Substance use during pregnancy: Overview of selected drugs

INTRODUCTION — 

Use and misuse of substances by pregnant individuals occurs globally. Identification of substance use allows for interventions aimed at reducing maternal and fetal risk by reducing or discontinuing substance use and initiating treatment when indicated. Challenges to care of people who use substances during pregnancy include a lack of screening tools that function across cultures and languages, barriers to patient disclosure of substance use, and limited treatment and risk reduction resources that have strong supporting evidence.

This topic will explore the impact of selected substances on pregnancy. Screening for substance use and laboratory testing are discussed separately.

●(See "Substance use during pregnancy: Screening and prenatal care".)

●(See "Urine drug testing".)

Related content specific to alcohol and opioid use in pregnancy are presented elsewhere.

●(See "Alcohol intake and pregnancy".)

●(See "Fetal alcohol spectrum disorder: Clinical features and diagnosis".)

●(See "Opioid use disorder: Overview of treatment during pregnancy".)

●(See "Neonatal abstinence syndrome (NAS): Management and outcome".)

In this topic, when discussing study results, we will use the terms "woman/en" or "patient(s)" as they are used in the studies presented. We encourage the reader to consider the specific counseling and treatment needs of transmasculine and gender-expansive individuals.

CHALLENGES IN ASSESSING DRUG IMPACT — 

A dose-dependent effect of any illicit or misused substance on pregnancy outcome is difficult to ascertain because data are scarce and confounded by the influence of other factors, including use of other substances, poor nutrition, poverty and related adverse stressors, comorbidities, inadequate prenatal care, and environmental factors, such as the COVID-19 pandemic, which saw an increase in overdose deaths in pregnant persons [1]. In addition, reliable ascertainment of the extent of substance use during pregnancy and drug dose/purity are very difficult.

The clinical manifestations of substance use disorders are diverse and differ by drug and setting (eg, usual dose, overdose, withdrawal). Combined with the physiologic changes of pregnancy and the clinical manifestations of coexisting pregnancy-related disease, diagnosis of patients presenting with serious clinical abnormalities can be challenging. For example, cocaine and amphetamine overdose can cause hypertension and seizures, similar to preeclampsia/eclampsia.

OPIOIDS — 

An online patient-oriented infographic is available to help with screening and counseling for opioid use disorder in pregnancy.

Prevalence — While opioid use is a global problem, opioid use by pregnant individuals living in the United States is an ongoing public health crisis.

●A US cohort study of nearly 22,000 pregnancies occurring between 1990 and 2021 reported an overall opioid exposure rate of 2.8 percent [2].

●By 2017, the estimated rate of maternal opioid-related diagnoses (MOD) had increased by nearly 5 per 1000 delivery hospitalizations compared with 2010, from 3.5 (95% CI 3.0-4.1) to 8.2 (95% CI 7.7-8.7) [3]. Analysis of discharge records from 47 states and the District of Columbia found MOD rates ranged from 1.7 (Nebraska) to 47.3 (Vermont) per 1000 delivery hospitalizations.

●Dispensing of prescription opioids to pregnant individuals decreased in the United States from 2000 to 2020. Rates of opioid prescribing and dispensing continue to be higher in publicly insured pregnant individuals (rate of 191 in 1,000 pregnancies) as compared with those who are privately insured (rate of 88 in 1,000 pregnancies) [4].

While some countries reported decreasing prevalence of opioid use during similar time periods, prevalence rates varied by income groups and did not drop for individuals in the lowest quintile of area-level income [5]. At least one study has reported higher opioid prescriptions for individuals also prescribed psychotropic medications compared with those who were not (26.5 versus 10.7 percent) [6]. (See "Opioid use disorder: Epidemiology, clinical features, health consequences, screening, and assessment".)

Complications from use — Multiple obstetric complications have been associated with opioid use disorder in pregnancy [7-9]. However, it is difficult to establish the extent to which these problems are due to opioids, opioid withdrawal, or other drugs used versus coexistent maternal medical, nutritional, psychological, and socioeconomic issues. For example, one study reported the increase in maternal cardiac events from 2002 to 2014 paralleled the rise in opioid use among pregnant persons in the United States, which raised questions about possible causality [10].

Pregnancy-associated complications include:

●Abruptio placentae

●Fetal death

●Intraamniotic infection

●Fetal growth restriction

●Fetal passage of meconium

●Preeclampsia

●Premature labor and birth

●Premature rupture of membranes

●Placental insufficiency

●Miscarriage

●Postpartum hemorrhage

●Septic thrombophlebitis

Unrelated to pregnancy, opioid use disorders are associated with risks, including financial, social, and psychological issues, that cause psychosocial stress, exposure to violence [11], and limit treatment and other life options [12].

Medication for opioid use disorder — The American College of Obstetricians and Gynecologists and the American Society of Addiction Medicine recommend treatment of opioid use disorder in pregnancy with medications rather than medically managed withdrawal or detoxification [13].

●Medication preferred to ongoing substance use – For pregnant patients with opioid use disorder, medication treatment with methadone or buprenorphine offers overwhelming advantages (eg, oral administration, known dose and purity, safe and steady availability, improved maternal/fetal/neonatal outcomes) compared with continued use of heroin or other illicit opioids.

●Options of buprenorphine or methadone – Both buprenorphine and methadone have proven efficacy in treating pregnant patients with opioid use disorder; neither is clearly superior as each has benefits and drawbacks (table 1). Advantages of buprenorphine include less severe neonatal opioid withdrawal syndrome and somewhat lower risk of congenital malformations (approximately 1 fewer malformation per 100 neonates) in children born to individuals treated with buprenorphine compared with methadone [14,15]. Methadone has been used in pregnant patients significantly longer than buprenorphine. Historically, buprenorphine monotherapy has been preferred over the buprenorphine/naloxone combination during pregnancy. However, a large population-based cohort study in the United States from 2000 to 2018 found combination treatment to be a safe option with equal if not more favorable neonatal and maternal outcomes [16]. The safety and efficacy of long-acting injectable buprenorphine during pregnancy has not been established. Naltrexone, a third US Food and Drug Administration (FDA)-approved medication for opioid use disorder, may be safe for continuation during pregnancy, although more data are necessary to make this determination [17]. Naltrexone is not currently recommended for initiation during pregnancy.

Regardless of which medication is chosen to treat opioid use disorder, treatment with medical therapy presents a unique opportunity to bring women into medical and obstetric care systems. Clinical use of methadone and buprenorphine in pregnant patients, as well as fetal/neonatal effects, are discussed in detail separately.

●(See "Opioid use disorder: Overview of treatment during pregnancy".)

●(See "Opioid use disorder: Pharmacotherapy with methadone and buprenorphine during pregnancy".)

●(See "Neonatal abstinence syndrome (NAS): Clinical features and diagnosis", section on 'NAS due to opioids'.)

●(See "Neonatal abstinence syndrome (NAS): Management and outcome".)

CANNABIS (MARIJUANA) — 

Cannabis and pregnancy is presented in detail separately. (See "Cannabis use and pregnancy".)

COCAINE

Use — Although data suggest that cocaine and other stimulant use is increasing globally [18,19], many more pregnant individuals smoke cigarettes, drink alcohol, or smoke cannabis than use cocaine [20-25]. (See "Cocaine use disorder: Epidemiology, clinical features, and diagnosis".)

Impact on pregnancy — Cocaine crosses the placenta and fetal blood-brain barrier; vasoconstriction is the major purported mechanism for fetal and placental damage [26]. The applicability of any of the studies on cocaine use in pregnancy is limited by methodologic shortcomings, such as failure to control for maternal age, parity, socioeconomic factors, and exposure to other drugs, alcohol, and cigarettes.

The few adequately controlled reports suggest that cocaine's effects are related to dose and stage of pregnancy. A meta-analysis including 31 studies that evaluated the relationship between maternal antenatal cocaine exposure and five adverse perinatal outcomes found cocaine use during pregnancy significantly increased the risks of [27]:

●Preterm birth (odds ratio [OR] 3.38, 95% CI 2.72-4.21)

●Low birth weight (OR 3.66, 95% CI 2.90-4.63)

●Small for gestational age infant (OR 3.23, 95% CI 2.43-4.30)

●Shorter gestational age at delivery (-1.47 weeks, 95% CI -1.97 to -0.98)

●Reduced birth weight (-492 grams, 95% CI -562 to -421 grams)

Others have reported increased risks of miscarriage, abruptio placentae, and decreased length (-0.71 cm) and head circumference (-0.43 cm) at birth [28-30]. Teratogenic effects have not been definitively proven. Cocaine enters breast milk and poses risk to the nursing infant. Cocaine use during lactation is strongly discouraged [31]. (See "Neonatal abstinence syndrome (NAS): Clinical features and diagnosis", section on 'Cocaine'.)

Cardiovascular cocaine toxicity is increased in pregnant individuals [26]. Cocaine toxicity usually causes hypertension, which may mimic preeclampsia. Beta-adrenergic antagonists (ie, beta blockers) should be avoided in the treatment of cocaine-related cardiovascular complications because they create unopposed alpha-adrenergic stimulation and are associated with coronary vasoconstriction and end-organ ischemia. This contraindication includes labetalol, which has predominantly beta-blocking effects. Hydralazine is preferred for treatment of hypertension in pregnant individuals who use cocaine [32]. Decisions regarding the administration of peripartum analgesia or anesthesia need to be individualized, taking into account factors such as the combined effects of cocaine, analgesia, and anesthesia on the patient's cardiovascular and hematologic status [33].

●(See "Cocaine: Acute intoxication".)

●(See "Cocaine use disorder: Epidemiology, clinical features, and diagnosis".)

●(See "Stimulant use disorder: Treatment overview".)

●(See "Clinical manifestations, diagnosis, and management of the cardiovascular complications of cocaine use".)

AMPHETAMINES, INCLUDING METHAMPHETAMINE

Prevalence — A diagnosis of amphetamine use disorder is becoming more common among individuals of reproductive age, including hospitalized pregnant females [19,34-36].

●A study of 2011 to 2019 California health system data reported annual adjusted prevalence rates of methamphetamine use ranged from a high of 0.24 percent in 2014 to a low of 0.17 percent in 2019 (use defined as positive self-report or positive toxicology test) [19].  

●In a study of US hospital discharge data, in 2014 to 2015, amphetamine use was identified in approximately 1 percent of deliveries in the rural West [37]. The study also reported amphetamine use was higher than opioid-use incidence for most areas (opioid use was higher in the Northeast). Deliveries complicated by amphetamine use had higher evidence of exposure to cannabis, cocaine, alcohol, and sedatives compared with control hospital deliveries. This study highlights the importance of screening pregnant individuals for multiple substances.

Impact — Methamphetamine (commonly known as speed, meth, or chalk, or as ice, crystal, or glass when smoked) is a powerfully addictive stimulant. It is a known neurotoxic agent that causes release of dopamine. Amphetamines and their byproducts cross the placenta [38]. No fetal structural abnormalities have been definitively associated with perinatal amphetamine exposure [39]. However, methamphetamine exposure during pregnancy has been associated with maternal and neonatal morbidity and mortality. In studies that controlled for confounders, methamphetamine exposure was associated with a two- to fourfold increase in risk of fetal growth restriction [40-42], gestational hypertension, preeclampsia, abruption, preterm birth, intrauterine fetal demise, neonatal death, and infant death [43]. A meta-analysis of eight studies that compared pregnancy outcomes for females using methamphetamines with control individuals also reported younger gestational age at birth, lower birth weight, smaller head circumference, shorter body length, and lower Apgar scores for exposed infants [44]. The meta-analysis did not find significant differences in the rates of preeclampsia and hypertensive disorders. Pregnant individuals who use methamphetamine are also at higher risk of syphilis and should be screened appropriately [45]. (See "Syphilis in pregnancy".)

Short-term neonatal effects and long-term outcomes in offspring, as well as methamphetamine use disorders and treatment of acute intoxication, are reviewed separately.

●(See "Neonatal abstinence syndrome (NAS): Clinical features and diagnosis", section on 'Amphetamines' and "Neonatal abstinence syndrome (NAS): Management and outcome", section on 'Other substances'.)

●(See "Methamphetamine: Acute intoxication".)

●(See "Methamphetamine use disorder: Epidemiology, clinical features, and diagnosis".)

RESOURCES

●American Society of Addiction Medicine (ASAM)

●Substance Abuse and Mental Health Services Administration (SAMHSA)

●American College of Obstetricians and Gynecologists (ACOG) offers free online Frequently Asked Questions infographics addressing opioid, cannabis, alcohol, and tobacco use in pregnancy.

●Perinatal Provider Toolkit by the Mid-America Addiction Technology Transfer Center (ATTC) Network, funded by SAMHSA

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Substance misuse in pregnancy" and "Society guideline links: Opioid use disorder and withdrawal" and "Society guideline links: Cannabis use disorder and withdrawal" and "Society guideline links: Cocaine use and cocaine use disorder".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

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

SUMMARY AND RECOMMENDATIONS

●Challenges in assessing drug impact – The effect of any illicit or misused substance on pregnancy outcome is difficult to ascertain because data are scarce and confounded by the influence of other factors, including polysubstance use (particularly alcohol and tobacco products), poor nutrition, poverty, comorbid disorders, and inadequate prenatal care. In addition, reliable ascertainment of the extent of drug use during pregnancy and drug dose/purity are very difficult. (See 'Challenges in assessing drug impact' above.)

●Opioids – Maternal opioid use disorder is associated with multiple obstetric complications, including pregnancy loss, fetal growth restriction, preeclampsia, preterm labor and birth, and fetal death. For pregnant individuals with opioid use disorder, treatment with methadone or buprenorphine should be offered; neither drug is clearly superior, but there is more experience with methadone. Medications for opioid use disorder are associated with fewer neonatal complications and side effects than medically managed withdrawal (detoxification) or continued use of nonprescribed opioids. Neonatal opioid withdrawal syndrome is typically less severe in neonates born to individuals treated with buprenorphine compared with individuals treated with methadone. Identification of opioid use and linkage to appropriate prenatal care are important for improved outcomes. (See 'Opioids' above.)

Related content on opioid use disorder in pregnancy is presented separately:

•(See "Substance use during pregnancy: Screening and prenatal care".)

•(See "Opioid use disorder: Overview of treatment during pregnancy".)

•(See "Opioid use disorder: Pharmacotherapy with methadone and buprenorphine during pregnancy".)

●Cocaine – Cocaine can cause vasoconstriction of uterine vessels, which is the probable major mechanism leading to placental abruption. Abruption can lead to spontaneous abortion, preterm labor and birth, and fetal death. Increased cardiovascular cocaine toxicity has also been reported for pregnant versus nonpregnant individuals. (See 'Cocaine' above.)

●Amphetamines – Amphetamines, including methamphetamine, cross the placenta. While no fetal structural abnormalities have been definitively associated with perinatal amphetamine exposure, methamphetamine use during pregnancy has been associated with fetal growth restriction, gestational hypertension, preeclampsia, abruption, preterm birth, intrauterine fetal demise, and neonatal and infant death [46]. (See 'Amphetamines, including methamphetamine' above.)