KEY POINTS
- 1.
In the United States an infant is born every 15 minutes who will develop symptoms of neonatal abstinence syndrome (NAS); each year, about 32,000 infants are estimated to develop NAS.
- 2.
The exposure of the developing fetus to stimulants, alcohol, cannabinoids, and antidepressant medication can all have a negative impact. To refer specifically to the impact of opioids, the term neonatal opioid withdrawal syndrome (NOWS) is preferred.
- 3.
We have summarized the information on the impact of transplacentally transferred opiates on the developing fetus. Various therapeutic options that are currently available for the management of NOWS or are under evaluation have been discussed.
- 4.
The effects of transplacentally transferred pharmacologic stimulants such as cocaine, methamphetamine, and prescription drugs; herbal stimulants such as kratom tea; alcohol; cannabinoids; and antidepressant medications have been described in separate sections.
Introduction
In the United States an infant is born with neonatal abstinence syndrome (NAS) every 15 minutes, with an estimated 32,000 babies with NAS born every year. This estimates only the infants with symptomatic withdrawal after prenatal opioid exposure. Additional use of substances during pregnancy, such as stimulants, alcohol, cannabinoids, and antidepressant medication, can all result in negatively impacting the developing fetus. Thus it is paramount to understand the mechanism of how each substance can result in exposure to the fetus and if any known therapies are effective to mitigate these changes.
Opioids
Opioids are a class of drugs that are usually used to reduce pain. This can include prescription medication, such as oxycodone, hydrocodone, fentanyl, morphine, and methadone, as well as illicit substances such as heroin. Use of these drugs by pregnant women can result in adverse outcomes such as stillbirth or preterm birth, NAS, and birth defects. From 1999 to 2014, across the United States, the rates of opioid use disorder at the time of delivery more than quadrupled. Infants exposed to opioids throughout pregnancy develop a dependence on the drug, with a resultant withdrawal once the drug is no longer present. The withdrawal was previously referred to as NAS, which is now more specifically termed neonatal opioid withdrawal syndrome (NOWS). Opioids can cross the placenta, thus resulting in exposure to the fetus. The following describes placental transport of opioids, the resultant symptoms in infants after birth, current therapeutic options, and the resultant impact on development.
Mechanism of In Utero Exposure
One puzzling aspect of neonatal opiate withdrawal is the lack of association between the maternal opiate dose during pregnancy and the incidence or severity of NOWS. A recent systematic review confirms the results of many smaller studies, namely that there is no currently known relationship between the maternal dose of methadone and the incidence or severity of NOWS. This lack of association is likely because the current thinking on the maternal–fetal–neonatal transfer and effect of opiate medications is oversimplified and does not account for the potential impact of drug metabolism and drug target variability. This drug metabolism and drug target variability is influenced by maternal and fetal genetics as well as the stage of gestation and fetal development. There have been some important efforts to understand the pathogenesis of NOWS ( Fig. 55.1 ), but we still do not have all the answers.
Many factors can affect the amount of free drug in the maternal circulation available for transplacental fetal transfer at any given time. It is known that maternal drug metabolism changes through different trimesters and that environmental factors such as maternal comedication and cigarette use can alter rates of drug metabolism and placental transport. , In addition, there is known genetic variation in opiate metabolism. The efficiency of placental metabolizing enzymes and placental opiate transport proteins such as multidrug resistant protein 1 (MDR1) and breast cancer resistance protein can dictate how much drug reaches the fetus for any specific mother-infant pair.
MDR1 is a known placental transporter for methadone. Using a single layer of placental cells in a dual perfusion model, Nanovskaya et al. showed that methadone transfer to the fetal circuit was increased by 30% by different MDR1 inhibitors. The authors concluded based on this experiment that the concentration of methadone in the fetal circulation is likely affected by the expression and activity of placental MDR1. Data from experiments in an ex vivo placental model provides evidence that buprenorphine transport across the placenta is not mediated by MDR1 but rather via passive diffusion. Buprenorphine crosses placental cells into the fetal circuit to a lesser degree than methadone, with less than 10% of initial maternal concentrations detected on the fetal side of the circuit after a 4-hour equilibration. This decreased transfer of buprenorphine is thought to be secondary to its highly lipophilic nature and significant tissue accumulation within the placenta compared with both the maternal and fetal compartments.
The fetal and neonatal blood-brain barrier also contribute to the risk of developing NOWS. On postmortem samples from gestational age 20 weeks to postmenstrual age 3 months, it was found that p-glycoprotein expression is very limited in the fetal and neonatal period compared with older infants and adults. This is important because p-glycoprotein plays a critical role in efflux of opiates from the central nervous system (CNS) back into the systemic circulation. There are currently no studies in humans to elucidate the extent of methadone or buprenorphine accumulation in the CNS.
Neonatal Opioid Withdrawal Syndrome Symptoms
Chronic in utero opiate exposure leads to activation of the fetal brain μ-opioid receptor. This leads to intracellular adaptations, including decreased adenylyl cyclase activity and decreased cyclic adenosine 3ʹ,5ʹ-cyclic monophosphate (cAMP) and release of excitatory neurotransmitters. After umbilical cord ligation at birth, there is an abrupt cessation to opiate exposure, which, as the newborn metabolizes and clears the maternal opiate, leads to an abrupt increase in adenylyl cyclase activity and downstream effects ( Fig. 55.2 ). This leads to a large increase in central sympathetic outflow, resulting in the symptoms of newborn opiate withdrawal. These symptoms include autonomic signs such as diarrhea, emesis, yawning, sneezing, and sweating. They also include CNS excitatory signs such as hyperirritability, tremors, hyperthermia, tachycardia, and poor sleep ( Fig. 55.3 ). In extreme and untreated cases of newborn opiate withdrawal, the neuroexcitatory neurotransmitter milieu of epinephrine and norepinephrine can lead to clinical seizures.
The duration of opiate withdrawal symptoms is highly variable and depends in part on which drugs were part of in utero exposure ( Table 55.1 ). NOWS as a result of methadone or buprenorphine tends to last longer than heroin or short-acting prescription drugs, but polypharmacy and multiple in utero exposures are common, and the way these modify NOWS severity and duration are poorly understood. The treatment of NOWS symptoms includes opiate replacement and slow weaning of postnatal treatment, providing the deranged CNS pathways time to reset and return to normal. Current research about optimal NOWS therapy seeks to find a balance between control of symptoms and avoiding prolonged and excessive opiate exposure.
| Onset, Duration, and Frequency of NAS | ||||
|---|---|---|---|---|
| Onset (h) | Frequency (%) | Duration (d) | ||
| Opioids | Heroin | 24–48 | 40–80 | 8–10 |
| Methadone | 48–72 | 13–94 | Up to 30+ | |
| Buprenorphine | 36–60 | 22–67 | Up to 28+ | |
| Prescription medication | 36–72 | 5–20 | 10–30 | |
| Kratom tea (high dose) | 6–33 | Unknown | 5–12+ | |
| Stimulants | Methamphetamine | 24 | 2–49 | 7–10 |
| Cocaine | 48–72 | 6 | Up to 7 | |
| Depressants | THC | 24–72 | Unknown | 7–30 |
| Alcohol | 3–12 | 2–5 | Up to 3 | |
| SSRIs | Prescription medication | 24–48 | 20–30 | 2–6 |
Treatment of Neonatal Opioid Withdrawal Syndrome
Nonpharmacologic Treatments
The most optimum treatment of NOWS is still a matter of debate. However, most clinicians agree on the need for adopting one standardized protocol and following this with close follow-up to optimize it for the particular clinical unit and the local patient population ( Fig. 55.4 ). There is universal agreement that nonpharmacologic treatments should be implemented prior to use of medications to alleviate NOWS. A simple yet critically important first step is to maintain the mother-infant dyad if possible. Many infants are moved to a newborn intensive care unit, which will then separate the pair. A meta-analysis of 6 studies and 549 patients showed a decrease in hospitalization by 10 days when rooming-in, or maintaining the mother-infant dyad, occurred. These infants had a reduction in the use of pharmacotherapy by 63%. Additional environmental measures such as minimizing stimulation through dim lighting and optimizing comfort through swaddling should be considered standard treatment for this patient population. Observing the infant’s response to environmental stimuli is critical to determine the best interventions to minimize overstimulation. Various signs of stress in the infant can be used to identify a stimulus as stressful, such as hiccups, color change (mottling, perioral cyanosis), excess gas, and even changes in breathing patterns.
If a woman is prescribed methadone or buprenorphine, the levels measured in breast milk have been observed to be low. This does not seem to be impacted by the maternal dose, and thus breastfeeding is considered safe. It has also been observed that breastfeeding can result in a shorter hospital stay and decreased need for pharmacologic treatment. Breastfeeding should be encouraged, although a recent review found that many women on opioid maintenance therapy did not breastfeed. There is discussion that it may be related to schedule demands on the woman; however, societal stigma may result in a lack of patient support, even in hospitals with the Baby-Friendly designation.
Mechanism of Action for Pharmacologic Treatments
Opiates are the mainstay of pharmacologic therapy for NOWS, although other nonopiate drugs such as clonidine show great promise as either monotherapy or adjunct therapy. Pharmacologic therapy is indicated for infants who fail nonpharmacologic interventions and display significant and persistent signs of opiate withdrawal, as quantified by a validated NOWS scoring tool.
Morphine and Methadone
Morphine and methadone are the most commonly used opiate to treat NOWS, but there are increasing data about buprenorphine as a primary modality. Morphine is a short-acting μ-opiate receptor agonist. Because of the short half-life of morphine, the best outcomes have been demonstrated when morphine doses are given no longer than 4 hours apart (generally with feedings). Methadone is a long-acting μ-opiate receptor agonist. The longer half-life of methadone provides less of a flux between peak and trough levels while also providing ease of administration at less frequent intervals. However, the long half-life necessitates waiting 48 to 72 hours to see the full effect of dosing changes; thus there is concern that it is less “easily titratable” than short-acting morphine.
Multiple studies have evaluated the differences in treating with morphine or methadone in an attempt to determine superiority. One such meta-analysis reviewed five studies and found no significant difference in opioid treatment days, length of hospital stay, and duration of treatment between morphine or methadone.
Buprenorphine
Buprenorphine is emerging as a safer and more efficient drug for adult detoxification and maintenance programs and has been studied during pregnancy as an alternative to methadone. Overall, it is showing great promise as a therapeutic agent for the treatment of NAS. Buprenorphine is a long-acting partial μ-opioid receptor agonist. At the molecular level, there are three well-described opioid receptors (μ-opioid receptor, δ-opioid receptor, and κ-opioid receptor). Morphine and methadone are among the opioids that act as agonists at each of these receptors, but buprenorphine differs because it has an antagonistic effect at the κ-opioid receptor. This molecular characteristic is thought to allow for less sedation and less respiratory depression among buprenorphine users.
The effect on neonates of the maternal use of buprenorphine during pregnancy has been well studied. A double-blind, double-dummy, flexible dosing, randomized controlled trial found that infants exposed to prenatal buprenorphine versus methadone had required significantly less morphine therapy (mean dose, 1.1 mg versus 10.4 mg; P < .0091), had a significantly shorter hospital stay (10.0 days versus 17.5 days; P < .0091), and had a significantly shorter duration of treatment for NAS (4.1 days versus 9.9 days; P < .003125) with no difference in neonatal or maternal adverse outcomes. A recent retrospective study showed similar results with less use of phenobarbital as adjunct therapy in infants exposed to buprenorphine prenatally. The first published use of buprenorphine for the treatment of NAS dates back to 2008 when Kraft and colleagues randomized 13 infants to receive sublingual buprenorphine (initial dose of 13.2 mcg/kg/day divided in three doses) and compared them to the same number of infants who were managed with their standard-of-care oral opium solution. There were no adverse effects noted in the buprenorphine-treated group. The mean length of treatment and the overall mean length of hospital stay were shorter in this group as well (mean length of treatment of 22 days compared with 32 days and overall mean length of hospital stay of 38 days compared with 27 days).
Additional studies have compared buprenorphine with other commonly used drugs in the treatment of NAS. A single-site, randomized, open-label trial was published in 2011 and compared buprenorphine at a dose of 15.9 mcg/kg/day given in three divided doses to morphine at a dose of 0.4 mg/kg/day in six divided doses. There were 12 infants in each arm, and again the results were in favor of treatment with buprenorphine. Infants had a 40% reduction in length of treatment (23 days versus 38 days) and a 24% reduction in length of hospital stay (32 days versus 42 days). Similar findings were seen among 126 infants in a single-site, double-blind, double-dummy clinical trial (BBORN), with infants randomly assigned in a 1:1 ratio to either receive sublingual buprenorphine or oral morphine and the corresponding placebo. Buprenorphine doses ranged from 15.9 mcg/kg/day to a maximum of 60 mcg/kg/day in three divided doses, and morphine sulfate ranged from 0.4 mg/kg/day to 1.0 mg/kg/day in six divided doses. The median duration of treatment was significantly shorter with buprenorphine than with morphine (15 days versus 28 days), as was the median length of hospital stay (21 days versus 33 days; P < .001 for both comparisons). Adjunctive phenobarbital was administered in 5 of 33 infants (15%) in the buprenorphine group and in 7 of 30 infants (23%) in the morphine group ( P = .36). Rates of adverse events were similar in the two groups. Extensive analyses of blood samples obtained from these infants have allowed extrapolation of a pharmacokinetic model for both buprenorphine and norbuprenorphine and identification of a novel relationship in the pharmacokinetics and pharmacodynamics of buprenorphine administration in NAS, thus paving the way to work toward optimization of buprenorphine dosing in future clinical trials.
Of note, buprenorphine use has also been compared with methadone therapy in a multicenter, retrospective cohort analysis in southwest Ohio where 38 infants treated with buprenorphine were compared with 163 treated with methadone after intrauterine exposure to short-acting opioids or buprenorphine. Buprenorphine therapy was associated with a significantly shorter course of opioid treatment (9.4 days versus 14.0 days) and a significantly decreased hospital stay (16.3 days versus 20.7 days) compared with methadone therapy. No difference was detected in the use of adjunct therapy (23.7% versus 25.8%) between treatment groups. The initiation dose of buprenorphine was 13.2 mcg/kg in three divided doses. At the time of this publication, an industry-sponsored phase 2, multicenter, double-blind, double dummy, randomized, two-arm parallel study is underway to evaluate the efficacy, safety, and pharmacokinetics of buprenorphine in babies with NAS.
Adjunctive Therapies
Phenobarbital and clonidine are also used in the treatment of withdrawal. Phenobarbital is no longer considered a first-line option for treatment for withdrawal due to higher incidence of seizures and need for longer treatment duration. As a gamma-aminobutyric acid (GABA) receptor agonist, phenobarbital has sedative effects, making some feel it is of benefit if infants have also been exposed to benzodiazepines. Clonidine is an α 2 -adrenergic receptor agonist and thus can impact the heart rate. A retrospective review found a decrease in heart rate in infants receiving clonidine and a mild increase in blood pressure once clonidine was discontinued that did not seem clinically significant. A review of three clinical trials and five observational studies concluded that clonidine did have effectiveness in both monotherapy and combinational therapy with minimal side effects. A study of 190 infants treated from 2005 to 2015 compared outcomes when using phenobarbital versus clonidine as adjunctive therapy to morphine. The length of morphine therapy and the length of stay was significantly decreased using clonidine compared with phenobarbital. Thus there may be a continued role for the use of phenobarbital and particularly for clonidine as adjunctive treatment in infants undergoing withdrawal.
A recent abstract in the Cochrane review library summarized the findings of all randomized controlled trials comparing different modes of pharmacologic therapy ( Table 55.2 ). Most practicing neonatologists would agree that more than which opiate agonist is chosen as primary therapy, having an evidence-based and agreed upon protocol for diagnosis and management of infants with NOWS is the most important tool for optimizing therapy.
| Studies on Diagnosis & Treatment of NAS | ||||||
|---|---|---|---|---|---|---|
| First Author, Year | Study Design | No. | Intervention | Comparator | Outcomes | Conclusions |
| Brown, 2015 | Prospective, randomized | n = 78 | Methadone | Morphine | Duration of treatment of NAS | Methadone resulted in shorter treatment compared with morphine |
| Bada, 2015 | Prospective, randomized | n = 31 | Morphine | Clonidine | Neurobehavioral performance | Clonidine may be a more favorable alternative to morphine for NAS treatment |
| Nayeri, 2015 | Randomized, open-label | n = 60 | Oral morphine sulfate | Phenobarbital | Duration of treatment Duration of hospital stay Requirement of adjunctive treatment | No significant difference between treatments |
| Raith, 2015 | Prospective, randomized | n = 28 | Acupuncture with pharmacologic treatment | Pharmacologic treatment alone | Duration of treatment | Acupuncture with pharmacologic treatment reduced duration of morphine treatment |
| Surran, 2013 | Prospective, nonblinded, block randomized | n = 68 | Clonidine | Phenobarbital | Duration of treatment | Clonidine resulted in shorter therapy time compared with phenobarbital |
| Kaft, 2010 | Randomized, open-label, active-control | n = 24 | Sublingual buprenorphine | Morphine | Safety Duration of treatment Duration of hospital stay | Sublingual buprenorphine was safer and more effective compared with morphine |
| Agthe, 2009 | Randomized, controlled, double blind | n = 80 | Clonidine | Placebo | Safety Duration of treatment Effectiveness | Clonidine reduced the duration of pharmacotherapy without causing short-term adverse cardiovascular outcomes |
| Kaft, 2008 | Randomized, open-label, active-control | n = 13 | Sublingual buprenorphine | Neonatal opium solution | Safety Duration of treatment | Sublingual buprenorphine was determined safe to treat NAS |
Long-Term Impact of Neonatal Opioid Withdrawal Syndrome
There remains a paucity of data in the neurodevelopmental outcomes of children following in utero opioid exposure with resultant withdrawal syndrome. However, studies are following these patients as they age with resultant outcomes. In Finland, buprenorphine is the most commonly used opiate, with 60% of infants exposed late in the pregnancy developing NOWS. One study followed this cohort until age 3 years and found that 11% had eye disorders, 5% had major congenital anomalies, and there was an increased incidence of dental caries and poor cognitive abilities. Lind and colleagues noted an increased incidence of congenital malformations such as oral clefts, ventricular septal defects and arterial septal defects, spina bifida, and congenital talipes equinovarus. Isolated cleft palate and isolated cleft lip were noted to have a higher prevalence in infants with NOWS compared with the general live population. Continued research is needed on neurodevelopmental outcomes of this high-risk population following in utero exposure to opiates.
Stimulants
According to reports from the U.S. Department of Health and Human Services report from 2015, stimulants, including cocaine, methamphetamines, and prescription stimulants, are the second most widely used and abused substances in the United States. The use of stimulants among pregnant women, particularly methamphetamine, has increased over time, an alarming trend as evidence mounts that these agents may negatively impact both maternal and fetal health. Results from the Infant Development, Environment, and Lifestyle (IDEAL) study across four clinical centers in the United States indicate that 6% of pregnant women used methamphetamine, a pattern similar to other regions of the world. Interestingly, one study found that 63% of methamphetamine-using pregnant women reported using throughout pregnancy.
Although cocaine has a short half-life (0.7–1.5 hours), its effects throughout the body are potent because it binds and blocks presynaptic monoamine reuptake transporters, resulting in the accumulation in the synaptic cleft of dopamine, serotonin, and norepinephrine, leading to enhanced and prolonged sympathetic effects. Cocaine rapidly crosses from maternal to fetal circulation and across the fetal blood-brain barrier by simple diffusion. Under normal circumstances, cocaine is rapidly metabolized by cholinesterase in the plasma and liver; however, cholinesterase is diminished in pregnant women and is even lower in the fetus, potentially resulting in increased exposure. After transfer from maternal to fetal circulation, preclinical evidence suggests that cocaine and its metabolites accumulate in the liver and brain. Mechanistically, cocaine results in acute and delayed vasoconstriction of maternal and fetal vessels, which can also result in an increased incidence of placental abruption.
Withdrawal after prenatal exposure to stimulants has not been thoroughly characterized, although a few studies have described withdrawal symptoms of stimulant-exposed neonates. In an early small retrospective study of 166 infants, with 74 infants exposed to amphetamine prenatally, exposed infants experienced increased levels of drowsiness during the first months of life, which resolved at the 1-year follow-up. Consistent with the previous study, the larger IDEAL study, which enrolled 412 patients across four centers in the United States, found that assessment within the first 5 days of life with the NICU Network Neurobehavior Scale revealed decreased arousal, increased stress, and poor quality of movement at birth. Importantly, this same study reported a dose-response of prenatal methamphetamine exposure, with increased CNS stress. Similarly, cocaine exposure has been associated with increased CNS stress, poor movement, poor visual and auditory following, hypertonicity, and drowsiness at birth. ,
Interestingly, in multiple other studies investigators employed scoring systems that were designed to evaluate NAS following opioid exposure. For example, one study found symptoms consistent with opioid withdrawal, including irritability, hyperactivity, and tremors, occurring between day of life 2 and 3. These results are consistent with a study of 104 methamphetamine-exposed or cocaine-exposed infants demonstrating altered neonatal behavioral patterns, as assessed by the Finnegan scoring system, similar to those of infants with neonatal opioid withdrawal. In a retrospective study of neonates whose mothers used methamphetamines during pregnancy, matched to unexposed controls, the incidence of methamphetamine-exposed infants with evidence of withdrawal symptoms was 49%, with 4% exhibiting severe withdrawal symptoms requiring pharmacologic intervention. Methamphetamine-exposed infants may develop jitteriness, drowsiness, and respiratory distress suggesting withdrawal; pharmacologic intervention is rarely indicated. ,
The paucity of new research aimed at characterizing neonatal abstinence after preterm stimulant exposure or avenues of pharmacologic treatment to better support these infants warrants attention from preclinical and clinical investigators.
Kratom Tea
Mitragyna speciosa, commonly called kratom, is a plant that grows in parts of Southeast Asia including Thailand, Malaysia, Indonesia, and Papua New Guinea. The plant leaves are used to make a tea, smoked, or made into a powder, and it is a widely available herbal supplement that is often advertised as a treatment for opioid withdrawal. While not classified as an opioid, it is an herbal alkaloid that has agonistic effects on μ-opioid receptors, similar in action to morphine. At the time of this publication, there are no U.S. Food and Drug Administration–approved uses for kratom and the safety profile continues to be evaluated. A recent survey of 3024 current and former users of kratom reported using the substance primarily for pain relief (48% of the respondents) and to help cut down on opioid use and/or relieve withdrawal (10% of the cases). Thus pregnant women are starting to use the herb, and reports of withdrawal symptoms in infants are beginning to be reported.
One such case was an infant born to a mother with history of opioid abuse but who had successful rehabilitation and a negative urine drug screen at hospital admission. The infant developed symptoms consistent with opioid withdrawal, including sneezing, jitteriness, irritability, a high-pitched cry, and hypertonia and required pharmacologic treatment. Another case of neonatal withdrawal following kratom exposure in utero resulted in oral morphine treatment for 2 months. There remain no diagnostic tests to screen for kratom use, and the impact on neonates and development continue to be researched.
Depressants
Alcohol
The current leading preventable cause of birth defects and intellectual and neurodevelopmental disabilities is prenatal alcohol exposure (PAE), which has led the American Academy of Pediatrics to state that no amount of alcohol is safe during pregnancy. Exposure to alcohol in utero may result in fetal alcohol spectrum disorder (FASD), which is a comprehensive term that includes PAE diagnoses, including fetal alcohol syndrome, alcohol-related birth defects, alcohol-related neurodevelopmental disorder, and neurobehavioral disorder associated with PAE. The impact of PAE was first described by Jones et al. in 1973; they reported patterns of craniofacial, limb, and cardiovascular defects in 8 children born to mothers who were chronic alcoholics. Diagnosis of fetal alcohol syndrome is now made by observing three characteristic facial features (smooth philtrum, thin vermillion border, and small palpebral fissures), growth deficits, and CNS abnormalities in the setting of maternal alcohol use. A recent study estimated the prevalence of FASD to range from 1.1% to 5.0% in the United States.
Alcohol readily crosses the placenta, which allows direct impact on the fetus during development. A review of 13 articles showed that multiple organ systems are impacted after PAE, including the brain, heart, kidneys, liver, gastrointestinal tract, and endocrine system. Aside from the facial abnormalities described above, additional abnormalities may occur including maxillary hypoplasia, cleft palate, and micrognathia. Unfortunately, PAE can also result in fetal death and is associated with sudden infant death syndrome. Cases of withdrawal in infants with alcohol exposure have been reported, with symptoms typically including irritability, tremors, seizures, abdominal distention, and opisthotonos. Additional signs of withdrawal may include a high-pitched cry, jitteriness, and a poor sleeping pattern. These symptoms may persist for up to 18 months.
Long-term impacts following PAE are better studied than other drugs used during pregnancy. A secondary analysis conducted from the Canadian component of the World Health Organization International Study on the Prevalence of FASD found individuals with FASD had impairments in perceptual reasoning, verbal comprehension, visual-motor speed and motor coordination processing speed, attention and executive function, visuospatial processing, and language, in combination with rule-breaking behavior and attention problems. Similar to preclinical models, a virtual water maze test in 10-year-old children found deficits in spatial navigation in those children heavily exposed to alcohol during pregnancy.
Cannabinoids
Cannabinoids (CBs) are a class of chemical compounds that act on CB receptors, including CB1R and CB2R. The ligands for the receptors include the endogenous CBs (endocannabinoids: anandamide; 2-arachidonoylglycerol) and the exogenous phytoCBs that are constituents of the hemp plant Cannabis sativa (lipophilic and psychoactive Δ 9 -tetrahydrocannabinol [THC]). Finally, synthetic CB analogs include WIN 55, 212-2, HU-210, and JWH-133. We have previously discussed the “double-hit hypothesis” as it relates to prenatal cannabis exposure (PCE). We contended that PCE, like a neurodevelopmental teratogen, delivers the “first hit” to the endocannabinoid signaling system (ECSS), which is composed in such a way that a second hit (i.e., postnatal stressors) will precipitate the emergence of a specific phenotype. We concluded that perturbations of the intrauterine milieu via exogenous CBs alter the fetal ECSS, predisposing the offspring to abnormalities in cognition and altered emotionality. We argued that young women who become pregnant should immediately take a “pregnant pause” from using cannabis. Here we will discuss the state of PCE during fetal and adolescent development and subsequent epigenetics alterations. We will highlight epigenetic alterations and fetal malprogramming in adults exposed to cannabis in utero and in adolescence and in subsequent generations conceived by individuals with germ cell cannabis exposure.
According to a 2018 Pew Research Center survey, 62% of Americans were in favor of legalizing cannabis compared with 31% in 2000, which reflects an increase in societal permissiveness toward cannabis and coincides with the growing perception that cannabis is safe and, therefore, believed to have no adverse effects on fetal or adolescent development. There are several reasons why cannabis use during pregnancy and cannabis use disorder are on the rise, including legalization of medical and recreational cannabis use in approximately 50% of U.S. states, selective breeding for more potent cannabis strains containing higher levels of THC and lower levels of cannabidiol (CBD), , increased amount of THC delivered in cigar-sized blunts versus joints, and attenuation of pregnancy-induced nausea and vomiting. , Additionally, substantiated childhood maltreatment ; increased cannabis use in disabled adults, the never-married, low income groups, and urbanites ; and maternal stressors such as psychopathology, healthcare access, and nutritional, social, and underrepresented group member statuses all contribute to increased use of cannabis. Cannabis is the illicit drug most commonly used by Americans aged 18 to 25 years, and from 2002 to 2017, the incidence of cannabis use during pregnancy grew at an alarming rate. Societal permissiveness toward cannabis use highlights the importance of elucidating the long‐term consequences (inter/transgenerational epigenetic alterations) of PCE on fetal and adolescent neurodevelopment and neuroplasticity, which may lead to cognitive, behavioral, emotional, and psychological consequences and a predisposition to drug abuse in adulthood and in subsequent offspring. To date, evidence regarding the effects of PCE remains inconsistent or inconclusive due to comparisons between less potent cannabis strains of yesteryear versus today, confounding genetic, environmental, and polysubstance use variables, and limited sample sizes or methodological issues. Conversely, although data connecting cannabis exposure in utero and in adolescence is far from unequivocal, enough evidence has been amassed to make tight associations between fetal and adolescent cannabis exposure and adulthood mental health abnormalities. Much consternation and no unequivocal preponderance of evidence exists demonstrating an association between PCE and transgenerational epigenetic inheritance (i.e., parent-child-grandchild transmittance of information, who were never exposed to cannabis, which affects phenotypic traits without altering the DNA sequence).
Epigenetic perturbations, induced by PCE, during critical fetal and adolescent developmental periods can lead to persistent alterations in gene expression via DNA methylation (DNA Me), remolding, and posttranslational histone modifications of the nucleosome core particle, consisting of approximately 146 base pairs of DNA wrapped around a histone octamer (2 × each core histone: H2A, H2B, H3, and H4). , Additional small RNAs (<200-nucleotide-long, noncoding, RNA-silencing molecules; microRNA, miRNA) regulate gene expression by changing chromatin structure into transcriptionally permissive euchromatin or inactive heterochromatin. DNA Me at specific gene loci is known to persist during germ cell maturation, , making these methylation loci potential candidates for inter/transgenerational and, perhaps, multigenerational inheritance of cannabis effects. Nucleosomal modification has been associated with the persistent effects of cannabinoids in the nucleus accumbens and hippocampal neurons and glioma and lymph node cells. , Histone lysine (K) Me has been shown to produce persistent alterations in gene expression. MiRNAs have been deemed important regulators of multigenerational inheritance in Caenorhabditis elegans , , and the epigenome, comprising chemical compounds that covalently bond to DNA without altering the sequence and modulate gene expression, has been shown to persist through cell division and may be inherited multigenerationally, providing the cellular bull’s eye for perinatal cannabis exposure, thereby rendering the epigenome a significant candidate for the perpetuation of abnormal neurodevelopment and neuroplasticity. Szutorisz and colleagues state that evidence suggests that the ECSS modulated via CB1R and CB2R mediates cellular functions in different tissues via epigenetic modifications via DNA Me, , histone methylation, and miRNAs, highlighting the role of the ECSS system in regulating cellular functions via epigenetic alterations, and they suggest that modulation of these mechanisms with cannabis use may have life-long neurobiological and functional impact. D’Addario et al. reviewed epigenetic regulation of the ECSS in detail. Figs. 55.5 and 55.6 show how epigenetic effects from adult cannabis exposure can influence subsequent generations of offspring via intergenerational and transgenerational inheritance. Table 55.3 is a detailed compilation of evidence of epigenetic modifications and fetal malprogramming induced by cannabinoid exposure in utero and in adolescence.
