Marijuana and Maternal, Perinatal, and Neonatal Outcomes

Etiology

Delta-9-tetrahydrocannabinol (THC) is the main psychoactive chemical in marijuana. THC is lipid-soluble and hence easily distributed to the brain and fat. THC readily crosses the placenta and can reach high fetal concentrations on repeated exposures.[1] It has also been shown to be present in breast milk making the fetus and newborn at risk of exposure.[2][3][4]

The chemical structure of THC is similar to endogenous cannabinoids that affect the areas of the brain influencing pleasure and memory. Cannabinoids exert their neurological effects through cannabinoid receptor type 1 (CB1) which plays an important role in the development of a fetal brain, its neurotransmitter systems, and neuronal migration and differentiation. Animal studies have shown that fetal exposure to exogenous cannabinoids can affect normal brain development.[5] Marijuana smoking results in a significantly increased respiratory burden of carbon monoxide and increased blood carboxyhemoglobin levels, much higher than smoking tobacco.[6][7]

The two most studied cannabinoids are tetrahydrocannabinolic acid and cannabidiolic acid. In the body, these are decarboxylated to their active analogs, THC, and cannabidiol (CBD). CB1 and CB2 are both G protein-coupled receptors. Agonists at CB1 receptors cause decreased neuronal signaling across the synapse where the receptors are activated. THC increases acetylcholine release in the hippocampus; dopamine in the nucleus accumbens; and acetylcholine, glutamate, and dopamine in the prefrontal cortex. CBD acts as an inverse agonist at CB1 receptors.

There is little research on the effects of the currently available strengths of cannabis products or on administration routes other than smoking.

Epidemiology

About 2% to 5% of pregnant women self-report the use of marijuana during pregnancy.[8] These rates are as high as 14 to 28% among low-income urban women.[9] In a survey conducted by the Pregnancy Risk Assessment Monitoring System (PRAMS), 9.4% of women in Vermont reported using marijuana during their pregnancy. Additionally, several studies have reported that more than half of marijuana users continue its use during pregnancy.[10] Use is greatest in women 20 to 24 years. 17% of pregnant nonusers and 65% of pregnant marijuana users felt there were no health risks with marijuana.[11]

The prevalence of marijuana use during pregnancy is increasing likely due to easy availability secondary to legalization, perceived safety, and potential benefit for nausea during pregnancy.[12] The use of marijuana is also associated with high rates of other substance use disorders. This puts a mother and her fetus at risk of multiple exposures.

Pathophysiology

Human studies on marijuana have been limited by the fact it is a Schedule 1 narcotic. Most studies are retrospective or observational, limited by small sample size and confounding polysubstance use. THC has been shown to cause structural brain changes in humans, specifically of the nucleus accumbens is reported. The effect of THC on human trophoblastic tissues suggests that THC alters both cytotrophoblast and syncytiotrophoblast cellular remodeling and may inhibit normal placental growth and development.[13] This is thought to relate to the greater odds of miscarriage or stillbirth of those who smoke marijuana as compared with nonusers.

Several studies have noticed an increased risk of spontaneous preterm birth with marijuana use during pregnancy.[14][15] In utero marijuana, exposure has been associated with a significant decrease in birth weight according to some studies while others report no difference when accounting for other maternal drug use.[16][17]

Maternal cannabis use showed no association with decreased infant Apgar scores at 1 and 5 minutes, resuscitation, respiratory distress syndrome, intubation following delivery, jaundice, sepsis, and hypoglycemia.[16] There is an increased risk for neonatal intensive care admissions but no increased risk of fetal anomalies or chromosomal abnormalities.[18]

History and Physical

Every prenatal visit should be an opportunity to evaluate for drug use. Marijuana users are likely to use other drugs of abuse and are likely to have a history of psychiatric disorders like anxiety and depression. For every pregnant woman identified as using marijuana, history should be focused on substance use and mental health disorders along with social and environmental stressors.[19]

Clinical findings depend on the phase of drug use. A patient can have euphoria, anxiety, dry mouth, and tachycardia during the acute intoxication phase, while depression, decreased appetite, restlessness, and irritability are likely during the withdrawal phase. Signs of drug dependency and sleep disturbances may also be seen.

In neonates, marijuana exposure is not linked to any dysmorphic features. Neonates with in utero exposure to marijuana are likely to have low birth weight. Smaller head circumference may be seen, especially if there is co-exposure with tobacco. Marijuana exposure does not cause any withdrawal signs in neonates. But, since these infants are at extremely high risk of multiple drug exposures, the clinical examination findings can be consistent with withdrawal from other drugs such as nicotine or opioids. Prenatal marijuana use will display altered responses to visual stimuli, a high-pitched cry, and increased trembling.

Evaluation

The American Academy of Pediatrics (AAP), American College of Obstetricians and Gynecologists (ACOG), and the American Society for Addiction Medicine recommend that all pregnant women be screened for drug use, including marijuana. Universal screening for substance use disorder should be accomplished with a validated questionnaire. Women, once identified with drug use, should be counseled further and referred for treatment. ACOG advises against recommending medical marijuana during preconception, pregnancy, and lactation.

Patient self-report and laboratory testing are used to assess maternal marijuana use. Urine testing is the most commonly used laboratory test and can be used for both recent and chronic use. In addition, cord blood or meconium testing can detect THC exposure from the second trimester onwards.

There are legal ramifications of positive drug testing. Every effort should be made to obtain informed consent from a patient before the testing. Health care providers must report to child protective services for newborns exposed to illicit substances, including marijuana, to concern child abuse and neglect. However, individual state requirements may vary widely, and hence all health care providers should be aware of their state’s legal requirements for reporting.

There are clear long-term effects of neonatal exposure. 

Treatment / Management

U.S Food and Drug Administration (USFDA) has not approved any medication for the treatment of marijuana use. Pregnant women identified using marijuana should be referred for psychological counseling, detoxification, and psychiatric services. The goal is the eventual cessation of any drug use. Neonates exposed to marijuana should be evaluated for exposure to other drugs and managed accordingly. Marijuana and tobacco exposure routinely does not need medical treatment. Simultaneous exposure to drugs such as opioids may require a prolonged hospital stay and neonatal opioid withdrawal syndrome management.[20] Due to THC exposure's long-term effects, these children should be carefully monitored for age-appropriate developmental milestones and referred for early intervention services if any deficits are observed.

Differential Diagnosis

Clinical findings of drug use and drug dependency can be similar to several psychiatric illnesses like generalized anxiety disorder, panic attacks, and depression. Besides, signs and symptoms of marijuana use overlap with those of several other drugs like amphetamines and benzodiazepines. This makes it challenging to identify drugs of abuse without a thorough medical and psychiatric history, as well as toxicology screens.

Prognosis

Marijuana and Maternal Health

Pregnant marijuana users are more likely to be underweight, have lower educational and socioeconomic status, and use other drugs like alcohol. There are some reports that marijuana use is associated with depression and anxiety. Women using marijuana during pregnancy have a higher risk of anemia and spontaneous preterm birth.[16][14] Exposure to THC can enhance placental permeability, increase placental resistance and reduce placental circulation. However, no association has been found between marijuana use and some other pregnancy-related complications such as gestational diabetes, gestational hypertension, antepartum or postpartum hemorrhage, and placental abruption.[14][18]

Similar to tobacco smoking, marijuana smoke also contains respiratory and carcinogenic toxins. Concomitant use of marijuana and tobacco, as compared to tobacco alone, is linked to an increased risk of maternal asthma and preeclampsia.[21]

Marijuana and Breastfeeding

Breastfeeding has numerous benefits for the infant and the mother and should be the ideal choice for infant nutrition. It helps to improve mother-child bonding, which is especially important in mothers using drugs. However, breastfeeding by a drug-using mother puts the infant at risk of drug exposure, which can outweigh the benefits of breastfeeding.

Moderate amounts of THC are excreted in human breast milk.[2] An infant can ingest about 0.8% of the weight-adjusted maternal dose in a single feeding.[4] Infants exposed to THC through breast milk can have sedative effects, poor sucking as well as delayed growth. However, these newborns are also exposed to THC during pregnancy. This makes it difficult to identify if the effects seen in newborns are from fetal or neonatal exposure. Besides, marijuana is often combined with tobacco, and as a result, the effects can be a result of co-exposure.

Since an infant’s first few months are an important phase for brain growth, the biological properties of THC can affect the proper development of the brain. As a result, despite a lack of clear and convincing data, groups like ACOG, AAP, and the Academy of Breastfeeding Medicine recommend against the use of marijuana while breastfeeding. These mothers use should be encouraged to breastfeed but strongly recommended to abstain from its use.[10]

Childhood and Adolescence

School-aged children often show gaps in problem-solving skills and memory. They may have increased depressive and anxiety symptoms and decreased attention span.[22] In adolescence, there is an increased risk of delinquency and an increased likelihood of early age of onset of marijuana use.[23]

Complications

Stillbirth/Abortion Risk

One population-based study found increased THC use among women with stillbirth, but another study by Warshak et al. did not find any association.[18] At this time, there is insufficient evidence to link THC with the risk of stillbirth or abortion.[24]

Fetal Growth

Fetal exposure to THC is associated with decreased birth weight but not birth length or head circumference. The decrease in birth weight ranges from 84 g to 109 g.[16][25][26] The decrease in birth weight is likely due to fetal growth restriction due to fetal hypoxia from increased carbon monoxide and carboxyhemoglobin levels in the blood.[5][15][27] Marijuana and tobacco, if used together, have been linked to a decrease in birth weight and head circumference.[21]

Congenital Malformation

Few studies have examined the correlation between THC exposure and congenital disabilities. These studies suggest that maternal marijuana use during pregnancy is associated with an increased risk of anencephaly, esophageal atresia, diaphragmatic hernia, gastroschisis, and ventricular septal defect.[28][29] Conversely, Warshak et al. reported no association between marijuana exposure and fetal anomalies.[18]

Neonatal Outcomes

Some studies have identified an association between maternal THC use and a decrease in gestational age.[16][30] However, this has not been a consistent finding.[26][28] Fetal exposure to THC has been linked to an increased likelihood of admission to neonatal intensive care unit (NICU) and an increasing trend towards prolonged neonatal hospitalization. No significant association has been found between maternal THC use and other neonatal outcomes like jaundice, respiratory distress syndrome, APGAR scores, hypoglycemia, and sepsis.

Childhood Outcomes

Effects of perinatal THC exposure start getting noticeable as early as four years of age. Young children are likely to show lower scores on verbal reasoning and memory tasks, poor language comprehension, visual and perceptual functions. These effects are found to be dose-dependent. Deficits are seen in impulse control, problem-solving, attention span, and analytical skills among older-age children. Lower global achievement, reading, spelling and, math scores are also seen in this age group.