Byron C. Calhoun1
(1)
Department of Obstetrics and Gynecology, West Virginia University-Charleston, Charleston, WV, USA
Byron C. Calhoun
Email: Byron.calhoun@camc.org
Keywords
PregnancyAddictionsMorbidity and mortalitySubstance abuse
The national substance abuse rates have been estimated to be between 2.8 and 19 % [1–3]. The most recent data available (2013 data) reported by the Substance Abuse and Mental Health Services Administration (SAMHSA) in 2015 found a 2.6 % rate of illicit drug use in the United States in 2013 [4]. However, most concerning are the much higher rates of substance use in the reproductive age cohorts. The rates at 12–17 years of age were 3.5 %; the 18–25 years of age an astonishing 7.4 %; and the 26–44 years of age 3.1 %. This data demonstrates the significant public health issue substance abuse and illicit drug use in women’s reproductive health particularly in obstetrical care. SAMHSA depends heavily on the use of survey data, self-reporting, and reporting from healthcare entities. The data are not generally linked to actual substance testing or necessarily verified with biologic samples.
In light of these findings, the American College of Obstetricians and Gynecologists (ACOG) and the American Society of Addiction Medicine (ASAM) have both developed guidelines for recommendations related to drug use during pregnancy [5, 6]. The ACOG and ASAM guidelines are summarized below:
ACOG
· Universal screening for drug use in females of reproductive age.
· Screening at first prenatal or intake visit and at least once per trimester thereafter.
· Consider drug testing (with patient consent) when screening tests are positive.
· Refer for substance abuse treatment for all pregnant women who have evidence of drug use in pregnancy.
· Protect physician–patient relationship.
ASAM
· Prenatal education about all drugs for all pregnant patients.
· Universal screening to identify “at risk” women including repeat follow-up assessments.
· Culturally competent public prevention programs to educate the public about realistic dangers of drug use in pregnancy.
· Education of healthcare providers in the care and management of women with evidence of drug use before, during, and after pregnancy.
· Women who are pregnant should receive priority admission to substance treatment facilities.
Adolescents present a particularly vulnerable population and may need more detailed screening questions about alcohol and drug use with regard to driving, self-esteem, relaxation, interpersonal relations including family, and any type of trouble (school or legal). Adolescents also present issues in confidentiality that must be dealt with in the context of substance abuse. Consultation with various state guidelines and legislation is recommended.
Tobacco
Tobacco abuse continues to be a major problem among adolescents. SAMHSA 2015 (using 2013 data as last completed year of analysis) reported that 5.6 % of adolescents age 12–17 (approximately 1.4 million adolescents) admitted to using cigarettes within a month of the 2013 survey [7]. Cigarette usage was also higher in metropolitan areas (8.4 %) compared to rural areas (5.1 %). SAMHSA further reported that the number of US adolescents using cigarettes had dropped from 9.0 to 5.6 % from 2009 to 2013. There were significant drops in usage reported in whites, blacks, and Hispanics. Even so, these are concerning statistic given the fact these young women are in the reproductive age range and suffer the same ill-effects of tobacco on pregnancy.
Maternal cigarette smoking during pregnancy has always been a concern due to its association with poor maternal and fetal outcome. The association between maternal tobacco abuse and the elevated risk for low birth weight, preterm delivery, and IUGR are all well documented in the literature [8]. In 2002, 11.4 % of women giving birth in the United States admitted to smoking during their pregnancy [9]. Although this has improved from years past, in West Virginia the percentage of women smoking during pregnancy has increased to 35.7 %. From 2000 to 2005, West Virginia experienced an increase in smoking rates during all stages of reproduction: before, during, and after pregnancy [10].
Evidence regarding the negative effects of nicotine on fetal development is well established in existing literature. Tobacco use during pregnancy has been shown to cause significant changes within maternal and fetal cell transcriptomes involved in the deregulation of many biological processes critical for both growth and development [11]. It has also been found that tobacco use also causes significant reductions of placental vascularization [12]. These findings are related to subsequent fetal morbidities including small for gestational age infants (SGA), intrauterine growth retardation (IUGR), low birth weight, premature rupture of membranes, stillbirth, and sudden infant death syndrome [13–16]. In addition, smoking increases the risk for the following: cryptorchism in males [17], orofacial clefts [18], and asthma and bronchopulmonary hyperreactivity [19, 20]. Perinatal morbidities include increased risk for placental abruption [21], fetal malpresentation [22], preterm birth [23, 24], and stillbirth [25, 26]. Mental disorders are also increased among women with nicotine dependence [27]. Recently findings about prenatal exposure to tobacco include an association of reduced brain growth in fetuses [28]; significant increase in attention deficit/hyperactivity, oppositional defiant disorder, and conduct disorder [29, 30]; and risk of poor school performance during adolescence [31].
England et al. 2013 demonstrated that preterm, premature rupture of membranes (PPROM) increased <28 by an odds ratio of 5.28 [CI 2.20–12.7]; <32 weeks odds ratio 2.36 [1.09–5.11]; <37 weeks odds ratio 1.97 (CI 1.32–2.94); and >37 weeks odds ratio [CI 0.92–11.0] with >10 cigarettes per day [32]. Kyrklund-Blomberg and Cnattingius 1998 found in a study of approximately 70,000 smokers in Sweden an almost double the rate of PPROM among nonsmokers (6.5/1000) versus smokers (11.5/1000) who smoked at least 10 cigarettes a day [33].
Baba et al. 2013 found an increased risk of stillbirth with an odds ratio of 1.59 (1.40–1.80) [34]. Varner et al. 2014 compared women who never smoked to those who reported smoking 1–9 cigarettes with an increased odds ratio of 1.77 (95 % CI 1.13–2.80) and for those smoking ≥10 cigarettes per day had an odds ratio for stillbirth of 2.17 (95 % CI 1.25–3.78) [35]. In another study by Hyland et al. 2013 demonstrated an increase in stillbirth rate with an odds ratio of 1.44 (1.20–1.73) in smokers [36]. These researchers also found that high levels of secondhand smoke (SHS) exposure, women with >10 years of childhood exposure, adult home >20 years, and adult work exposure >10 years had an adjusted odds ratio of 1.55 for stillbirth (95 % CI 1.21–1.97) [36]. They also found in this same cohort of high SHS exposure and adjusted odds ratio of 1.17 (95 % 1.05–1.30) and an adjusted odds ratio of 1.61 (95 % CI 1.16–2.24) for ectopic pregnancy [36].
The attribution of tobacco to IUGR in the United States has been stated as about 13.7 % of all births [37]. Horta et al. 1997 found an increased odds ratio for IUGR of 1.59 (95 % 1.30–1.95) in the cohort of patients who smoked compared to those who did not smoke [38]. They found a direct dose–response association with the number of cigarettes smoked and the risk of IUGR [38]. Therefore, since pregnant women who use tobacco are at an increased risk for adverse perinatal outcomes, their pregnancy is considered high-risk and requires monitoring and surveillance. This surveillance includes ultrasounds to monitor growth after 28–32 weeks, non-stress testing/biophysical profiles for fetal well-being beginning at 28–32 weeks, and/or, fetal Doppler surveillance. Most practitioners consider these patients significant high risk for adverse perinatal outcome and do not allow them to progress beyond 40 0/7 weeks gestation. Many suggest induction of labor at 39 0/7 weeks gestation with a favorable cervix ought to be considered in tobacco abuse patients due to their high-risk status.
Opioids
Substance abuse in pregnancy has well-known deleterious effects on neonates. These effects differ with respect to the substance ingested and can include neonatal abstinence syndrome (NAS), low birth weight, intrauterine fetal demise, and structural abnormalities such as gastroschisis.
The national substance abuse rates have been estimated to be between 2.8 and 19 % [1–3]. These reported rates vary based upon the population screened and the method of screening used. The lowest number reported in the study by Ebrahim and Gfroerer utilized a population survey of the entire United States [1] while the highest rates reported (19 %) by Azadi and Dildy utilized urine toxicology testing [3]. Chasnoff et al. developed a self-reporting screening tool that estimated that 15 % of the population studied continued to use substances of abuse after becoming aware of the pregnancy [2].
Opioid dependence, including methadone maintenance, has been linked to fetal death, growth restriction, preterm birth, meconium aspiration, and NAS [39, 40]. NAS may be present in 60–90 % of neonates exposed in utero with up to 70 % of affected neonates with central nervous system (CNS) irritability that may progress to seizures [40]. Up to 50 % of neonates may experience respiratory issues, feeding problems, and failure to thrive [41]. These issues are present as well in those infants whose mothers’ are on methadone maintenance [42]. However, with methadone the onset of NAS may be delayed for several weeks [42]. Some authors recommend 5–8 days of maternal hospitalization while their neonates’ undergo observation for NAS [43]. However, most insurance plans will not reimburse for the prolonged uncomplicated maternal stay while awaiting neonatal detoxification.
A randomized controlled study of 175 pregnant patients (89 methadone/86 buprenorphine) comparing methadone to buprenorphine by Jones et al. 2010 found both methadone and buprenorphine found that 57 % (41/75) of neonates had NAS with methadone and 47 % (27/58) of neonates had NAS with buprenorphine [42]. The buprenorphine cohort had shorter hospital stays (10.0 versus 17.5 days, P < 0.0091) and shorter days of treatment for NAS (4.1 versus 9.9 days, P < 0.003125) [44].
The incidence of opioid relapse in pregnant opioid abusing women is very high with 41–96 % relapsing. This mirrors the relapse rate of the general population at 1 month of 65–80 % [45, 46]. Over 90 % of patients will relapse at 6 months after medication-assisted withdrawal [47]. Buprenorphine (Subutex™) appears to have no difference in outcomes with regard to treatment of opiate addicted women. The same NAS and neonatal affects are present [48].
Recent work published by Montgomery et al. 2006 compared the performance of meconium samples versus the testing of umbilical cord tissue [49]. This study showed concordance of the testing methods that correlated at or above 90 % for all substances analyzed. Follow-up work included a study in which umbilical cord samples were collected and tested if high-risk criteria for substance abuse were identified. Out of this cohort, 157 of 498 (32 %) cords tested positive for substances of abuse [50]. Stitely et al. 2010 found similar results in their study of cord samples in eight regional hospitals in West Virginia with 146/759 (19.2 %) of umbilical cord samples collected at delivery that were positive for either illicit substances or alcohol [51].
The number of newborns treated for NAS has increased dramatically in West Virginia. In data collected from the Cabell Huntington Hospital in Huntington, WV, the number of neonates treated for NAS increased from 25 in 2003 to 70 in 2007 [51]. The cost difference in the care of an otherwise healthy neonate with NAS compared to a normal full-term healthy neonate was estimated to be $3934 in the Cabell-Huntington cohort. Because of the added costs associated with the increased risk of prematurity, the average cost of all infants with NAS was $36,000 compared to $2000 for a normal neonate [52].
Unfortunately, according to SAMHSA 2015 (using 2013 data as last completed year of analysis), over 6.9 million people age 12 years or older had illicit drug dependence or abuse [53]. Further, SAMHSA reports the dismal statistic that only 13.4 % (about some 917,000 treated/6.9 million people with a problem) received treatment. Most startling as well was that 8 out of 10 people with illicit drug dependence or abuse did not perceive a need for treatment for their illicit drug use. Considerable disconnect exists between people’s perceptions of illicit drug use with addiction and the reality of addiction their lives. It is not clear from the SAMHSA data that treatment is not always available with a lack of services for addictions and mental health or that the individuals have never been questioned or confronted regarding their illicit substance abuse or addiction. Better treatment is needed not only for pregnant women but all drug-dependent individuals. Much work remains in this realm.
Cocaine, Amphetamines, and Stimulants
Cocaine has known adverse effects in pregnancy. In particular, it has been linked with placenta-associated syndromes (PAS). PAS include placental abruption, oligohydramnios, placental infarction, gestational hypertension, preeclampsia, and eclampsia. Mbah et al. 2012 found that cocaine increased the risk for PAS by 58 % and noted an increased OR of 1.48 (95 % CI 1.33–1.66) [54]. They also found the most increased risk with cocaine exposure in placental abruption with an OR of 2.79 (95 % CI 2.19–3.55).
Exposure to cocaine prenatally investigated by Bauer et al. 2005 found several clinical and physical findings including: born 1 week earlier, weighing 322 g less, 1.7 cm shorter, and 1.0 cm smaller head circumference [55]. Exposed infants also had a significantly higher frequency of CNS symptoms with OR of 1.7 (99 % CI 1.2–2.2), autonomic nervous system symptoms with OR 1.5 (99 % CI 1.0–2.1), and increased infection rates with OR 3.1 (99 % CI 1.8–5.4). Opiates plus cocaine had an additive effect for CNS/ANS signs with an OR of 4.8 (95 % CI 2.9–7.9). Tobacco plus cocaine was also additive with an OR of 1.3 (CI 95 % 1.04–1.55) with ½ ppd and OR of 1.4 (95 % CI 1.2–2.6) with 1 ppd. Cocaine exposure also increased the risk of IUGR, prematurity, and low birth weight with an OR of 2.24 for IUGR, 1.25 for prematurity, and 3.59 for low birth weight [56].
Neurobehavior deviations in children exposed to cocaine have been found to be increased in the motor, sensory, and integrative functions. These neurologic “soft-signs” include ten different areas: speech, balance, coordination, double simultaneous stimulation (extinction), gait, sequential finger-thumb opposition, muscle tone, graphesthesia (inability to identify forms with tactile stimulation, i.e., a number drawn in palm), stereognosis (inability to identify an object by touch), and choreiform signs [57]. Cocaine was also associated by Breslau et al. 1999, with subnormal IQ and learning disorders with children with normal IQs [58]. These effects were found to be present particularly in the behavioral issues in longitudinal studies of children from birth 7 years of age [59]. These effects even after controlling for substance use, demographic factors, family violence, and family members psychological issues. Lester et al. 2003 even estimated that the cost to society with regard to special needs and education cost over $25,000,000 a year for cocaine exposure [60].
Amphetamine abuse, like cocaine, has been associated in pregnancy with vaginal bleeding, abruption placenta, placenta previa, premature rupture of membranes, decreased head circumference, low birth weight, tremulousness, irritability, poor feeding, and autonomic instability [61]. Nguyen et al. 2010 found a significant risk for SGA infants when adjusting for covariates of alcohol, tobacco, and marijuana use [62]. The increased OR was 2.05 compared to non-amphetamine abusers (95 % CI 1.24–3.37).
Treatment of amphetamine abuse with fluoxetine and imipramine may be useful but is not a panacea for treatment. A recent review by the Cochrane Collaboration in 2001 (reissued in 2009) noted that medications are of limited use in treatment of amphetamine abuse [63]. They note that there are very limited trials at this time to be able to suggest what is the best way to treat amphetamine abuse.
Alcohol
Heavy use of alcohol is a known teratogen leading to fetal alcohol syndrome (FAS) which includes CNS dysfunction, microcephaly, learning disabilities, and facial abnormalities. Affected individuals may have some or all of the manifestations of the syndrome.
Fetal alcohol syndrome (FAS) includes the following classic phenotype and includes:
· Evidence of growth retardation (prenatal or postnatal): height and weight equal to or less than the tenth percentile, corrected for racial norms and sex.
· Evidence of deficient brain growth and/or abnormal morphogenesis, including one or more of the following: structural brain anomalies or head circumference equal to or less than the tenth percentile (microcephaly).
· Evidence of a characteristic pattern of minor facial anomalies, including two or more of the following: short palpebral fissures (equal to or less than the tenth percentile), thin vermillion border of upper lip, and smooth philtrum.
Fetal alcohol spectrum disorders include the following:
· FAS with and without confirmed maternal alcohol exposure.
· Partial FAS: This is a diagnostic classification that includes known or unknown maternal alcohol exposure. It includes minor facial anomalies and evidence of other either prenatal and/or postnatal growth delay or structural brain abnormalities or microcephaly.
· Alcohol related birth defects (ARBD): Due to exposure to alcohol and may cause structural defects in multiple organ systems. This includes anomalies in cardiac (atrial-septal defect, ventriculoseptal defect, conotruncal anomalies), skeletal (radioulnar synostosis and vertebral defects), renal (aplastic/hypoplastic/dysplastic kidneys), eyes (strabismus, ptosis, vascular and nerve anomalies), and ears (conductive and sensorineural hearing defects). There may also be minor anomalies of the hands, ears, and chest wall with pectus carinatum/excavatum.
· Alcohol related neurodevelopmental disorder (ARND) which includes significant cognitive and behavioral abnormalities. There is a marked loss of complex task completion, higher level receptive language, expressive language disorder, and even disordered behaviors.
Shankaran et al. 2007 found that neurobehavioral deviations in children exposed to cocaine and have been found to be increased in the motor, sensory, and integrative functions [64]. These neurologic “soft-signs” include ten different areas: speech, balance, coordination, double simultaneous stimulation (extinction), gait, sequential finger-thumb opposition, muscle tone, graphesthesia (inability to identify forms with tactile stimulation, i.e., a number drawn in palm), stereognosis (inability to identify an object by touch), and choreiform signs. Children exposed to both cocaine and alcohol had an increased OR of 6.4 (95 % CI 2.5–16.6) of having a two or more of the soft signs of abnormal behaviors compared to unexposed children [64]. Children exposed in utero to binge drinking also had increased OR of 3.6 (95 % CI 1.0–12.8) of having at least two abnormal neurobehavioral findings [64]. The prevalence of FAS and FASD varies across various populations but there are affected adults and children in all races and ethnic groups. In the USA, the estimate of the alcohol use disorders is estimated at 0.5–2 per 1000 live births with FAS. FASD appears to be more common and is estimated that up to 1 % of live births affected [65].
These neurologic deficits will persist into adulthood. No safe amount of alcohol ingestion has been found in pregnancy and there is no treatment for the effects of alcohol on the fetus. Total abstinence is recommended in pregnancy. Unfortunately, alcohol rehabilitation has had little written in pregnancy and until recently no ability to verify chronic use of alcohol due to its volatile nature and inability to test for its presence.
Lastly, treatment for alcohol dependence or abuse, according to the SAMHSA 2013 data, appears no better than that for substance dependence or abuse. SAMHSA reports some 17.3 million people greater than age 12 years have been found to have alcohol dependence or abuse [66]. Of that 17.3 million, only 1.1 million (6.3 %) received treatment. Nine out of ten individuals with alcohol dependence or abuse did not perceive a need for treatment for their alcohol use. There was no difference in treatment rates by health insurance status, socioeconomic status, or rural versus urban areas. Once again, perceptions by individuals is sorely lacking regarding the harmful effects of their alcohol dependence or abuse. Also, it is not possible from the SAMHSA data to determine if treatment is not available due to a lack of services for addictions and mental health, or, that the individuals have never been questioned or confronted regarding their illicit substance abuse or addiction.
Sedatives
Barbiturates appear to be part of the anticonvulsant drug syndrome consisting of an increase in major malformations, growth retardation, and hypoplasia of the midface and fingers. The relative risk for major malformations with anticonvulsant therapy was found to be 4.2 [67]. Also, the use of high dose barbiturates at term may lead to respiratory depression and withdrawal in the neonate.
Benzodiazepine use has been associated with possible cleft lip and palate but the data appear inconclusive due to exposure to other substances, particularly alcohol. Abuse of the benzodiazepines near delivery may result in a neonate with poor muscle tone and respiratory depression.
Sedative withdrawal is less common than with the opioids and may be delayed with long acting benzodiazepines such as diazepam. Most neonates do not require therapy but for severe withdrawal Phenobarbital is the drug of choice. The dosing generally begins orally or intramuscularly at 2–4 mg/kg of body weight every 8 h. The dose is then tapered 10–20 % per day over 5–10 days [68]. Benzodiazepine dependence and detoxification must be done gradually to reduce symptoms. Little has been written about benzodiazepine detoxification in pregnancy.
Inhalants/Solvents
Inhalants and solvents represent a small and select group of pregnant patients. Estimates note that up to 12,000 women may use inhalants while pregnant [69]. There is a suggestion of decreased fertility and spontaneous abortion with inhalants [69]. It is not clear if the infertility is a direct effect of the inhalants on ovarian and testicular function or a secondary effect due to CNS effects on the hypothalamic axis. Clinical reports note that the adverse effects of solvents on the fetus include low birth weight, facial and other physical abnormalities, microcephaly, and delayed neurologic/physiologic maturation.
Marijuana
Marijuana remains the most frequently used illicit drug in the Western countries with roughly 20 million (7.5 %) of adult population using marijuana in last month [70]. Prevalence of use in pregnancy ranges from 3 to 34 % in the literature [71]. It is estimated that up to one third of the active psychogenic compound of delta-9-tetrahydrocannabinol (THC) crosses the placenta to the fetus with smoking marijuana [72]. Studies report increased rates of fetal distress, growth retardation, and adverse neurodevelopmental outcomes with prenatal exposure to cannabis. Also, several studies note that infants born to regular cannabis users have increased tremors, exaggerated startle response, and poor habituation to novel stimuli [73]. This pathogenic impact is further substantiated with epidemiological and clinical studies documenting impulsive behavior, social deficit, cognitive impairment, consumption of addictive substances, and psychiatric disorders with in utero exposure. The studies found that by age 10 years, marijuana exposed children in particular have increased hyperactivity, inattention, and impulsive behaviors. These children also have increased delinquency and externalizing behavioral problems compared to age comparable children without exposure to THC [74]. A recent case control study by Varner et al. found that THC use increased the rate of stillbirth with an OR of 2.3 (95 % CI 1.13–4.81) [35]. The effects of marijuana on preterm birth have been mixed but at least two large Australian retrospective studies demonstrate a possible increased risk of preterm birth. These two studies found an increased OR of 1.5 (CI 95 % 1.1–1.9) in one study and preterm birth rate of 18.8 % versus 5.8 % (P < 0.001) in the other [75, 76]. There does not appear to be evidence at this time in the literature that marijuana use is associated either decreased birth weight or congenital anomalies. There is evidence to support a mild withdrawal syndrome similar to opioid withdrawal associated with cannabis exposure. Therapy is rarely indicated.
Comorbidities
Comorbidities with multiple psychiatric issues in the patients with substance abuse issues must be considered. The 2011 USA National Survey on Drug Use and Health found that 17.5 % of adults with a mental illness had a co-occurring substance use disorder; involving some 7.98 million people [77]. Significant numbers of patients with substance dependence have affective disorders including: depression, mania, schizoaffective disorders, schizophrenia, borderline personality, and bipolar disorders. A study by Kessler et al, 1994 in the United States, attempting to assess the prevalence of dual diagnosis with substance abuse and mental illness, found that 47 % of patients with schizophrenia had a substance misuse disorder at some time in their life [78], and Regier et al. 1990 found the chances of developing a substance abuse disorder were significantly higher among patients suffering from a psychotic illness than in the those without a psychotic illness [79]. Another study looked at the extent of substance abuse in a group of 187 chronically mentally ill patients living in a community setting. According to the clinician’s evaluations, about 33 % of the sample used alcohol, street drugs, or both, during the 6 months before evaluation [80].
Therefore, many authors recently note that detoxification must be linked with a combination of behavioral therapy with contingency management therapy [81, 82]. Behavioral therapy consists of the use of addictions counselors and counseling to assist substance and alcohol abusers to remain drug and alcohol free. Finally, many agree the liberal use of biologic testing for abstinence verification should be a part of any robust addictions programs. Monitoring of compliance assists in building accountability in the patients and demonstrates commitment to consistent oversight in achieving sobriety and health in the individuals.
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