Journal of Perinatology https://doi.org/10.1038/s41372-020-0708-z

REVIEW ARTICLE

Marijuana: the effects on , the fetus, and the newborn

Gilbert I. Martin1,2

Received: 10 February 2020 / Revised: 18 May 2020 / Accepted: 28 May 2020 © The Author(s), under exclusive licence to Springer Nature America, Inc. 2020

Abstract There is growing evidence that there is an increased use of () during the perinatal period. This review summarizes pertinent legislation (past and present) and the physiology and pathophysiology of cannabis use during pregnancy. The literature which involves issues concerning cannabis and pregnancy is expanding but at present has many gaps and unanswered questions. The effects on the newborn are significant and treatment recommendations including are presented. Also included is a description of developmental delay during the first 2 years of life in exposed to prenatal marijuana. In addition, this commentary discusses the increase use of the newer “synthetic” which have greater psychotropic activity and can cause significant harm.

1234567890();,: 1234567890();,: Introduction United States Federal Bureau of Narcotics produced litera- ture saying that marijuana was an addicting substance Throughout the world the use of marijuana for both med- which led users to narcotics addiction. It was then portrayed icinal and recreational use has increased dramatically over as a “gateway drug”. The Marijuana Tax Act of 1937 placed the past decade and especially in the last few years. Along a tax on the sale of cannabis [1]. In the 1950s marijuana was with the opioid crisis, the use of many drugs has become known as an accessory to the “beat generation”. In the commonplace. It has been difficult to design randomized 1960s there was increase use by college students and hip- controlled investigations which investigate the effects of pies as its widespread acceptance became a symbol of marijuana on the developing fetus, newborn, , and rebellion against authority. In 1970, the Controlled Sub- . However with the passage of legislation (state) we stance Act [2] repealed the Marijuana Tax Act and mar- will be able to in a relatively short period of time achieve a ijuana was listed as a Schedule I drug along with heroin, greater understanding of the effects of marijuana. Exposed LSD and ecstasy. In 1972 the National Commission on newborns can develop symptoms from Δ-9-tetra- Marijuana and Drug Abuse recommended “partial prohibi- hydrocannabinol (THC) exposure, but treatment of this tion” and “lower penalties” for possession of a small withdrawal is variable. The following material will expand amount of marijuana. our knowledge about the effects of marijuana on the fetus In 1996 the Compassionate Use Act in California (also and newborn. known as Proposition 215) was the first state to legalize marijuana for medicinal use for chronic illness [3]. The United States Supreme Court (2005) opined that the Federal Marijuana history and legislation government had the constitutional authority to prohibit marijuana for all purposes. The Court indicated that Con- Marijuana was part of a list of drugs in the United States gress and the Food and Drug Administration should resolve Pharmacopeia from 1850 to 1942. However, in 1930 the this issue. Complicating matters, many states have passed laws recognizing marijuana’s medicinal value. In 2012 California and Washington became the first states to lega- lize marijuana for recreational use. In 2014, the * Gilbert I. Martin Rohrabacher-Farr or Commerce Justice Science Amend- [email protected] ment was signed into law. This amendment does not just 1 Loma Linda’s Children’s Hospital, Loma Linda, CA, USA prevent Federal direct interference with state implementa- 2 NICU, Emanate Health Queen of the Valley Campus, 1115 South tion but it also ends Federal raids, arrests, Sunset Ave, West Covina, CA 91790, USA criminal prosecutions, and other Federal interference G. I. Martin regulations. It is clear that Federal agencies are grappling pattern that produces wide leaflets that express themselves with state conflicts. In 2016 guidelines and policies were in a light green hue. In general, the marijuana plant has produced to manage the conflict between Federal and State broad leaves, dense-type buds and a bushy appearance. Laws dealing with marijuana. As of 2019 there are five categories of state legalization descriptions. These categories are: legalized, medical and decriminalized, medical, decriminalized, and fully Illegal. Ten states have completely legalized the sale of marijuana for medical, recreational purposes. Recent polls in the United States have represented that the majority of Amer- icans now favor some form of marijuana legalization. With the increasing prevalence of cannabis use there is a decreasing perception of risk of harm from cannabis pro- Cannabis produces a variety of different compounds ducts [4]. The conflict is increased as the Federal govern- called “Cannabinoids”. These compounds include Δ 9- ment through the Controlled Substances Act does not (THC) and (CBD). THC recognize the difference between medical and recreational induces psychoactive effects. CBD is a phytocannabinoid, use of cannabis. and is made by extracting the material from the cannabis Further complicating matters is that marijuana produc- plant and then diluting it with a carrier oil like coconut or tion and its various types have created a new “cottage seed oil. CBD contains a minimal concentration of industry”. New products have been produced which con- THC and therefore is not psychotropic. Recently synthetic centrates the THC and delivery systems such as vaping and marijuana had been produced which are man made and are eating the THC (dabbing) and allows a more immediate and chemically different then cannabis. The other name for longer lasting effects on the central nervous system. There these is “fake weed” because it are over 700 cannabis strains that have been recognized as imitates the effects of marijuana. The packaging and mar- new marijuana products. Growers are experimenting with keting of these products is enticing to the public. The . Varieties of names are chosen and can chemicals present in these synthetic marijuana imitations reflect different properties of the plant (taste, color, and are often unknown and variable. The effects on the brain of smell). Growers are also experimenting with hybrid vari- synthetic cannabinoids are much stronger than regular eties which can be cultivated to vary clinical effects. New cannabis and include paranoid delusions, , severe product names of these strains include, , agitation, hallucinations, and even total memory loss. The Bedrocan, Blue Dream, Charlotte’s Web, Green Crack, and most common names for these synthetic cannabinoids are Skunk to name a few. Fiscally, marijuana economics is K2, Spice, Spike, Mr. Happy, Scooby Snax, and . It is potentially a billion dollar business. illegal to sell, possess, or distribute synthetic cannabinoids. Many states count on the revenue from taxes on mar- Possession of these products can in fact result in felony ijuana sales in determining fiscal budgets. charges. There are now issues regarding driving under the influ- ence of marijuana (drugged driving) and there are varied legal positions regarding this practice. Will criminal pro- secution for marijuana use during pregnancy deter women The from seeking prenatal care which can only have a deleter- ious effect on morbidity and mortality? The endocannabinoid system (EDS) is involved in reg- ulating and modulating movement, memory, thinking, coordination, appetite, thermoregulation, sleep, pain, plea- Cannabis classifications sure sensations, the immune system response, and sensory and time perception [5]. THC is a phytocannabinoid which Marijuana is defined as a variety of cannabis that contains is similar in structure to . Because of this more than 0.3% THC and produces psychotropic or similarity in chemical structure, THC attaches to the can- euphoric effects. There are several species of cannabis nabinoid receptors on the neurons, activates them, and the which are recognized. These include ,a final effects are those described above. This EDS is critical warm-weather species categorized by tall plants and thin to normal function. We know in children, adolescents and leaves; , a cold water species with short that THC may alter function of the hippocampus and dense plants and dark broad leaves; is a orbitofrontal cortex which deals with memory and focus. short and stalky plant, with a rugged and shaggy growth The effects of THC on the hippocampus in the newborn is Marijuana: the effects on pregnancy, the fetus, and the newborn unknown and there have been no descriptions which newborn and as a neuroprotectant for neuronal loss [14]. describe that THC prevents newborns learning how to suck The CB1 receptor when stimulated by cannabinoids induces and swallow. However, the hippocampus does contain a a reduction in GABA (Gamma-aminobutyric acid) which is large amount of C1 receptors which are functionally sig- a prevalent inhibitory transmitter in the central nervous nificant in the newborn sucking reflex [6]. These issues system [15]. deserve further investigation. THC activates these protein-coupled receptors. CB1 Another area of concern is the effect of THC on the receptors in the placenta can impair fetal growth by inhi- dopamine release system in the newborn. The interaction biting cytotrophoblastic proliferation. In addition, cannabi- between cannabinoids and dopamine are complex and evi- noids acting on the CB1 receptors influence the dence in both human and animal studies are conflicting. differentiation embryologically of neural cells from stem Acutely, THC causes an increase in dopamine release and cells in the brain [9]. Cannabinoids have a direct effect on neuronal activity. It is interesting however that long term cellular processes which potentially can influence embry- use of THC blunts the dopamine system [7]. If brain ogenesis and fetal development. These include disruption of metabolic activity is studied using functional magnetic normal angiogenesis, inducing apoptosis leading to pre- resonance imaging and positron emission tomography, it is mature cellular death, impairment, and reduced cellular noted that indirect measurement of dopamine’s effect can be migration and disruption of DNA replication [9]. In animal identified through changes in cerebral blood flow and glu- studies [13] prenatal exposure to cannabinoids evoked long- cose metabolism. These interactions need further investi- lasting functional alterations on developing cortical neu- gation especially to determine the effects on neonatal rons. Therefore fetal exposure to THC has a negative behavior and biochemistry [8]. potential for neonatal and childhood development. CB2 receptors are in the immune system and hemato- poietic cells [16]. These receptors are instrumental in pain Cannabinoids and pregnancy relief and immunologic activity. After the CB2 receptor is stimulated there are intracellular pathways which are signaling is necessary for pre-implementation activated. CB2 receptors are also found in the brain development, uterine receptivity during implantation, and expressed by microglial cells. With the advent of selective fallopian tube function which is responsible as the fertilized and increasing sensitivity in identifying CB2 receptors, egg flows into the [9, 10]. When the fertilized egg these CB2 receptors have now been identified on fetal attaches to the uterine wall (implantation) there are well- astrocytes [6]. defined processes that determine the embryological out- come. Cannabinoids can affect implantation and fallopian motility. Cannabinoids and pregnancy: pharmacokinetics

Cannabinoids and pregnancy: CB1 and CB2 The pharmacokinetics of cannabis is variable depending receptors upon the route of administration and therefore absorption. Smoking allows for rapid drug delivery while ingestion Endocannabinods and their receptors (CB1, CB2) are pre- depends upon absorption, breakdown of the drug in the sent in early gestation. These cannabinoid receptors are part stomach, and metabolism in the liver [17]. Since cannabi- of the EDS which is imperative to many physiological noids are lipophilic, when present in the bloodstream they processes [11]. These receptors are in a class of the G readily cross the placenta into the fetus [18, 19]. protein-coupled receptors superfamily [12]. There are two main cannabinoid receptors, CB1 and CB2. The CB1 receptors are present in the placenta, brain, kidney, lungs, Cannabinoids and pregnancy: metabolism and liver. The CB1 receptor in the placenta is involved in the regulation of serotonin transporter activity. The fetal Metabolically, THC decreases fetal folic acid uptake which brain requires serotonin in the development of critical is essential for placental and embryo development. Folic neural circuits. The CB1 (CB1R) is acid is essential for fetal growth and since it is not syn- presynaptic and acts as an important signaling platform thesized de novo, dietary supplementation is necessary [13]. The neuromodulatory role of CB1R signaling is most during pregnancy. Folic acid deficiency is well known to important during as mature synaptic produce neural tube defects. THC interferes with folic acid activity is not present. It has been suggested that the CB1 by disturbing syncytiotrophoblast development. It is inter- receptor is necessary for the initiation of sucking in the esting that acute cannabinoid consumption results in no G. I. Martin effect on the update of folic acid while chronic use of Cannabinoids and breastfeeding cannabinoids is more consistent in the effects of disturbing folic acid metabolism [20]. The excretion of marijuana into human milk depends on the chemical characteristics of the drug. Molecular weight, solubility, and the pH of the drug Cannabinoids and pregnancy: other factors must be considered. THC is 99% protein bound and has a low molecular weight and increased lipid solubility. One big concern regarding cannabinoid exposure deals with Therefore, there is storage of THC in lipid predominate embryogenesis and interference with vascular endothelial tissue such as the brain. There continues to be insufficient growth factor (VEGF) by restricting movement of human data to conclude that maternal marijuana use during umbilical vein endothelial cells which induces apoptosis. breastfeeding is safe. It is because of this lack of informa- VEGF [21, 22] is involved with regulation of the angio- tion that the recommendation from both the American genic cascade. Academy of Pediatrics (AAP) [28] and The American On a cellular level, cannabinoid disrupts DNA replica- College of Obstetricians and Gynecologists (ACOG) [29]is tion, cellular motility, and cellular migration and replica- that marijuana use should be discouraged during this tion. The latter is a critical process in embryogenesis, breastfeeding period. especially in fetal brain development. As mentioned pre- Studies have evaluated [30] the concentration of Δ-9-tet- viously, CB1 receptors are in the fetal brain and play an rahydrocannabinol, 11-hydroxy-Δ-9-tetrahydrocannabinol, important role in the differentiation into neurons, and sup- CBD, and in breastmilk using liquid chromato- porting tissue such astrocytes or oligodendrocytes [23]. graphy mass spectrometry electrospray ionization. Results Neural stem cells (NSCs) can proliferate incorrectly leading showed that Δ-9 THC was detectable for up to 6 days after to anatomical cerebral dysgenesis. NSCs vary in different reported use. Even though definitive data is lacking, both the areas of the brain and if this signaling process is disrupted AAP and the American Congress of Obstetricians and the results on the growing fetus can be extensive. Gynecologist advise that marijuana use should be dis- In addition THC induces a neurotrophic factor (brain- couraged while breastfeeding. Conflicting information derived neurotrophic factor—BDNF) which is necessary for regarding marijuana metabolites in breastmilk revolves “synaptic efficiency, neuronal survival, new neuron differ- around the macronutrient components of foremilk and hind- entiation as well as long-term memory” [10]. milk. The number of times that a mother used marijuana It has also been suggested that cannabinoids and parti- per day was a predictor of THC concentrations in milk. There cularly THC decreases the levels of a microtubule-binding is a critical need for research to measure concentration of protein in axons identified as superior cervical ganglion 10 marijuana products in breastmilk and subsequent neonatal (SCG10/stathmin-2) which are necessary for organized plasma concentrations. The variables regarding intake make brain wiring [24]. investigations of this type difficult to accomplish. There is a pathway called the “MAPK/ERK” pathway Alvarez et al. [31] completed a chart review to assess which is important for the development of the blood- developmental milestones during well-child visits at 6, 9, placental barrier [25–27]. Normal MAPK/ERK is required 12, 15, 18, and 24 months of age. Logistic regression to form the syncytiotrophoblast which separates fetal and revealed that prenatal marijuana exposure was associated maternal circulation and is part of the cascade for embry- with developmental delay. The affected developmental ogenesis. These deviations potentially can alter develop- domains were fine motor and social in nature. There are ment. Signaling during embryogenesis can effect neural longitudinal studies in children of women who smoke crest migration, somit remodeling, and peripheral nervous marijuana during pregnancy and there are consistent out- system differentiation. comes regarding development. These include an increase in As further research continues (both bench and clinical) impulsivity, hyperactivity, delinquent behavior, memory we will learn more about the use during dysfunction, and decrease IQ scores [32]. Other investiga- pregnancy. During pregnancy the use of cannabis in the past tions involve human neurodevelopment in infants whose was mainly inhalation through smoking. This pathway with mothers use cannabis in pregnancy [33, 34]. added toxins increased the effects of the cannabis on the There is reason for concern, but the results are variable maternal lung. In today’s world, the different products with changes in habituation, sleep patterns, and motility available with varying degrees of purity, complicates the during the first several weeks of life. Unlike the neonatal toxic effects of smoking or ingesting marijuana. abstinence syndrome (NAS) with guidelines for therapy, In a short period of time results of these epidemiological there is no well-defined clinical approach to withdrawal in investigations shall increase our knowledge regarding the neonates who are exposed only to marijuana through effect of cannabis on embryogenesis and fetal development. breastmilk. Based upon the pathophysiology of marijuana’s Marijuana: the effects on pregnancy, the fetus, and the newborn effects, there is certainly “justification” to advise against a large number of infants with signs and symptoms which any type of marijuana exposure in the breastfed infant. can be attributed to marijuana. These include: Unfortunately, the literature is unclear about cannabis use during breastfeeding and the effects on the newborn and 1. Increased moro-reflex (startle response) infant. The baby gets on an average 2.5% of the maternal 2. Tremors THC dose through breastmilk. However, the accuracy of 3. High pitched cry these numbers depends upon the collection of the breast- 4. Abnormal sleep pattern milk and if the assay was done on the foremilk versus 5. Increased muscle tone hindmilk [30]. Another consideration is that the highest 6. Uncoordinated suck-swallow reflex concentration of THC in breastmilk occurs 1 h after can- 7. Increased irritability nabis consumption. There are falling concentrations over 8. Tachycardia the next 8 h [35]. 9. Increased blood pressure Even though this section discussed cannabinoid and 10. Seizures breastfeeding, there are also infant complications with 11. Thermoregulation instability paternal cannabis use. There remains a possible risk of 12. EEG—sleep disturbance SIDS in babies who have been exposed to marijuana through paternal smoking [36]. Note that many of these descriptors are similar to what is present with opioid withdrawal.

Observation information—conflicts Case presentation As marijuana exposures during pregnancy increases, there will be more scientific studies which better define mar- You are called by the nurse in the regular nursery ijuana’s effects on the fetus and newborn. As the numbers regarding a 2½ day old infant boy who was born at are still small, the results are variable and oftentimes con- 38 weeks by a cesarean section to a 26-year-old G2P1 flicting. Prenatal exposure to cannabis did not have a sta- for failure to progress. The infant’s weight was 2150 g tistically negative effect on length or head circumference. (10th%tile); length 44.5 cm (10th%tile), and head cir- Some systemic reviews [35] concluded that there was no cumference 32 cm (25th%tile). Baby’s ponderal index association between cannabis exposure and IUGR/SGA was 2.4 (25%tile). Mother’s history included the use of infants. Other investigations believe that cannabis exposure marijuana throughout her entire pregnancy. The nurse does affect fetal growth [37]. There apparently is no asso- reported that the baby was irritable and a “poor feeder. In ciation between cannabis use and gestational age. There is spite of the history of marijuana use, mother was allowed also no correlation between maternal cannabis use and to breast feed. Mother was attempting breastfeeding, but Apgar scores, development of jaundice, hypoglycemia, and/ there was difficultyinlatchingon.Itwasalsonotedthat or sepsis. the baby had an increased moro-reflex which was “In summary, the evidence for independent, adverse described as an exaggerated startle response. On exam- effects of marijuana on human neonatal outcomes and ination the baby exhibited tremors which disappeared prenatal development is limited, and inconsistency in find- when the baby’s extremities were restrained. The baby’s ings may be the result of the potential confounding caused muscle tone was described as increased. In addition, the by the high correlation between marijuana use and use of cry of the baby was described as “high pitched”. other substances such as cigarettes and alcohol, as well as The baby presented does have several of the clinical sociodemographic risk factors. However, the evidence from symptoms which are listed above. These include irritability, the available research studies indicate the reasons for con- feeding difficulties, and exaggerated startle reflex, tremors, cern, particularly in fetal growth and early neonatal beha- increased muscle tone, and a high pitched cry. viors [28]”.

Treatment of the newborn with marijuana Clinical signs/symptoms in the newborn withdrawal period Since the acute effects of marijuana exposure are potentially Based upon a review of the literature and the pathophy- neurobehavioral it seems appropriate that therapy is directed siology of the effects of marijuana we should be faced with to modifications of the newborn environment if symptoms G. I. Martin occur. Presently there is no indication for using References medications. Environmental and non-pharmacologic interventions: 1. Marijuana Tax Act of 1937, Pub. L. 75-238, 50 Stat. 551, enacted August 2, 1937 was a United States Act that placed a tax on sale of cannabis. 1. A dimly lit room environment 2. Controlled Susbstance Act (CSA). Pub L. 91-513, 84 Stat. 1236, 2. Minimal sensory or environmental stimulation (noise enacted October 27, 1970, codified at 21 U.S.C. 801 et. seq. is the reduction) statute establishing federal U.S. drug policy underwhich the 3. 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