately administered, and maternal treatment and education are initiated. Neonatal assessment primarily focuses on recognizing clinical features of neonatal problems with neuroregulatory functioning and signs of withdrawal.

Clinical features of withdrawal in the substance-exposed infant — Clinical signs of neonatal substance withdrawal encompass dysfunction in four neurobehavioral domains: autonomic regulation, attention and state control capacities, responses to sensory stimuli, and motor and tone control. Infants undergoing withdrawal can have neurobehavioral dysregulation in any or all of these four domains. Manifestations include a high-pitched cry, irritability, sleep/wake disturbances, alterations in tone or movement, feeding difficulties, gastrointestinal and autonomic disturbances, respiratory problems, and failure to thrive.

Neonatal neurobehavioral dysregulation is most commonly associated with opioid exposure (referred to as neonatal abstinence syndrome [NAS] or neonatal opioid withdrawal syndrome [NOWS]), but other substances, including alcohol [13,14], benzodiazepines [15,16], nicotine [17], and psychiatric medications (eg, antidepressants or antipsychotics [18,19]), may present with similar findings. For infants exposed to maternal polysubstance use, including opioid exposures in combination with other substances such as cocaine [20], nicotine [21], and serotonin receptor inhibitors (SRIs) [22], the polysubstance exposure can exacerbate the infant's expression and/or severity of opioid-induced neurobehavioral dysregulation [9]. (See "Neonatal abstinence syndrome", section on 'Clinical manifestations'.)

The clinical presentation of infants with in utero substance exposure is variable and is dependent on the substance(s) of exposure, timing, and amount of the last maternal consumption, the presence of concomitant conditions, maternal and infant metabolism and excretion, infant sex, and genetic and epigenetic factors [23,24]. As a result, if there is concern for prenatal substance use exposure, the length of hospitalization should be sufficient to detect any subsequent signs of withdrawal. This reduces the chance that an infant will develop signs of withdrawal after discharge, which may result in maltreatment and maternal relapse in an unsupportive environment. For infants exposed to opioids, the hospitalization should be a minimum of four to five days.

Neonatal testing — Although testing in the neonate to detect the presence of substances can be performed in a variety of biological specimens (eg, urine, meconium, and umbilical cord blood), the clinical utility of these tests is limited, as discussed below [25,26]:

Urine screening reflects a relatively short window of exposure and, for the most part, can only detect recent use (table 1) [27]. Negative toxicology screening results do not rule out a substance use disorder, and positive results do not quantify maternal use or necessarily reflect a substance use disorder. Urine toxicology screening does not detect prenatal alcohol exposure.

Meconium analysis is sensitive and specific for substances that are excreted either in the hepatobiliary system (eg, metabolites of heroin, cocaine, and cannabinoids) or intestinal tract [28,29]. However, testing may not be available on-site at birth hospitals, and results from outside reference laboratories are often not received in time to affect management in the postpartum period. In addition, collection of appropriate meconium samples can be challenging, as meconium may be passed in utero or be contaminated with transitional stools. The delayed passage of meconium may result in a delayed diagnosis of substance exposure. Furthermore, meconium levels may not reflect periods of abstinence closer to term because meconium testing reflects exposures in the second and third trimesters, which may unfairly reflect negatively on pregnant people who are in substance use disorder treatment.

Testing of umbilical cord blood and tissue by using drug class-specific immunoassays appears to be a promising method of testing and is easier to collect than meconium [30]. However, its utility in medical management is limited because it does not quantify maternal use nor reflect periods of drug abstinence closer to delivery. Furthermore, testing may not be available on-site so that results from outside laboratories are not received in time to affect management. Use of umbilical cord assays may be helpful in cases in which the infant develops signs of NAS and the mother/caregiver denies illicit substance use or licit substance misuse.

Legal requirements — If screening for substance use by biologic testing is performed, clinicians must be aware of the legal requirements needed for consent and for reporting when a diagnosis of prenatal substance exposure is made. Each birth institution should adopt a policy that complies with local laws and avoids discriminatory practices [25].

Clinicians must be aware of the legal requirements for reporting infants affected by prenatal substance exposures, and each birth institution should adopt a policy that complies with local laws and avoids discriminatory practices. In the United States, the Child Abuse Prevention and Treatment Act requires health care professionals to facilitate referral infants with prenatal substance use exposure and their caregivers to community-based, family support programs known as Plans of Safe Care. These programs address the health and other needs of the infant and the substance use disorder treatment needs of the affected caregiver and others in the family [31]. The linked website provides a list for each state's reporting requirements and available plans of care.

DIAGNOSIS — The diagnosis of prenatal substance exposure is based on a positive maternal screening based on maternal history and/or identification of a substance or its metabolites in maternal urine, or identifying neonatal signs of substance withdrawal or neurobehavioral dysregulation related to in utero substance exposures. Infrequently, neonatal testing may confirm the diagnosis of prenatal substance exposure in infants with signs of neurobehavioral dysregulation and negative maternal screening. (See "Neonatal abstinence syndrome", section on 'Clinical manifestations'.)

GENERAL MANAGEMENT APPROACH — General management for the infant of a person with a substance use disorder includes the following:

Optimal environment — A multidisciplinary team that includes social services, substance use disorder treatment counselors, obstetricians, pediatricians, and psychiatrists (if warranted) best meet the needs of both the mother/caregiver and infant before and after delivery.

Rooming-in (ie, the co-location of mother/caregiver and infant care after delivery and beyond) is the preferred inpatient setting for the care of the mother/caregiver and infant because it provides the best environment for mother/caregiver-infant interaction. Rooming-in has been shown to lessen the severity of withdrawal signs for infants with neonatal abstinence syndrome (NAS) [32]. The environment should be modified to support both maternal and infant self-regulation.

For mother/caregivers with a history of sexual trauma, additional attention to the environment is needed [33]. For example, unknown caregivers at night, "tethering" to the bed with IVs, exposed breasts or body parts, or the sight/scent of blood in the genital area may cause psychologic trauma or flashbacks for people who have experienced abuse. These issues can be addressed with discussion and environmental modification. People who have experienced trauma should be referred at the earliest opportunity for care by an experienced psychiatric provider.

Maternal care — Optimal mother/caregiver care includes the following:

Careful evaluation of the mother's/caregiver's history – Comorbidities in people with substance use disorder are common and include medical/obstetrical concerns, multiple, interrelated health and psychosocial adversities (maternal depression and anxiety, intimate partner violence victimization, housing, and employment instability). (See "Substance use during pregnancy: Screening and prenatal care", section on 'Prenatal care of individuals with substance use disorder' and "Intimate partner violence: Diagnosis and screening" and "Unipolar major depression during pregnancy: Epidemiology, clinical features, assessment, and diagnosis".)

Maternal education and support – The mother/caregiver should be engaged early so that they understands the infant's behavior and can establish a better bond. Education and therapy should be provided to promote maternal self-regulation and the mother/caregiver's ability to support the infant's behavioral and physiological organization/self-regulation [34].

During the birth hospitalization, ongoing assessment of the interaction between the mother/caregiver and infant (ie, reading and of infant cues and responding contingently) is important to facilitate understanding of the infant's strengths and challenges, optimize handling and response to the infant, and modify the infant's environment to support his/her optimal functioning. It is important that the mother/caregiver be treated in a non-judgmental fashion by all care providers, and that the use of pejorative language (eg, addict, methadone baby, NAS baby) and attitudes be avoided.

Maternal therapy – Mother/caregiver and neonatal outcomes are improved when mother/caregivers are cared for in an integrated perinatal program that provides substance use disorder counseling and treatment (medication assisted if needed) with comprehensive prenatal and postnatal care [35,36].

Identification of familial and community supports for maternal engagement in treatment and health care for herself and the infant.

Maintenance of the mother/caregiver confidentiality is important.

Initial newborn assessment and care — All substance-exposed infants should be observed for a period of time after delivery to observe for signs of neurobehavioral dysregulation and symptoms of neonatal abstinence syndrome.

Clinicians caring for prenatally substance-exposed infants should provide the following:

Observation for the development of signs of neurobehavioral dysregulation related to substance exposures. In general, infants with any substance exposure should be hospitalized for four to five days.

Identification of poly-substance exposure and its effects on the infant. Nicotine and benzodiazepines can augment the clinical manifestations of withdrawal for infants with prenatal exposure to opioids, barbiturates, and/or alcohol [9].

Infant assessment of gestational age, size of the infant, and evidence of congenital infection or malformation.

Prematurity and fetal growth restriction – Prematurity and fetal growth restriction may be directly related to specific exposures such as cocaine and nicotine). In addition, mothers with substance use disorder are less likely to have prenatal care and have other concomitant conditions (eg, poor nutrition) that increase the risk of prematurity and fetal growth restriction [6]. Prematurity and IUGR increase morbidity and mortality in affected infants compared with term infants born appropriate size for gestational age (AGA). (See "Preterm birth: Definitions of prematurity, epidemiology, and risk factors for infant mortality", section on 'Risk factors for preterm birth' and "Infants with fetal (intrauterine) growth restriction".)

Congenital infections – Infants born to mother/caregivers with substance use disorders are at higher risk for congenital infections, and assessment needs to include screening and identifying evaluation for maternal infections, including hepatitis, syphilis, and human immunodeficiency virus (HIV) [37]. (See "Overview of TORCH infections" and "Prenatal evaluation of women with HIV in resource-rich settings" and "Hepatitis viruses and the newborn: Clinical manifestations and treatment".)

While not common, congenital malformations do occur at higher rates in substance-exposed children compared with the general population. In particular, offspring exposed to prenatal opioids are at risk for cardiac defects and neural tube defects in [38-40]. (See "Neonatal abstinence syndrome", section on 'Clinical findings'.)

Initial nonpharmacologic support — Nonpharmacologic care is the first-line treatment for all substance-exposed infants and is individualized to each mother/caregiver-infant dyad. It begins ideally prenatally, or at the time of birth and extends throughout the hospitalization period and beyond, regardless of the infant's need for pharmacotherapy for NAS. The goal is to optimize the environment and handling of the infant to promote regulation and decrease the signs of neurobehavioral dysregulation associated with in utero substance exposures. This care is comprised of comprehensive assessment of the infant and maternal functioning, alterations in the environment and handling to minimize signs of neurobehavioral dysregulation in the infant and to promote a healthy caregiver-infant communication and interaction. Properly applied nonpharmacologic care may not obviate the need for pharmacologic care, but a comprehensive program has been shown to reduce overall utilization of pharmacologic therapy. (See "Neonatal abstinence syndrome", section on 'Nonpharmacologic care'.)

Neonatal pharmacotherapy — Pharmacologic therapy is initiated for infants who, despite adequate nonpharmacologic care, display signs of withdrawal that are sufficiently severe to compromise the infant's ability to regulate movements or autonomic function, feed, or to interact with caregivers.

For infants with prenatal exposure to opioids, our center uses a predetermined criteria for opioid therapy based on an abstinence scoring system (form 1). Opioid-containing medications such as morphine and methadone are first-line pharmacotherapies for opioid exposures. (See "Neonatal abstinence syndrome", section on 'Pharmacologic therapy'.)

For infants with prenatal exposure to barbiturates or benzodiazepines without other substances, phenobarbital is the preferred first-line drug. The long half-life (40 hours) makes this medication difficult to titrate and wean in the infant, and results in less frequent dosing than opioids. Furthermore, there are concerns about phenobarbital effects on longer-term child development, therefore this medication should be used judiciously.

For infants with NAS who are exposed to multiple substances, including opioids and barbiturates or benzodiazepines, opioid therapy remains the preferred initial treatment. Some infants whose signs remain severe on a maximum dose of opioid improve with a second drug (eg, clonidine or phenobarbital). (See "Neonatal abstinence syndrome", section on 'Addition of second agent, if necessary'.)

Breastfeeding — Breast milk and breastfeeding have a large potential benefit, particularly for infants and their mother/caregivers affected by substance use disorder, and should be encouraged where possible. However, because all substances are excreted into breast milk, guidelines have been developed that promote safe breastfeeding practices for infants of mother/caregivers with substance use disorder.

Although, it is known that many substances are excreted into breast milk, resulting in negative effects on nursing infants, data are limited for specific drugs regarding their concentration within breast milk and their effects on the infant [41,42]:

Amphetamine – Found in breast milk at concentrations 2.8 to 7.5 times maternal plasma [43,44].

Cocaine – Variability in cocaine levels in breast milk with high concentrations possible [45]. Neonatal intoxication from breastfeeding has been reported [46].

Opioids – Neonatal toxicity (central nervous depression), including neonatal deaths, has been reported due to opioid exposure in breast milk due to maternal opioid use (eg, oxycodone and methadone) [47-50].

Based on available data, breastfeeding should be encouraged for people enrolled in a supervised methadone maintenance program and who meet certain criteria [51]. Postpartum people who are on a stable methadone regimen should be encouraged to do so regardless of maternal methadone dose, as concentrations of methadone in breast milk are low and unrelated to maternal dose [52]. People maintained on buprenorphine may also be encouraged to breastfeed, as concentrations of buprenorphine and metabolites in breast milk are low [53]. (See "Neonatal abstinence syndrome", section on 'Feeding'.)

Cannabis – Although delta-9-tetrahydrocannabinol (THC) is the main psychoactive compound in cannabis, there are over 450 components in cannabis smoke, many of which are toxic. THC is transferred into breast milk at low concentrations, with infants ingesting a mean of 2.5 percent of the parental dose, with estimates of daily infant dose of 8 mcg/kg per day [54] and a concentration of 9.5 ng/mL [55]. In one study, THC was detected in breast milk up to six days after last maternal use [55]. However, another study that included non-abstinent and abstinent mothers based on plasma testing, reported that detectable THC was present in breast milk for all subjects and for up to six weeks after delivery, making recommendations for people to pump and dump breast milk until THC is undetectable unrealistic [56]. Breastfeeding from chronic THC users has been reported to be associated with delayed motor development at one year of age [57]. Other reported infant effects include sedation, low tone, and poor sucking [58].

Phencyclidine – In one case report, high concentrations of phencyclidine were noted in breast milk [59].

Alcohol – The amount of alcohol in breastmilk is approximately 5 to 6 percent of the weight-adjusted parental dose and is similar to maternal blood levels [60]. Newborns metabolize alcohol at approximately half the rate of adults [61]. Breastfeeding from alcohol-consuming parents appears to decrease neonatal milk intake, and alters neonatal sleep-wake cycles [62-64]. Parental alcohol consumption during lactation has been associated with later negative effects on child development, specifically reduced abstract reasoning at six to seven years, in a dose-dependent manner [65].

Guidelines for breastfeeding — The mother/caregiver's decision to breastfeed does not necessarily reflect abstinence from drugs of substance use disorder [66]. Unfortunately, there have been legal decisions that have implicated ingestion of breast milk from a mother with substance use disorder as a cause of neonatal death without supporting scientific data [67]. As a result, guidelines have been developed focused on promoting safe breastfeeding for infants of people with substance use disorder.

People with substance use disorder who meet all of the following criteria should be supported in their decision to breastfeed their infants [51]:

People engaged in substance use disorder treatment who have provided their consent to discuss progress in treatment and plans for postpartum treatment with a substance use disorder treatment counselor, and the counselor endorses that the mother has been able to achieve and maintain sobriety prenatally.

People who plan to continue in substance use disorder treatment in the postpartum period.

People who have been abstinent from illicit substances for 90 days prior to delivery and have demonstrated the ability to maintain sobriety in an outpatient setting.

People who have a negative maternal urine toxicology testing at delivery except for prescribed medications.

People who received adequate prenatal care.

People who do not have a valid medical contraindication to breastfeeding (eg, HIV infection).

People who are not taking a medication that is contraindicated during lactation. Methadone and buprenorphine maintenance are not contraindications to breastfeeding in most stable women without other contraindications for breastfeeding.

People with substance use disorder under the following circumstances should be carefully evaluated, and a recommendation for suitability or lack of suitability for breastfeeding is determined by coordinated care planning among perinatal providers and substance use disorder treatment providers:

People relapsing to illicit substance use or licit substance misuse in the 90- to 30-day period prior to delivery, but who maintained abstinence within the 30 days prior to delivery.

People with concomitant use of other prescription (eg, psychotropic agents) medications.

People who engaged in prenatal care and/or substance use disorder treatment during or after the second trimester.

People who attained sobriety only in an inpatient setting.

Contraindications — People with substance use disorder under the following circumstances should be discouraged from breastfeeding (see "Breastfeeding: Parental education and support", section on 'Contraindications to breastfeeding'):

People who did not receive prenatal care.

People who relapsed into illicit substance use or licit substance misuse in the 30-day period prior to delivery, including cannabis.

People who are not willing to engage in substance use disorder treatment, or who are engaged in treatment but are not willing to provide consent for contact with the counselor.

People with positive maternal urine toxicology testing for illicit substances or misuse of licit substance at deliver.

People who do not have confirmed plans for postpartum substance use disorder treatment or pediatric care.

People who demonstrate behavioral qualities or other indicators of active substance use.

Postdischarge care — Postdischarge care includes:

Continued support for the mother/caregiver, including a treatment program for substance use disorder that will accept the infant and provide medication for opioid use disorder if warranted, psychiatric care when needed, and postpartum obstetric care including contraceptive care if desired by the mother/caregiver.

Safe housing and case management for the mother/caregiver and infant.

Pediatric care for the infant is provided by a knowledgeable provider. This pediatric care is instituted prior to hospital discharge and accessible by the mother in the event that the infant is difficult to care for or develops any signs of late onset of withdrawal or illness. This pediatric care should include frequent appointments and developmental assessment to identify, and if needed, to manage, any ongoing neurodevelopmental concerns for the child.

CLINICAL CONSEQUENCES FOR INFANT AND FETUS

Overview — When considering clinical sequelae or the infant related to in utero substance exposures, it should be noted that it is difficult to determine the relative contribution of prenatal substance exposure versus the effects of maternal and neonatal comorbidities [68].

Reported consequences for offspring exposed to prenatal substance use include the following:

Substance withdrawal or neurobehavioral dysregulation that presents after birth

Increased risk of congenital malformations with specific substances, low birth weight (BW) for gestational age (GA) due to fetal restriction, prematurity, prenatally acquired infections, and complications of delivery

Long-term adverse effects on child development

Psychosocial comorbidities — People with substance use during pregnancy often have other stresses (eg, trauma/violence exposure, poor prenatal care, poverty) or illnesses (eg, psychiatric comorbidities, infections) during pregnancy or after delivery that may negatively impact their infant. These factors may contribute to the observed increased risk for child maltreatment associated with in-utero substance-exposed infants compared with non-substance exposed peers [69-71]. As a result, additional support is frequently required from medical providers and community-based services to help parents and families care for their child while coping with ongoing comorbidities. However, intervention and referral should occur in the absence of pejorative/punitive attitudes.

Effects of specific substances — The effects of specific substances are discussed in the following sections.

Nicotine — Although tobacco use is not considered a substance use disorder in pregnancy, the negative neonatal impact of prenatal maternal cigarette smoking is well established and is discussed separately. (See "Cigarette and tobacco products in pregnancy: Impact on pregnancy and the neonate", section on 'Adverse outcomes'.)

Alcohol: Fetal alcohol spectrum disorder — Alcohol freely crosses the placenta and is known to be teratogenic. Infants whose mothers consume alcohol during pregnancy can have chronic nonreversible sequelae. Fetal alcohol syndrome (FAS) and fetal alcohol spectrum disorder (FASD) are terms used to describe the range of effects, including lifelong consequences, that can occur in an individual who was prenatally exposed to alcohol.

The clinical manifestations, diagnosis, and management of FASD are discussed separately. (See "Fetal alcohol spectrum disorder: Clinical features and diagnosis" and "Fetal alcohol spectrum disorder: Management and prognosis".)

Opioids — The term "opioid" refers to natural and synthetic substances with morphine-like activity. Opioid exposure in utero can predispose the infant to withdrawal after delivery.

The clinical manifestations, diagnosis, and management of NAS are discussed separately. (See "Neonatal abstinence syndrome".)

Cocaine — Cocaine use during pregnancy has been associated with adverse effects on the offspring:

During pregnancy and at delivery, complications include spontaneous abortion, fetal demise, placental abruption, prematurity, and fetal growth restriction [72]. Data from large prospective case-controlled studies have shown that prematurity and fetal growth restriction were more likely to occur in exposed infants, but there was no teratogenic effect of cocaine despite previous case reports of genitourinary and cardiac abnormalities [37,73-75]. (See "Substance use during pregnancy: Overview of selected drugs", section on 'Cocaine'.)

Newborn infants with prenatal cocaine exposure may exhibit neurobehavioral abnormalities [37,76] which are most commonly noted between 48 and 72 hours of life [25,77]. In a prospective case-control study, infants known to be exposed only to cocaine compared with control infants were more likely to have central and autonomic neurologic symptoms, including tremors, high-pitched cry, irritability, excess suck, hyperalertness, and episodes of either apnea or tachypnea [37]. There appeared to be a dose-response relationship with increased exposure resulting in increased neonatal hyperactivity and inability to orient to the environment [78,79]. Other studies have reported that cocaine-exposed infants within the first week of life have an increased rate of abnormal auditory brainstem responses and transient abnormal electroencephalographic changes (EEG) compared with nonexposed infants [80,81]. Prenatal cocaine exposure is associated with structural deficits in the infant brain [82], which has been associated with functional connectivity and neurobehavioral disruptions [83,84].

Long-term effects – It has been difficult to ascertain whether there are direct long-term effects of prenatal cocaine on neurobehavioral development. The research in this area has been hampered by the difficulty in controlling confounding variables (such as postnatal psychosocial factors and prenatal exposure to other substances) and in accounting for the indirect effect of cocaine on biological variables (such as prematurity and fetal growth restriction):

A 2009 systemic literature review for studies that evaluated the effects of prenatal cocaine exposure in children greater than six years of age reported that after controlling for confounding variables, prenatal cocaine exposure was associated with impairments in sustained attention and behavioral self-regulation among school-aged children [85].

Subsequent studies have also demonstrated that cocaine exposure affects short and long term neurodevelopment during infancy through adolescence:

-As noted above, neonatal neurobehavioral findings include irritability, jitteriness, tremors, and hypertonia; and at one month of age, affected infants have poorer arousal and behavioral regulation and higher excitability [86].

-In older children, several studies have reported subtle language and cognitive delays, increased symptoms of attention deficit hyperactivity disorder (ADHD), poor auditory attention skills, and reduced short-term verbal memory [87-89].

-In adolescents, prenatal cocaine exposure has been reported to result in poor perceptual organization, visuospatial information processing, attention, executive function, and behavioral organization; and language delays [90,91].

Cannabis — There is increasing evidence that perinatal cannabis use adversely impacts the neurodevelopment and growth of the developing fetus and infant, including persistent changes in higher-level cognition and psychological well-being [2,92,93]. However, data are often confounded by other factors and determining the direct effect of only cannabis is challenging [93,94]. As a result, we concur with the recommendation in the American Academy of Pediatrics Clinical Report that pregnant and breastfeeding people be advised not to use cannabis based on the available data on potential adverse effects on fetal growth and child development (see 'Breastfeeding' above) [4]. For pregnant and postpartum people who unable to stop cannabis use, referral for further intervention and treatment should be offered. (See "Substance use during pregnancy: Overview of selected drugs", section on 'Cannabis (marijuana)'.)

Neonatal outcome

Prematurity and growth

-Systematic reviews of the use of cannabis during pregnancy reported adverse neonatal effect.

In the first report, infants exposed prenatally to cannabis had a decrease in BW (mean difference in weight of 110 g for exposed versus unexposed neonates) and a higher likelihood of needing admission to a NICU [95].

In the second systematic review, an analysis that controlled for tobacco use found that infants prenatally exposed to cannabis were more likely to be preterm compared with nonexposed infants [96]. Uncontrolled analyses found that exposed infants had lower BWs and Apgar scores.

-Subsequent publications have also reported negative effects on fetal growth and increased risk of prematurity [97-101]. This was illustrated by a population-based retrospective cohort study comparing over 9000 prenatal cannabis users with nonusers that reported cannabis use was associated with twice the rate of preterm birth <37 weeks of gestation (12 versus 6 percent), and increased rates of infants with intrauterine growth restriction (IUGR), placental abruption, transfer to neonatal intensive care, and five-minute Apgar score less than 4/10 [97]. Another report found an increased rate of neonatal care unit admissions after legalization of the use of recreational cannabis but not an increased incidence of IUGR [102].

Potential teratogenic effect ‒ Although there are no data on a direct teratologic effect of prenatal cannabis exposure, indirect evidence has been reported showing an increased rate of congenital anomalies (cardiac and central nervous defects and Down syndrome) in areas with increased cannabis use during pregnancy (eg, Colorado) [103].

Neurodevelopmental outcome

Autism – A population-based study of 508,025 live births based on link data from birth registry and health administrative databases reported an increased incidence of autism for offspring of mothers who used cannabis during pregnancy compared with non-exposed children (4.00 versus 2.42 per 1000 person years [adjusted hazard ratio 1.51, 95% CI 1.17-1.96]) [104]. There was also a trend towards an increase in intellectual disability and learning disorders for exposed children, but these findings did not reach statistical significance. As noted by the authors, limitations of this observational study included reliance on the accuracy of the data based on self-reporting of use of cannabis during pregnancy and the diagnosis of autism in the offspring, as well as an exclusion rate of 25 percent. Nevertheless, these results support our approach of advising people not to use cannabis during pregnancy.

Other areas of impairment – Several studies have reported impaired neurodevelopmental outcome, particularly in areas of sustained attention, visuospatial function, hyperactivity, and problem solving [93,105-114]. It should be noted that most of these studies were performed at a time when cannabis was much less potent, and the negative effects of prenatal exposures may be more pronounced with greater potency of the drug over the last two decades [92].

Amphetamines — Amphetamines are addictive stimulants that can be misused or used as illicit drugs. The most widely used illicit forms include methylenedioxymethamphetamine (MDMA, "ecstasy") and methamphetamine ("ice," "crystal").

Reported negative effects of prenatal amphetamine exposure on the offspring include:

Prematurity and fetal growth restriction – Use of illicit amphetamines during pregnancy increased the risk of prematurity and fetal growth restriction [115-122].

Fetal and neonatal death – Prenatal exposure to amphetamines are associated with increased risk of fetal demise and neonatal and infant deaths. (See "Substance use during pregnancy: Overview of selected drugs", section on 'Amphetamines, including methamphetamine'.)

Data are insufficient to determine the effects of prenatal amphetamine exposure for the following:

Withdrawal – It is unclear whether amphetamine exposure in utero causes withdrawal in the neonate. Reports are limited by the inability to separate the effect of amphetamine alone from the effect of other substances used in utero, and by the small number of reported patients [123,124]. Reported symptoms include shrill cry, irritability, jerkiness, diaphoresis, and sneezing. In contrast, a large prospective study found no increase in neonatal withdrawal symptoms between methamphetamine-exposed neonates and matched controls [125].

Risk of congenital anomalies – It remains uncertain whether prenatal exposure to amphetamines increases the risk of congenital anomalies. In two large cohort studies, there was no increased incidence of congenital anomalies associated with mothers who used amphetamine analogs for therapeutic reasons (eg, to achieve weight loss) during pregnancy compared with mothers without amphetamine use [126,127]. However, in another cohort study, mothers who had children with a congenital malformation were more likely to have a history of using dextroamphetamine during pregnancy than those with a normal infant and the risk increased with earlier exposure to amphetamine during pregnancy [128]. This last study was limited because significant confounding variables (ie, other substance exposures, and maternal socioeconomic status) were not considered.

Neurodevelopmental outcome – The effect of prenatal amphetamines on neurodevelopmental outcome in exposed children may be confounded by other factors, including another substance exposure, socioeconomic factors, and adversity after birth [129-133]. There are numerous reports that suggest that prenatal amphetamine exposure is associated with cognitive problems, including learning and memory difficulties [129,130,134,135] and persistent motor delays [136], as well as neuroimaging findings of structural brain abnormalities, particularly in the striatum [137]. Impact may be dependent on the degree of exposure, as one prospective study, which controlled for confounding factors, reported that motor and mental impairment were only observed in infants with heavy prenatal exposure [138]. However, a longitudinal study of 339 children, including 171 individuals who were exposed prenatally to methamphetamine, did not observe any behavioral problems related to prenatal methamphetamine exposure at 3, 5, and 7.5 years of age [132]. Rather, behavioral issues were associated with caregiver psychological symptoms and the quality of the home.

Phencyclidine — Phencyclidine hydrochloride (PCP, or "angel dust") can act both as a central nervous system stimulant and depressant. There are limited data on the effect of prenatal PCP exposure on offspring.

There are conflicting reports on whether prenatal exposure increases the risk of prematurity or fetal growth restriction [139-141]. These studies are limited by the small number of patients with only PCP exposure.

Several observational studies have reported neurobehavioral abnormalities in the neonate with prenatal PCP exposure. These include hypertonicity, irritability, sleep problems, and temperature instability [141-144]. However, these studies are limited by the small number of patients and they do not consider other confounding variables (such as other substance exposure and mother's socioeconomic background).

Barbiturates — Barbiturates are used in the treatment of seizures but are also used illicitly. Prenatal barbiturate exposure is associated with both neonatal withdrawal symptoms and congenital malformations. Exposed infants are usually full term and appropriate weight for gestational age (GA). The teratogenic effect of barbiturates is discussed separately. (See "Risks associated with epilepsy during pregnancy and postpartum period", section on 'Phenobarbital'.)

The incidence of phenobarbital withdrawal is not known. If withdrawal occurs, signs present at a median age of seven days of life (range 2 to 14 days). Withdrawal has been separated into two stages [145]:

Acute stage – Irritability, constant crying, sleeplessness, tremors, hiccups, and mouthing motions.

Subacute stage – Voracious appetite, frequent regurgitation, gagging, episodic irritability, sweating, sleep disturbances, and increased sensitivity to sound. This stage may last from two to four months and is due to the slow metabolism and excretion of barbiturates by the neonate. [146].

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Basics topics (see "Patient education: Fetal alcohol syndrome (The Basics)" and "Patient education: Alcohol and drug use in pregnancy (The Basics)")

SUMMARY AND RECOMMENDATIONS

Infants of people with substance use disorder can be exposed to licit substances (alcohol, nicotine, and cannabis in some places), illicit drugs (eg, heroin, cocaine), licit drugs (eg, opioid-containing pain relievers, psychotropic medications), or medications used to treat maternal opioid use disorder (methadone, buprenorphine or buprenorphine-naloxone) or maternal psychiatric disorder (eg, serotonin receptor inhibitors). For most infants with prenatal substance exposure, polysubstance is more common than exposure to a single substance. (See 'Epidemiology' above.)

In the United States, the consent process for neonatal testing and the legal implications of a positive result vary among the states (Propublica website). The clinician needs to be aware of the local laws and changes that affect infants with prenatal substance exposure and their mothers. (See 'Legal requirements' above.)

The clinical presentation of infants with in utero substance exposure is variable and is dependent on the substance(s), timing, and amount of the last maternal use, genetic and epigenetic factors, and maternal and infant metabolism and excretion. Identification of the substances to which the fetus was exposed help in the clinical management of the substance-exposed infant. (See 'Neonatal assessment' above.)

Neonatal withdrawal occurs in infants with prenatal exposure to opioids, barbiturates, and/or alcohol. Polysubstance exposure can augment the severity of the withdrawal display. Infants undergoing withdrawal exhibit signs of neurobehavioral dysregulation, which are manifested as a high-pitched cry, irritability, sleep/wake disturbances, alterations in tone or movement, feeding difficulties, gastrointestinal and autonomic disturbances, respiratory problems, and failure to thrive. (See 'Clinical features of withdrawal in the substance-exposed infant' above.)

The diagnosis of prenatal substance exposure is based on a positive maternal screening and biologic testing, and/or clinical findings of neonatal withdrawal. (See 'Diagnosis' above.)

Provision of nonpunitive, comprehensive care for the dyad is important in the postnatal period, which is optimally provided by a multidisciplinary team that includes social services, substance use disorder treatment counselors, obstetricians, and pediatricians.

Management includes mother/caregiver assessment, as comorbidities are not uncommon in this population (eg, violence exposure, poor prenatal care, and psychiatric disorders), parental support and education, optimizing the environment for mother/caregiver-infant interaction and self-regulation, neonatal assessment and initiation of nonpharmacologic measures, and pharmacotherapy when necessary. (See 'General management approach' above.)

Prematurity, fetal growth restriction and congenital infections are associated with in utero substance exposure. In some cases, these findings are directly related to the specific substance (eg, nicotine, alcohol, and cocaine). (See "Cigarette and tobacco products in pregnancy: Impact on pregnancy and the neonate", section on 'Adverse outcomes' and "Fetal alcohol spectrum disorder: Clinical features and diagnosis" and "Fetal alcohol spectrum disorder: Management and prognosis" and 'Cocaine' above.)

Many substances of use/misuse are excreted into breast milk and if present can have negative effects on nursing infants. These include amphetamine, cocaine, heroin, cannabis, alcohol, and phencyclidine. Breastfeeding is contraindicated for people who relapsed into illicit substance use or licit substance misuse in the 30-day period prior to delivery, including cannabis. Breastfeeding is not contraindicated in stable methadone- or buprenorphine-maintained postpartum people who meet other criteria. (See 'Breastfeeding' above.)

Infants with prenatal cocaine exposure may exhibit neurobehavioral abnormalities that usually present between 48 and 72 hours of life. These include tremors, high-pitched cry, irritability, hyperalertness, and episodes of apnea or tachypnea. These symptoms appear to be due to a direct effect of cocaine rather than withdrawal. (See 'Cocaine' above.)

Other substances including cannabis, psychotropic medications, and stimulant drugs can produce signs of neurobehavioral dysregulation in the exposed infant as well as longer-term sequelae. (See 'Cannabis' above and 'Phencyclidine' above and 'Amphetamines' above.)

Infant with prenatal exposure to alcohol are at risk for poor neurodevelopmental outcome. (See "Fetal alcohol spectrum disorder: Clinical features and diagnosis", section on 'Central nervous system involvement' and "Fetal alcohol spectrum disorder: Management and prognosis", section on 'Prognosis'.)

  1. Haight SC, Ko JY, Tong VT, et al. Opioid Use Disorder Documented at Delivery Hospitalization - United States, 1999-2014. MMWR Morb Mortal Wkly Rep 2018; 67:845.
  2. Brown QL, Sarvet AL, Shmulewitz D, et al. Trends in Marijuana Use Among Pregnant and Nonpregnant Reproductive-Aged Women, 2002-2014. JAMA 2017; 317:207.
  3. Ko JY, Farr SL, Tong VT, et al. Prevalence and patterns of marijuana use among pregnant and nonpregnant women of reproductive age. Am J Obstet Gynecol 2015; 213:201.e1.
  4. Ryan SA, Ammerman SD, O'Connor ME, et al. Marijuana Use During Pregnancy and Breastfeeding: Implications for Neonatal and Childhood Outcomes. Pediatrics 2018; 142.
  5. Ebrahim SH, Gfroerer J. Pregnancy-related substance use in the United States during 1996-1998. Obstet Gynecol 2003; 101:374.
  6. Vega WA, Kolody B, Hwang J, Noble A. Prevalence and magnitude of perinatal substance exposures in California. N Engl J Med 1993; 329:850.
  7. Shor S, Nulman I, Kulaga V, Koren G. Heavy in utero ethanol exposure is associated with the use of other drugs of abuse in a high-risk population. Alcohol 2010; 44:623.
  8. Bakhireva LN, Shrestha S, Garrison L, et al. Prevalence of alcohol use in pregnant women with substance use disorder. Drug Alcohol Depend 2018; 187:305.
  9. Jansson LM, Di Pietro JA, Elko A, et al. Pregnancies exposed to methadone, methadone and other illicit substances, and poly-drugs without methadone: a comparison of fetal neurobehaviors and infant outcomes. Drug Alcohol Depend 2012; 122:213.
  10. Huybrechts KF, Bateman BT, Desai RJ, et al. Risk of neonatal drug withdrawal after intrauterine co-exposure to opioids and psychotropic medications: cohort study. BMJ 2017; 358:j3326.
  11. Committee Opinion No. 711: Opioid Use and Opioid Use Disorder in Pregnancy. Obstet Gynecol 2017; 130:e81.
  12. Krans EE, Campopiano M, Cleveland LM, et al. National Partnership for Maternal Safety: Consensus Bundle on Obstetric Care for Women With Opioid Use Disorder. Obstet Gynecol 2019; 134:365.
  13. Pierog S, Chandavasu O, Wexler I. Withdrawal symptoms in infants with the fetal alcohol syndrome. J Pediatr 1977; 90:630.
  14. Robe LB, Gromisch DS, Iosub S. Symptoms of neonatal ethanol withdrawal. Curr Alcohol 1981; 8:485.
  15. Wikner BN, Stiller CO, Bergman U, et al. Use of benzodiazepines and benzodiazepine receptor agonists during pregnancy: neonatal outcome and congenital malformations. Pharmacoepidemiol Drug Saf 2007; 16:1203.
  16. Iqbal MM, Sobhan T, Ryals T. Effects of commonly used benzodiazepines on the fetus, the neonate, and the nursing infant. Psychiatr Serv 2002; 53:39.
  17. Pichini S, Garcia-Algar O. In utero exposure to smoking and newborn neurobehavior: how to assess neonatal withdrawal syndrome? Ther Drug Monit 2006; 28:288.
  18. Gentile S. On categorizing gestational, birth, and neonatal complications following late pregnancy exposure to antidepressants: the prenatal antidepressant exposure syndrome. CNS Spectr 2010; 15:167.
  19. Sinclair L. Antipsychotic labels to cite risks to newborns. Psychiatric News 2011; 46:12. http://psychnews.psychiatryonline.org/newsarticle.aspx?articleid=108442 (Accessed on April 08, 2013).
  20. Mayes LC, Carroll KM. Neonatal withdrawal syndrome in infants exposed to cocaine and methadone. Subst Use Misuse 1996; 31:241.
  21. Choo RE, Huestis MA, Schroeder JR, et al. Neonatal abstinence syndrome in methadone-exposed infants is altered by level of prenatal tobacco exposure. Drug Alcohol Depend 2004; 75:253.
  22. Wachman EM, Newby PK, Vreeland J, et al. The relationship between maternal opioid agonists and psychiatric medications on length of hospitalization for neonatal abstinence syndrome. J Addict Med 2011; 5:293.
  23. Jansson LM, Velez M. Neonatal abstinence syndrome. Curr Opin Pediatr 2012; 24:252.
  24. Wachman EM, Hayes MJ, Brown MS, et al. Association of OPRM1 and COMT single-nucleotide polymorphisms with hospital length of stay and treatment of neonatal abstinence syndrome. JAMA 2013; 309:1821.
  25. Hudak ML, Tan RC, COMMITTEE ON DRUGS, et al. Neonatal drug withdrawal. Pediatrics 2012; 129:e540.
  26. Bio LL, Siu A, Poon CY. Update on the pharmacologic management of neonatal abstinence syndrome. J Perinatol 2011; 31:692.
  27. Marijuana Drug Test Detection Times. www.canorml.org/healthfacts/drugtestguide/drugtestdetection.html (Accessed on February 17, 2016).
  28. Ostrea EM Jr, Brady MJ, Parks PM, et al. Drug screening of meconium in infants of drug-dependent mothers: an alternative to urine testing. J Pediatr 1989; 115:474.
  29. Ostrea EM Jr, Knapp DK, Tannenbaum L, et al. Estimates of illicit drug use during pregnancy by maternal interview, hair analysis, and meconium analysis. J Pediatr 2001; 138:344.
  30. Kyle AR, Carmical J, Shah D, et al. UHPLC-MS/MS quantification of buprenorphine, norbuprenorphine, methadone, and glucuronide conjugates in umbilical cord plasma. Biomed Chromatogr 2015; 29:1567.
  31. https://cff-cav56vrdcl.netdna-ssl.com/wp-content/uploads/2020/05/Judicial_Officers_POSC_Brief-1.pdf (Accessed on July 28, 2021).
  32. Abrahams RR, Kelly SA, Payne S, et al. Rooming-in compared with standard care for newborns of mothers using methadone or heroin. Can Fam Physician 2007; 53:1722.
  33. Jansson LM, Velez ML, Butz AM. The Effect of Sexual Abuse and Prenatal Substance Use on Successful Breastfeeding. J Obstet Gynecol Neonatal Nurs 2017; 46:480.
  34. Velez M, Jansson LM. The Opioid dependent mother and newborn dyad: non-pharmacologic care. J Addict Med 2008; 2:113.
  35. Armstrong MA, Gonzales Osejo V, Lieberman L, et al. Perinatal substance abuse intervention in obstetric clinics decreases adverse neonatal outcomes. J Perinatol 2003; 23:3.
  36. McGlade A, Ware R, Crawford M. Child protection outcomes for infants of substance-using mothers: a matched-cohort study. Pediatrics 2009; 124:285.
  37. Bauer CR, Langer JC, Shankaran S, et al. Acute neonatal effects of cocaine exposure during pregnancy. Arch Pediatr Adolesc Med 2005; 159:824.
  38. Yazdy MM, Mitchell AA, Tinker SC, et al. Periconceptional use of opioids and the risk of neural tube defects. Obstet Gynecol 2013; 122:838.
  39. Broussard CS, Rasmussen SA, Reefhuis J, et al. Maternal treatment with opioid analgesics and risk for birth defects. Am J Obstet Gynecol 2011; 204:314.e1.
  40. Lind JN, Interrante JD, Ailes EC, et al. Maternal Use of Opioids During Pregnancy and Congenital Malformations: A Systematic Review. Pediatrics 2017; 139.
  41. American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108:776.
  42. Sachs HC, Committee On Drugs. The transfer of drugs and therapeutics into human breast milk: An update on selected topics. Pediatrics 2013; 132:e796.
  43. Bartu A, Dusci LJ, Ilett KF. Transfer of methylamphetamine and amphetamine into breast milk following recreational use of methylamphetamine. Br J Clin Pharmacol 2009; 67:455.
  44. American College of Obstetricians and Gynecologists Committee on Health Care for Underserved Women. Committee Opinion No. 479: Methamphetamine abuse in women of reproductive age. Obstet Gynecol 2011; 117:751. Reaffirmed 2017.
  45. Winecker RE, Goldberger BA, Tebbett IR, et al. Detection of cocaine and its metabolites in breast milk. J Forensic Sci 2001; 46:1221.
  46. Chasnoff IJ, Lewis DE, Squires L. Cocaine intoxication in a breast-fed infant. Pediatrics 1987; 80:836.
  47. Hendrickson RG, McKeown NJ. Is maternal opioid use hazardous to breast-fed infants? Clin Toxicol (Phila) 2012; 50:1.
  48. Lam J, Kelly L, Ciszkowski C, et al. Central nervous system depression of neonates breastfed by mothers receiving oxycodone for postpartum analgesia. J Pediatr 2012; 160:33.
  49. West PL, McKeown NJ, Hendrickson RG. Methadone overdose in a breast-feeding toddler. Abstracts of the 2009 North American Congress of Toxicology Annual Meeting. Sept 21 to 26, 2009, San Antonio, TX.
  50. Madadi P, Kelly LE, Ross CJ, et al. Forensic Investigation of Methadone Concentrations in Deceased Breastfed Infants. J Forensic Sci 2016; 61:576.
  51. Academy of Breastfeeding Medicine Protocol Committee, Jansson LM. ABM clinical protocol #21: Guidelines for breastfeeding and the drug-dependent woman. Breastfeed Med 2009; 4:225.
  52. Jansson LM, Choo R, Velez ML, et al. Methadone maintenance and breastfeeding in the neonatal period. Pediatrics 2008; 121:106.
  53. Jansson LM, Spencer N, McConnell K, et al. Maternal Buprenorphine Maintenance and Lactation. J Hum Lact 2016; 32:675.
  54. Baker T, Datta P, Rewers-Felkins K, et al. Transfer of Inhaled Cannabis Into Human Breast Milk. Obstet Gynecol 2018; 131:783.
  55. Bertrand KA, Hanan NJ, Honerkamp-Smith G, et al. Marijuana Use by Breastfeeding Mothers and Cannabinoid Concentrations in Breast Milk. Pediatrics 2018; 142.
  56. Wymore EM, Palmer C, Wang GS, et al. Persistence of Δ-9-Tetrahydrocannabinol in Human Breast Milk. JAMA Pediatr 2021; 175:632.
  57. Astley SJ, Little RE. Maternal marijuana use during lactation and infant development at one year. Neurotoxicol Teratol 1990; 12:161.
  58. Liston J. Breastfeeding and the use of recreational drugs--alcohol, caffeine, nicotine and marijuana. Breastfeed Rev 1998; 6:27.
  59. Kaufman KR, Petrucha RA, Pitts FN Jr, Weekes ME. PCP in amniotic fluid and breast milk: case report. J Clin Psychiatry 1983; 44:269.
  60. Mennella JA, Beauchamp GK. The transfer of alcohol to human milk. Effects on flavor and the infant's behavior. N Engl J Med 1991; 325:981.
  61. Idänpään-Heikkilä J, Jouppila P, Akerblom HK, et al. Elimination and metabolic effects of ethanol in mother, fetus, and newborn infant. Am J Obstet Gynecol 1972; 112:387.
  62. Giglia R, Binns C. Alcohol and lactation: A systematic review. Nutrition & Dietetics 2006; 63:103.
  63. Mennella J. Alcohol's effect on lactation. http://pubs.niaaa.nih.gov/publications/arh25-3/230-234.htm (Accessed on April 08, 2013).
  64. Mennella JA, Gerrish CJ. Effects of exposure to alcohol in mother's milk on infant sleep. Pediatrics 1998; 101:E2.
  65. Gibson L, Porter M. Drinking or Smoking While Breastfeeding and Later Cognition in Children. Pediatrics 2018; 142.
  66. Frank DA, Bauchner H, Zuckerman BS, Fried L. Cocaine and marijuana use during pregnancy by women intending and not intending to breast-feed. J Am Diet Assoc 1992; 92:215.
  67. Ariagno R, Karch SB, Middleberg R, et al. Methamphetamine ingestion by a breast-feeding mother and her infant's death: People v Henderson. JAMA 1995; 274:215.
  68. Bada HS, Das A, Bauer CR, et al. Low birth weight and preterm births: etiologic fraction attributable to prenatal drug exposure. J Perinatol 2005; 25:631.
  69. Deutsch SA, Donahue J, Parker T, et al. Factors Associated with Child-Welfare Involvement among Prenatally Substance-Exposed Infants. J Pediatr 2020; 222:35.
  70. Puls HT, Anderst JD, Bettenhausen JL, et al. Newborn Risk Factors for Subsequent Physical Abuse Hospitalizations. Pediatrics 2019; 143.
  71. Uebel H, Wright IM, Burns L, et al. Reasons for Rehospitalization in Children Who Had Neonatal Abstinence Syndrome. Pediatrics 2015; 136:e811.
  72. Cain MA, Bornick P, Whiteman V. The maternal, fetal, and neonatal effects of cocaine exposure in pregnancy. Clin Obstet Gynecol 2013; 56:124.
  73. Behnke M, Eyler FD, Garvan CW, Wobie K. The search for congenital malformations in newborns with fetal cocaine exposure. Pediatrics 2001; 107:E74.
  74. Battin M, Albersheim S, Newman D. Congenital genitourinary tract abnormalities following cocaine exposure in utero. Am J Perinatol 1995; 12:425.
  75. Lipshultz SE, Frassica JJ, Orav EJ. Cardiovascular abnormalities in infants prenatally exposed to cocaine. J Pediatr 1991; 118:44.
  76. Eyler FD, Behnke M, Garvan CW, et al. Newborn evaluations of toxicity and withdrawal related to prenatal cocaine exposure. Neurotoxicol Teratol 2001; 23:399.
  77. Chasnoff IJ, Bussey ME, Savich R, Stack CM. Perinatal cerebral infarction and maternal cocaine use. J Pediatr 1986; 108:456.
  78. Eyler FD, Behnke M, Conlon M, et al. Birth outcome from a prospective, matched study of prenatal crack/cocaine use: II. Interactive and dose effects on neurobehavioral assessment. Pediatrics 1998; 101:237.
  79. Chiriboga CA, Brust JC, Bateman D, Hauser WA. Dose-response effect of fetal cocaine exposure on newborn neurologic function. Pediatrics 1999; 103:79.
  80. Tan-Laxa MA, Sison-Switala C, Rintelman W, Ostrea EM Jr. Abnormal auditory brainstem response among infants with prenatal cocaine exposure. Pediatrics 2004; 113:357.
  81. Doberczak TM, Shanzer S, Senie RT, Kandall SR. Neonatal neurologic and electroencephalographic effects of intrauterine cocaine exposure. J Pediatr 1988; 113:354.
  82. Grewen K, Burchinal M, Vachet C, et al. Prenatal cocaine effects on brain structure in early infancy. Neuroimage 2014; 101:114.
  83. Salzwedel AP, Grewen KM, Vachet C, et al. Prenatal drug exposure affects neonatal brain functional connectivity. J Neurosci 2015; 35:5860.
  84. Salzwedel AP, Grewen KM, Goldman BD, Gao W. Thalamocortical functional connectivity and behavioral disruptions in neonates with prenatal cocaine exposure. Neurotoxicol Teratol 2016; 56:16.
  85. Ackerman JP, Riggins T, Black MM. A review of the effects of prenatal cocaine exposure among school-aged children. Pediatrics 2010; 125:554.
  86. Conradt E, Sheinkopf SJ, Lester BM, et al. Prenatal substance exposure: neurobiologic organization at 1 month. J Pediatr 2013; 163:989.
  87. Bandstra ES, Morrow CE, Mansoor E, Accornero VH. Prenatal drug exposure: infant and toddler outcomes. J Addict Dis 2010; 29:245.
  88. Lambert BL, Bauer CR. Developmental and behavioral consequences of prenatal cocaine exposure: a review. J Perinatol 2012; 32:819.
  89. Beeghly M, Rose-Jacobs R, Martin BM, et al. Level of intrauterine cocaine exposure and neuropsychological test scores in preadolescence: subtle effects on auditory attention and narrative memory. Neurotoxicol Teratol 2014; 45:1.
  90. Singer LT, Minnes S, Min MO, et al. Prenatal cocaine exposure and child outcomes: a conference report based on a prospective study from Cleveland. Hum Psychopharmacol 2015; 30:285.
  91. Landi N, Avery T, Crowley MJ, et al. Prenatal Cocaine Exposure Impacts Language and Reading Into Late Adolescence: Behavioral and ERP Evidence. Dev Neuropsychol 2017; 42:369.
  92. ElSohly MA, Mehmedic Z, Foster S, et al. Changes in Cannabis Potency Over the Last 2 Decades (1995-2014): Analysis of Current Data in the United States. Biol Psychiatry 2016; 79:613.
  93. Grant KS, Petroff R, Isoherranen N, et al. Cannabis use during pregnancy: Pharmacokinetics and effects on child development. Pharmacol Ther 2018; 182:133.
  94. Jaques SC, Kingsbury A, Henshcke P, et al. Cannabis, the pregnant woman and her child: weeding out the myths. J Perinatol 2014; 34:417.
  95. Gunn JK, Rosales CB, Center KE, et al. Prenatal exposure to cannabis and maternal and child health outcomes: a systematic review and meta-analysis. BMJ Open 2016; 6:e009986.
  96. Conner SN, Bedell V, Lipsey K, et al. Maternal Marijuana Use and Adverse Neonatal Outcomes: A Systematic Review and Meta-analysis. Obstet Gynecol 2016; 128:713.
  97. Corsi DJ, Walsh L, Weiss D, et al. Association Between Self-reported Prenatal Cannabis Use and Maternal, Perinatal, and Neonatal Outcomes. JAMA 2019; 322:145.
  98. Crume TL, Juhl AL, Brooks-Russell A, et al. Cannabis Use During the Perinatal Period in a State With Legalized Recreational and Medical Marijuana: The Association Between Maternal Characteristics, Breastfeeding Patterns, and Neonatal Outcomes. J Pediatr 2018; 197:90.
  99. Metz TD, Allshouse AA, Hogue CJ, et al. Maternal marijuana use, adverse pregnancy outcomes, and neonatal morbidity. Am J Obstet Gynecol 2017; 217:478.e1.
  100. Kharbanda EO, Vazquez-Benitez G, Kunin-Batson A, et al. Birth and early developmental screening outcomes associated with cannabis exposure during pregnancy. J Perinatol 2020; 40:473.
  101. Bailey BA, Wood DL, Shah D. Impact of pregnancy marijuana use on birth outcomes: results from two matched population-based cohorts. J Perinatol 2020; 40:1477.
  102. Lockwood J, Moss A, Beck A, et al. The association between the legalization of recreational marijuana and both small for gestational age births and NICU admissions in Colorado. J Perinatol 2019; 39:1165.
  103. Reece AS, Hulse GK. Cannabis Teratology Explains Current Patterns of Coloradan Congenital Defects: The Contribution of Increased Cannabinoid Exposure to Rising Teratological Trends. Clin Pediatr (Phila) 2019; 58:1085.
  104. Corsi DJ, Donelle J, Sucha E, et al. Maternal cannabis use in pregnancy and child neurodevelopmental outcomes. Nat Med 2020; 26:1536.
  105. Fried PA, Watkinson B, Gray R. Differential effects on cognitive functioning in 9- to 12-year olds prenatally exposed to cigarettes and marihuana. Neurotoxicol Teratol 1998; 20:293.
  106. Fried PA, Watkinson B, Gray R. Differential effects on cognitive functioning in 13- to 16-year-olds prenatally exposed to cigarettes and marihuana. Neurotoxicol Teratol 2003; 25:427.
  107. Fried PA, Watkinson B. Differential effects on facets of attention in adolescents prenatally exposed to cigarettes and marihuana. Neurotoxicol Teratol 2001; 23:421.
  108. Fried PA, Watkinson B, Siegel LS. Reading and language in 9- to 12-year olds prenatally exposed to cigarettes and marijuana. Neurotoxicol Teratol 1997; 19:171.
  109. Huizink AC, Mulder EJ. Maternal smoking, drinking or cannabis use during pregnancy and neurobehavioral and cognitive functioning in human offspring. Neurosci Biobehav Rev 2006; 30:24.
  110. Leech SL, Richardson GA, Goldschmidt L, Day NL. Prenatal substance exposure: effects on attention and impulsivity of 6-year-olds. Neurotoxicol Teratol 1999; 21:109.
  111. Day NL, Leech SL, Goldschmidt L. The effects of prenatal marijuana exposure on delinquent behaviors are mediated by measures of neurocognitive functioning. Neurotoxicol Teratol 2011; 33:129.
  112. Leech SL, Larkby CA, Day R, Day NL. Predictors and correlates of high levels of depression and anxiety symptoms among children at age 10. J Am Acad Child Adolesc Psychiatry 2006; 45:223.
  113. Huizink AC. Prenatal cannabis exposure and infant outcomes: overview of studies. Prog Neuropsychopharmacol Biol Psychiatry 2014; 52:45.
  114. Paul SE, Hatoum AS, Fine JD, et al. Associations Between Prenatal Cannabis Exposure and Childhood Outcomes: Results From the ABCD Study. JAMA Psychiatry 2021; 78:64.
  115. Smith L, Yonekura ML, Wallace T, et al. Effects of prenatal methamphetamine exposure on fetal growth and drug withdrawal symptoms in infants born at term. J Dev Behav Pediatr 2003; 24:17.
  116. Hansen RL, Struthers JM, Gospe SM Jr. Visual evoked potentials and visual processing in stimulant drug-exposed infants. Dev Med Child Neurol 1993; 35:798.
  117. Oei JL, Kingsbury A, Dhawan A, et al. Amphetamines, the pregnant woman and her children: a review. J Perinatol 2012; 32:737.
  118. Smith LM, LaGasse LL, Derauf C, et al. The infant development, environment, and lifestyle study: effects of prenatal methamphetamine exposure, polydrug exposure, and poverty on intrauterine growth. Pediatrics 2006; 118:1149.
  119. Wright TE, Schuetter R, Tellei J, Sauvage L. Methamphetamines and pregnancy outcomes. J Addict Med 2015; 9:111.
  120. Nguyen D, Smith LM, Lagasse LL, et al. Intrauterine growth of infants exposed to prenatal methamphetamine: results from the infant development, environment, and lifestyle study. J Pediatr 2010; 157:337.
  121. Arria AM, Derauf C, Lagasse LL, et al. Methamphetamine and other substance use during pregnancy: preliminary estimates from the Infant Development, Environment, and Lifestyle (IDEAL) study. Matern Child Health J 2006; 10:293.
  122. Kalaitzopoulos DR, Chatzistergiou K, Amylidi AL, et al. Effect of Methamphetamine Hydrochloride on Pregnancy Outcome: A Systematic Review and Meta-analysis. J Addict Med 2018; 12:220.
  123. Eriksson M, Larsson G, Winbladh B, Zetterström R. The influence of amphetamine addiction on pregnancy and the newborn infant. Acta Paediatr Scand 1978; 67:95.
  124. Ramer CM. The case history of an infant born to an amphetamine-addicted mother. Clin Pediatr (Phila) 1974; 13:596.
  125. Kiblawi ZN, Smith LM, Diaz SD, et al. Prenatal methamphetamine exposure and neonatal and infant neurobehavioral outcome: results from the IDEAL study. Subst Abus 2014; 35:68.
  126. Heinonen OP. Birth Defects and Drugs in Pregnancy, Publishing Sciences Group, Inc, Littleton, MA 1977.
  127. Milkovich L, van der Berg BJ. Effects of antenatal exposure to anorectic drugs. Am J Obstet Gynecol 1977; 129:637.
  128. Nelson MM, Forfar JO. Associations between drugs administered during pregnancy and congenital abnormalities of the fetus. Br Med J 1971; 1:523.
  129. LaGasse LL, Derauf C, Smith LM, et al. Prenatal methamphetamine exposure and childhood behavior problems at 3 and 5 years of age. Pediatrics 2012; 129:681.
  130. Kiblawi ZN, Smith LM, LaGasse LL, et al. The effect of prenatal methamphetamine exposure on attention as assessed by continuous performance tests: results from the Infant Development, Environment, and Lifestyle study. J Dev Behav Pediatr 2013; 34:31.
  131. Eze N, Smith LM, LaGasse LL, et al. School-Aged Outcomes following Prenatal Methamphetamine Exposure: 7.5-Year Follow-Up from the Infant Development, Environment, and Lifestyle Study. J Pediatr 2016; 170:34.
  132. Chu EK, Smith LM, Derauf C, et al. Behavior Problems During Early Childhood in Children With Prenatal Methamphetamine Exposure. Pediatrics 2020; 146.
  133. Sankaran D, Lakshminrusimha S, Manja V. Methamphetamine: burden, mechanism and impact on pregnancy, the fetus, and newborn. J Perinatol 2022; 42:293.
  134. National Toxicology Program. NTP-CERHR monograph on the potential human reproductive and developmental effects of amphetamines. NTP CERHR MON 2005; :vii.
  135. Kwiatkowski MA, Donald KA, Stein DJ, et al. Cognitive outcomes in prenatal methamphetamine exposed children aged six to seven years. Compr Psychiatry 2018; 80:24.
  136. Singer LT, Moore DG, Min MO, et al. Motor delays in MDMA (ecstasy) exposed infants persist to 2 years. Neurotoxicol Teratol 2016; 54:22.
  137. Roussotte F, Soderberg L, Sowell E. Structural, metabolic, and functional brain abnormalities as a result of prenatal exposure to drugs of abuse: evidence from neuroimaging. Neuropsychol Rev 2010; 20:376.
  138. Singer LT, Moore DG, Min MO, et al. One-year outcomes of prenatal exposure to MDMA and other recreational drugs. Pediatrics 2012; 130:407.
  139. Tabor BL, Smith-Wallace T, Yonekura ML. Perinatal outcome associated with PCP versus cocaine use. Am J Drug Alcohol Abuse 1990; 16:337.
  140. Rahbar F, Fomufod A, White D, Westney LS. Impact of intrauterine exposure to phencyclidine (PCP) and cocaine on neonates. J Natl Med Assoc 1993; 85:349.
  141. Mvula MM, Miller JM Jr, Ragan FA. Relationship of phencyclidine and pregnancy outcome. J Reprod Med 1999; 44:1021.
  142. Chasnoff IJ, Burns WJ, Hatcher RP, Burns KA. Phencyclidine: effects on the fetus and neonate. Dev Pharmacol Ther 1983; 6:404.
  143. Golden NL, Kuhnert BR, Sokol RJ, et al. Neonatal manifestations of maternal phencyclidine exposure. J Perinat Med 1987; 15:185.
  144. Wachsman L, Schuetz S, Chan LS, Wingert WA. What happens to babies exposed to phencyclidine (PCP) in utero? Am J Drug Alcohol Abuse 1989; 15:31.
  145. Desmond MM, Schwanecke RP, Wilson GS, et al. Maternal barbiturate utilization and neonatal withdrawal symptomatology. J Pediatr 1972; 80:190.
  146. Finnegan LP, Mitros TF, Hopkins LE. Management of neonatal narcotic abstinence utilizing a phenobarbital loading dose method. NIDA Res Monogr 1979; 27:247.
Topic 5010 Version 51.0

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