Course BASIC_Graduate level learning material about the challenges of human reproductive medicine in a changing Europe

2021-1-HU01-KA220-HED-000027613 - COHRICE

SYLLABUS

Pregnancy with substance abuse, women on the margins of the society

(Basic level)

Use and misuse of substances by pregnant women is continuously increasing. Identification of substance use during pregnancy allows for interventions aimed at improving maternal and fetal health, in part by linking to appropriate services and initiating appropriate treatment and medications. Challenges include lack of screening, barriers to patient admitting substance use, and limited resources for interventions and treatment.

Definition: The use of illegal drugs or the use of prescription or over-the-counter drugs or alcohol for purposes other than those for which they are meant to be used, or in excessive amounts, leading to medical, social, physical, emotional and job-related problems. Substance use and abuse during pregnancy carries both serious maternal disorders and fetal development and health disorders. 

The following risk factors can be related to substance use in pregnancy [1]:

• late initiation of prenatal care or multiple missed prenatal visits
• current mental health disorder or family history of substance use disorders
• a sudden change in behavior
• high-risk sexual behavior or history of sexually transmitted infections
• relationship problems, partner with substance use disorder
• obstetric history of unexplained sever obstetrical complication
• children not living with the mother
• history of medical problems frequently associated with drug use disorders 
• physical signs of drug use or physical signs of withdrawal
• poor dentition

The obstetrician is in key position to get the early diagnosis of substance abuse in pregnant women, also the obstetrician is the first provider to make a screening and if needed initiate a treatment (both pharmacologically and/or non-pharmacologically). Treatment initiated as a result of screening may be within the provider's practice or at another site.

The optimal screening method is not completely defined, in part of because of the limited comparative studies, the multiple screening test available and the range of substance evaluated. However early universal screening is recommended, because is not typically disclosed spontaneously by patients. The ACOG recommend that the screening should start with a detailed medical, family and social history using validated questionnaires. [2] Routinely performed toxicology testing (blood, saliva, urine, hair, sweat) are not endorsed, but a positive validated questionnaire respond should be followed by toxicology evaluations. Validated questionnaires available: 

1. Substance Use Risk Profile-Pregnancy Scale (SURP-P)
2. Proprietary 4P's Plus
3. National Institute on Drug Abuse (NIDA) Quick Screen
4. Modified Alcohol, Smoking and Substance Involved Screening Test (ASSIST)

The most practical and effective approach is to start with lawful and more socially accepted substances (example: tobacco, cigarette smoking, alcohol, cannabis use) the followed by questions about nonmedical use of over-the-counter drugs (example: pseudoephedrine) then use of prescription drugs (example: opioid analgesics, sedatives, stimulants), and finally questions about illegal substances (example: methamphetamine, cocaine, heroin, hallucinogens). If affirmative substance use has been found then the provider always have to ask the pattern of use and the time of last use, the route of administration (oral, intranasal, subcutaneous injection or intravenous). If intravenous drug use is detected always ask about the shared needles and do not forget about the sexually transmitted diseases (syphilis, HIV, hepatitis etc.). During history taking ask about the presence of tolerance and withdrawal symptoms and try to detect if there was a prior substance use treatment: self-help programs, detoxification or other pharmacological and non-pharmacological treatments. 

Laboratory testing:

• Maternal laboratory testing: There is no consensus regarding when drug tests should be used in pregnancy or the best method for analyzing biological samples (urine, blood, hair, saliva). Urine testing is the commonest. Positive tests for illicit drugs can have legal and economic implications, random testing could be unethical. 
• Neonatal laboratory testing: usually urinalysis, but this detect only recent maternal use. Another testing source is the meconium (formatting at 12 weeks of gestation, the presence and concentration of substance is related to the quantity, duration and timing of drug exposure). The meconium test can be used up to three days after the delivery. The neonatal hair can be used for narcotics, marijuana and cocaine tests. 

1. Tobacco use and abuse during pregnancy

Use of tobacco products, including cigarette smoking (most common), smokeless tobacco and electronic cigarettes are the most important modifiable risk factors associated with serious maternal, fetal and neonatal disorders. The prevalence of cigarette smoking is hard to establish, studies show a 7-11% of active smoking during pregnancy. [3, 4] Prudent and detailed early edication about the consequesces can make a difference in the tobacco usage, which higlights the preconceptional planning. Aviodance of electronic cigarettes is also recommended. 

The cigarette smoking is associated with a number of serious unfavorable obstetrical outcomes, including placental abrubtion, preterm premature rupture of the membranes (PPROM) causing preterm birth, placenta praevia, low birth weight (supplementation with high doses of folic acid is potentially reduce the incidence of small for gestational age and low birth weight infants), preterm labor and delivery, ectopic pregnancy and stillbirth. The pathophysiology is still unclear, but mechanisms are related to impaired gas exchange, direct toxicity and to sympathetic activation. Although the overall rate of congenital malformations does not seem to be higher among neonate born to pregnant women who smoke, but some studies show that smoking may increase the risk of some specific disorders: cleft lip with or without cleft palate, gastroschisis, anal atresia, transverse limb reduction defect, cardiac defects, digital anomalies (syndactyly, polydactyly, adactyly), bilateral renal agenesis or hypoplasia. The timing and the amount of exposure of tobacco product and the maternal age (older maternal age during pregnancy carries an increased risk of fetal anomalies) have a serious impact on developing fetal structural anomalies. 

A meta-analysis has shown that cigarette smoking during pregnancy is associated with a significant reduction in the risk of preeclampsia, but increases the risk of ectopic pregnancies, miscarriage, PPROM, placental abruption and placenta previa [5]. This advantage does not overrun the serious medical and obstetrical risks associated with cigarette smoking during pregnancy. Based on an in vitro experiment, the mechanism may be that cigarette smoke reduces fms-like tyrosine kinase-1 (sFlt-1) and increases placental growth factor (PGF), which is the opposite of the changes observed in women who develop preeclampsia. [6] Smoking just one cigarette a day during pregnancy causes a twofold increased risk of sudden unexpected infant death. 

2. Alcohol use and abuse during pregnancy

Pregnant women who drink may also be using other addictive or illicit substances. Alcohol consumption during pregnancy is common, and despite of public education effort the usage shows steady growth. The prevalence of alcohol consumption before and during pregnancy highlights the need to educate all reproductive age females about the potential harms of alcohol and other substances exposure on the developing fetus. In the United States 87% of self-reported women who drank alcohol before pregnancy quit drinking during pregnancy, 6.6% reduced their alcohol intake, and approximately 6.4% reported no reduction at all. [7] The alcohol crosses the placenta and it is known to be teratogenic to the fetus, causing irreversible central nervous system effects. A safe level of alcohol consumption during pregnancy has not been determined, national guidelines and medical societies from multiple countries recommend complete abstinence during all stages of pregnancy. The fetus is particularly vulnerable to maternal alcohol consumption because of inefficient and prolonged elimination, causing a prolonged exposure. Alcohol is eliminated from the fetus at a rate of only 3-4% of the maternal rate. In addition, much of the alcohol excreted by the fetus into the amniotic fluid is "recycled" through fetal swallowing of amniotic fluid and intramembranous absorption.

The effects vary depending upon the quantity and pattern of alcohol consumption, maternal and fetal genetics, maternal age, maternal nutrition, and smoking. Prenatal exposure to alcohol, besides the tobacco use, is the leading preventable cause of congenital anomalies and developmental disabilities. The most severe consequences are stillbirth and fetal alcohol spectrum disorder (FASD). Significant alcohol exposure during the trimesters causes deleterious effects: 

• Trimester: facial anomalies, major structural anomalies (brain anomalies!!!)
• II. Trimester: risk of spontaneous abortion
• III. Trimester: affects weight, length, and brain growth. Neurobehavioral effects may occur with a range of exposures throughout gestation, even in the absence of facial or structural brain anomalies.

Fetal alcohol spectrum disorder (FASD) is a term describing the range of effects that can occur in an individual whose mother drank alcohol during pregnancy. These effects may include physical, mental, behavioral, and/or learning disabilities with possible lifelong implications. The prevalence is 0,77-2%, highest in the European region and lowest in the Eastern Mediterranean region. [8] FASD include the following conditions: 

• Fetal alcohol syndrome (FAS), including partial FAS
• Fetal alcohol effects (FAE)
• Alcohol-related birth defects (ARBD)
• Alcohol-related neurodevelopmental disorder (ARND)

Clinical features of FAS: three characteristic facial features (short palpebral fissures, thin vermillion border, and smooth philtrum), central nervous system abnormalities (structural anomalies, recurrent non-febrile seizures, developmental, learning and cognitive problems, behavioral problems) and growth retardation. Most individuals with alcohol spectrum disorder are diagnosed during childhood. For unknown reasons, older maternal age, high parity, and African-American or Native American ethnicities appear to increase the risk of FAS. 

Children who are suspected to have an FASD should be referred to a qualified team of specialists for assessment that includes examination for facial dysmorphic features, growth, and a complete neurobehavioral evaluation, which includes intelligence (IQ) testing, an assessment of memory, executive function, language, visual motor integration, functional and adaptive skills, and processing speed. 

3. Cannabis (marijuana) use in pregnancy

The cannabis is a psychoactive drug from the cannabis plant and can be used by smoking, vaporizing, within food or as an extract, having various effects: euphoria, altered states of mind and sense of time, impaired short-memory and body movement, anxiety, hallucinations, panic, paranoia and psychosis. In 2013, between 128 and 232 million people used cannabis (2.7% to 4.9% of the global population between the ages of 15 and 65) [9]. Cannabis is one of the most commonly used substance during pregnancy (2%). Studies show a conflicting data regarding the possible risk of preterm birth and low birth weight in cannabis smoking during pregnancy. The recommendation is to avoid using it during pregnancy and lactation because of the concerns for the neurodevelopmental impact on the developing fetus and neonate. 

Nausea and vomiting in pregnancy may be a risk factor for prenatal cannabis use. Paradoxically, chronic cannabis use can also cause a hyperemesis syndrome, of which patients and clinicians may be unaware [10, 11]. 

The obstetrical outcomes related to marijuana use in pregnancy is difficult to assess because of the available conflicting data and because of the multiple confounding factors (tobacco, alcohol and other substance use), but there is a relation with preterm birth and small for gestational age infants. The cannabis use was associated with a threefold increased risk of neonatal morbidity and death, with an altered neurobehavioral outcomes (increased risk of autism spectrum disorder). There is no correlation with congenital anomalies. 

4. Pseudoephedrine use in pregnancy: 

Pseudoephedrine is a sympathomimetic drug and can be used as a nasal/sinus decongestant, as a stimulant or as a wakefulness-promoting agent in higher doses. The abuse of oral decongestants, including the pseudoephedrine, is increasing worldwide and should generally be avoided during the first trimester because of an uncertain risk of several rare birth defects [12]. Pseudoephedrine can be used in pregnancy in females without hypertension. There is an uncertain, but possible association with gastroschisis and limb reduction defects, also reduces the uteroplacental blood flow which can be another potential serious effect of the pseudoephedrine abuse in pregnancy. 

5. Opioid use and abuse during pregnancy: 

Opioids are synthetic and semi-synthetic drugs, mainly used for medical purposes as painkillers for chronic non-cancer- and cancer related pain, cough, diarrhea and constipation, shortness of breath and hyperalgesia. Opioids include:

• legal (by prescription) drugs: oxycodone, hydrocodone, codeine, morphine
• illegal drugs: heroin, synthetic opioid such as fentanyl.

Opioid use by pregnant women is increasing, in the US 2,8% of pregnancies are exposed to opioid use at some point [13]. Obstetrical risk are multiple: increased risk of abruption placentae, fetal death, premature labor, preeclampsia, miscarriage, fetal growth restriction. An important maternal risk is the dose dependent myocardial ischemia and infarction. Treatment for individuals with opioid abuse is recommended, because of the neonatal opioid withdrawal syndrome. Treatment is recommended to be done with medications rather than medically supervised detoxification, medication treatment with methadone or buprenorphine offers overwhelming advantages compared with continued use of heroin or other illicit opioids. The use of naloxone as an opioid antagonist is not recommended, because it will cause a strong and life threatening neonatal withdrawal effect. 

Opioid related neonatal abstinence syndrome: One advantage of buprenorphine is that neonatal opioid withdrawal syndrome is typically less severe in neonates born to individuals treated with buprenorphine compared with methadone. Using buprenorphine during pregnancy to treat maternal opioid abuse will lower the neonatal hospital stay, shorter duration of treatment for NAS and will lower doses of morphine for treatment of NAS. 

6. Sedative abuse during pregnancy: 

Sedatives encompass a wide variety of drugs with different mechanisms of action that can induce depression of the central nervous system. Most common sedatives are the barbiturates and the benzodiazepines. 

6.1. Barbiturates: 

Barbiturates are nonselective central nervous system depressants that used to be the treatment to sedate patients or to induce and maintain anesthesia. Nowadays they have been largely replaced by the benzodiazepines, primarily because they can induce tolerance, physical dependence and serious withdrawal symptoms. Nevertheless, certain barbiturates are still in use as anticonvulsants (phenobarbital) and to induce anesthesia (thiopental). The use during pregnancy carries an increased risk of major congenital malformations: neural tube defect, congenital heart and urinary tract defects, skeletal abnormalities and oral clefts. Risks associated with barbiturate use during pregnancy can be minimized by preconception planning and careful management during pregnancy.

6.2. Benzodiazepines:

Benzodiazepines are sedative-hypnotic agents that have been in clinical use for decades. BZDs are safer than older sedative-hypnotic agents, such as barbiturates, and thus are commonly used for sedation and to treat anxiety, seizures, withdrawal states, insomnia, and agitation. Due to their diversified use and wide therapeutic index, benzodiazepines are widely prescribed, and nearly 50 different agents are available worldwide. Most common benzodiazepines: alprazolam, clonazepam, lorazepam. Benzodiazepines are often used during pregnancy to manage severe anxiety or agitation, and drug with short half-life (lorazepam) are preferred. Data available suggest that benzodiazepines are not associated with an increased risk of fetal development malformations, but some studies suggest avoiding them, because the observed elevated risk or oral cleft and pylorostenosis. [14] The abuse of the benzodiazepines unquestionably increases the risk of miscarriage, preterm birth and intrauterine growth restriction. Chronic administration of benzodiazepines close to delivery can cause neonatal toxicity and withdrawal, including low Apgar score, apnea, hypothermia, hyperreflexia, hypertonia or hypotension, irritability, lethargy, poor feeding and vomiting. If withdrawal symptoms are observed, they can persist for up to 3 months. 

7. Methamphetamine use during pregnancy:

Methamphetamine is a powerfully addictive stimulant that causes the release and blocks the reuptake of monoamine neurotransmitters, including dopamine, norepinephrine, and serotonin. Methamphetamine is most often smoked or snorted and is less commonly injected or ingested orally. The incidence is rising, in the US 1% of deliveries were exposed of methamphetamine in utero. Users usually are multiple substance abusers (cannabis, cocaine, alcohol, sedatives). Methamphetamines are known to be neurotoxic and they can cross the placenta, also no fetal structural abnormalities have been definitely associated with perinatal amphetamine exposure and it is unclear whether the exposure causes withdrawal in neonates. Some studies show a twofold or fourfold increase in risk of intrauterine growth restriction, preeclampsia, placental abruption, preterm birth or intrauterine, neonatal and infant death. 

8. Cocaine abuse during pregnancy: 

Cocaine is a central nervous system stimulant mainly used for its euphoric effects. The drug is often snorted, applied topically to the mouth, or it can be dissolved and injected into a vein. Cocaine stimulates the reward pathway in the brain. Mental effects can be: intense feeling of happiness, sexual arousal, loss of contact with reality or agitation, while physical effect include: tachycardia, sweating and dilated pupils. The cocaine usage during pregnancy is increasing as the other substances listed above and its impact of pregnancy makes it also dangerous: crossing the fetal blood-brain barrier causes vasoconstriction, being the major mechanism for fetal and placental damage. The effects is related to dose and stage of pregnancy. Cocaine use during pregnancy significantly increases the risk of: preterm birth, low birth weight and small for gestational infant, miscarriage, abruption placentae, decreased length (-0,71 cm) and head circumference (-0,43 cm) at birth. [15] Teratogenic effects have not been definitively established. 

In pregnant individuals the cardiovascular cocaine toxicity is increased, causing hypertension. This hypertension may mimic preeclampsia. Beta-adrenergic antagonists (beta blockers) should be avoided in the treatment of cocaine-related cardiovascular complications because it will also create an alpha-adrenergic stimulation: coronary vasoconstriction and end-organ ischemia.  Hydralazine is preferred for treatment of hypertension in pregnant individuals who use cocaine [16] 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. [17]

Neonatal abstinence syndrome (NAS)

An infant born to a person with a substance use disorder is at risk for withdrawal, commonly referred to as neonatal abstinence syndrome (NAS). NAS is a variable, complex, and incompletely understood spectrum of signs of neonatal neurobehavioral dysregulation. Most common agents that can cause NAS are: opioids, nicotine and cigarettes, benzodiazepines. As substance use is rising worldwide, so is the incidence of NAS. The pathophysiology of NAS and factors that influence its severity are not completely understood, but altered levels of neurotransmitters such as norepinephrine, dopamine, and serotonin are presumed to play a significant role. 

The major signs and symptoms of NAS are: 

• Sleep and wake cycle disturbances manifested by fragmented sleep with short sleep cycles and difficulty maintaining an alert state.
• Alterations in tone or movement manifested by hypertonicity, tremors, jitteriness.
• Autonomic dysfunction manifested by sweating, sneezing, mottling, fever, nasal stuffiness, and frequent yawning.
• Easy overstimulation, sensitivity, or hyperarousal resulting in irritability and crying with any stimuli. 
• Difficulties with feeding (suck-swallow incoordination and oral hypersensitivities resulting in poor weight gain, respiration (tachypnea) and gastrointestinal problems (gassiness, vomiting, loose stools).

Depending upon the recent history of exposure and the half-life of substance elimination the onset of NAS varies. Diagnosis of NAS can be made based on maternal history of substance abuse, the neonatal signs and symptoms and on the neonatal testing: urine, hair, umbilical cord blood and meconium. 

Management of NAS: Non-pharmacologic care is based on individualization of the care. Small, frequent feedings are recommended. Breastfeeding is recommended when appropriate. Identification and eliminating of overstimulating factors is essential. The pharmacologic therapy include morphine, methadone or buprenorphine. Avoiding the naloxone (opioid antagonist) is recommended, because it may precipitate rapid withdrawal symptoms in the neonate. 

References:

[1] History taking and substance abuse counseling with the pregnant patient., Klein RF, Friedman-Campbell M, Tocco RV, Clin Obstet Gynecol. 1993;36(2):338.

[2] Committee Opinion No. 711: Opioid Use and Opioid Use Disorder in Pregnancy., Obstet Gynecol. 2017;130(2):e81

[3] Curtin SC, Matthews TJ. Smoking Prevalence and Cessation Before and During Pregnancy: Data From the Birth Certificate, 2014. Natl Vital Stat Rep. 2016 Feb 10;65(1):1-14. PMID: 26905977.

[4] Curtin SC, Matthews TJ. Smoking Prevalence and Cessation Before and During Pregnancy: Data From the Birth Certificate, 2014. Natl Vital Stat Rep. 2016 Feb 10;65(1):1-14. PMID: 26905977.

[5] Castles A, Adams EK, Melvin CL, Kelsch C, Boulton ML. Effects of smoking during pregnancy. Five meta-analyses. Am J Prev Med. 1999 Apr;16(3):208-15. doi: 10.1016/s0749-3797(98)00089-0. PMID: 10198660.

[6] Mehendale R, Hibbard J, Fazleabas A, Leach R. Placental angiogenesis markers sFlt-1 and PlGF: response to cigarette smoke. Am J Obstet Gynecol. 2007 Oct;197(4):363.e1-5. doi: 10.1016/j.ajog.2007.06.025. PMID: 17904960.

[7] Kitsantas P, Gaffney KF, Wu H, Kastello JC. Determinants of alcohol cessation, reduction and no reduction during pregnancy. Arch Gynecol Obstet. 2014 Apr;289(4):771-9. doi: 10.1007/s00404-013-3056-9. Epub 2013 Oct 23. PMID: 24150521

[8] Lange S, Probst C, Gmel G, Rehm J, Burd L, Popova S. Global Prevalence of Fetal Alcohol Spectrum Disorder Among Children and Youth: A Systematic Review and Meta-analysis. JAMA Pediatr. 2017 Oct 1;171(10):948-956. doi: 10.1001/jamapediatrics.2017.1919. PMID: 28828483; PMCID: PMC5710622.

[9] https://courses.lumenlearning.com/wm-abnormalpsych/chapter/cannabis-related-disorders/

[10] Young-Wolff KC, Sarovar V, Tucker LY, et al. Association of Nausea and Vomiting in Pregnancy With Prenatal Marijuana Use. JAMA Intern Med 2018; 178:1423.

[11] Braillon A, Bewley S. Cannabinoid hyperemesis syndrome: implications for pregnancy. BMJ 2019; 366:l5587.

[12] Yau WP, Mitchell AA, Lin KJ, et al. Use of decongestants during pregnancy and the risk of birth defects. Am J Epidemiol 2013; 178:198.

[13] Characteristics of Individuals in the United States Who Used Opioids During Pregnancy. Nguyen RHN, Knapp EA, Li X et al, J Womens Health (Larchmt). 2022;

[14] Wikner BN, Stiller CO, Bergman U, Asker C, Källén B. Use of benzodiazepines and benzodiazepine receptor agonists during pregnancy: neonatal outcome and congenital malformations. Pharmacoepidemiol Drug Saf. 2007 Nov;16(11):1203-10. doi: 10.1002/pds.1457. PMID: 17894421.

[15] Gouin K, Murphy K, Shah PS, Knowledge Synthesis group on Determinants of Low Birth Weight and Preterm Births. Effects of cocaine use during pregnancy on low birthweight and preterm birth: systematic review and metaanalyses. Am J Obstet Gynecol 2011; 204:340.e1.

[16] Kuczkowski KM. The effects of drug abuse on pregnancy. Curr Opin Obstet Gynecol 2007; 19:578.

[17] Kuczkowski KM. The cocaine abusing parturient: a review of anesthetic considerations. Can J Anaesth 2004; 51:145.

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