Illicit Drug Use in Pregnancy: Effects and Management CME

Rajashekhar Moorthy Madgula, MD; Teodora Groshkova, MSc, C Psychol, MSc, PhD; Soraya Mayet, MD Authors and Disclosures CME Released: 03/18/2011; Valid for credit through 03/18/2012
Abstract and Introduction Abstract

Drug misuse in pregnancy is a complex public-health problem with potentially serious adverse effects for the mother, fetus and extending to the developing child. Early detection by screening of all pregnant women and those planning pregnancies should be a priority. This article focuses on the effects and management of illicit drug use in pregnancy. The assessment of the pregnant drug user needs to sensitively explore drug use, psychiatric and physical comorbidity, social and family circumstances of the individual. The impact on any dependent children is a crucial part of the assessment. The use of assessment tools can inform future planning. Management requires a coordinated, multidisciplinary approach to ensure seamless transition and individualized care. Pharmacological treatments are available for opioid dependence, while benzodiazepine dependency would require withdrawal. Psychosocial interventions are an integral part of management. There is a need to understand the context in which drug use occurs and to develop cost-effective treatments.
Introduction

Drug misuse in pregnancy is a complex and increasing public-health problem. Estimates of drug misuse in pregnant women vary across the world and the populations studied. In the USA, the 2004 Survey on Drug Use and Health showed that 5% of American women reported the use of an illicit drug during pregnancy.[1] In the UK, national estimates for pregnant drug users are lacking, but studies report that approximately a third of drug users in treatment are female and over 90% of these women are of childbearing age (1539 years of age).[2] A study comparing the profiles of pregnant drug users presenting to a perinatal addictions service in London (UK) found illicit heroin use (38%), followed by cocaine use (24%) as primary drugs of abuse, with polysubstance use common.[3] In Europe, it is estimated that there may be as many as 30,000 pregnant women using opioids each year and the number of pregnant women using drugs other than opioids may be equally high.[4] Australian research reported an 8% prevalence of drug use among women who were pregnant or breastfeeding.[5] The wide variation in prevalence is influenced by sampling techniques, response rates, sample sizes and the population studied. Selfreporting may be low, and interviews and screening to confirm drug use may lead to increased

rates of prevalence. Research in this vulnerable population is compounded by ethical issues, which has made large-scale and adequately powered studies difficult to conduct. Drug misuse and dependence in pregnancy is associated with a wide variety of adverse maternal and child outcomes.[6,7] Appropriate obstetric and neonatal care can reduce the rate of complications in these pregnancies and improve maternal and child outcomes. This article will attempt to address the individual effects of various illicit drugs, the available treatment options and remaining challenges. The scope of this article is focused on illicit drug use. Alcohol and nicotine, therefore, have not been addressed, although they have potent adverse effects with a wide spectrum of disorders linked to consumption in pregnancy. Assessment and effects of various drugs are initially discussed, followed by a separate discussion on pharmacological treatments and psychosocial interventions. This article focuses on the management of drug use during pregnancy and does not discuss the specific management of delivery and neonatal care.
Assessment of the Pregnant Frug User Screening

Substance misuse is generally not identified prior to conception and may be hidden until delivery or not detected by healthcare professionals. Pregnancy may be unplanned, with late antenatal booking and poor engagement with services.[8] When assessing women, it may be useful to consider a blanket approach and screen all women for substance misuse. While this does occur in some services, the screening method is generally via verbal assessment and drug screens (e.g., urine or saliva drug screens) are not normally conducted.[3] While controversial, this may be a useful technique for detecting drug use. Self-reporting rates are very variable and can be low. Meconium testing has been used to increase detection rates. The Maternal Lifestyle Study looked at cocaine use along with other drug use in pregnancy by meconium screening of infants and gas chromatography as a confirmatory test in a study of over 8500 women. A total of 38% of women who denied any use on self-report were positive on screening.[9] Sweat testing has also been useful to monitor compliance in small samples of pregnant drug users.[10] Once substance misuse is detected, education regarding the adverse effects and advice to stop illicit drug use is likely to be useful.
Drug Use

Many women have faced stigmatization and rejection from family, friends, health and social services, and are reluctant to divulge information. Conversely, if trust is established, many may be happy to openly discuss their drug habit and circumstances. The booking history would need to look in detail at the pattern, mode, frequency, single and/or polydrug use, and illicit and prescription drug use to establish the severity of substance misuse. Polydrug use appears to be very common in pregnant addicts. The Maternal Lifestyle Study also highlighted the prevalence of polydrug use. Only 2% of mothers reported that they used only cocaine during pregnancy and mothers were 49-times more likely to use another drug, such as opiates, marijuana, alcohol or tobacco if they used cocaine.[9] If polydrug use is present it will be important to ascertain whether they are at a recreational level of use or have reached dependence levels. Differentiating dependent from recreational drug use is a key factor in proper management, and standardized

diagnostic criteria as detailed in the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV[11] or the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10)[12] should be used. The role and success of previous treatments, including psychosocial and pharmacological treatments in the community or in-patient setting, including rehabilitation, would need to be established. The individuals attitude to the substance misuse and changes in motivation in relation to being pregnant must be sensitively explored. In a proportion of women pregnancy results in a reduction of substance misuse[6] but there is a high risk of relapse postpartum. In some injecting drug users the stress of pregnancy and parenthood may lead to escalating drug use.[6] Substance use during the lifetime of the pregnant women, times of abstinence and previous treatments received, are important to ascertain.
Comorbidity

Psychiatric comorbidity is of particular importance and dual diagnosis is a common occurrence in this population.[13,14] A south Australian study found substance misusers to have almost threetimes the odds to have a psychiatric condition.[6] Thus, eliciting detailed history of comorbid mental-health problems along with prescribed medication and compliance is vital to formulate prevailing and potential risks to maternal and fetal wellbeing, and to help better plan and coordinate care between agencies. In intravenous drug users, injection practices such as sharing needles, syringes and other paraphernalia need to be ascertained to investigate for blood-borne diseases. Substance misuse increases the risk of sexually transmitted diseases, hepatitis B, hepatitis C and HIV.[5,6,10] History related to inflammation at injection sites, accidental overdoses, sepsis and thromboses, all of which can be which can be life-threatening, needs to explored. Malnutrition is a frequent physical comorbidity that contributes to adverse fetal outcomes.

Lifestyle & Environment

Maternal lifestyle, socioeconomic situation, family support, partners drug habits (if applicable) and relationship issues, including domestic violence, would be a key part of the assessment. Substance abuse is often associated with domestic violence,[13] sexual abuse and drug use by responsible partners.[13] Involving the partner where possible in the care would increase the chances of successful outcomes. The individual may engage or continue to be engaged in prostitution, which increases the risk of sexually transmitted infections, or commit crimes to fund the drug habit and are involved with the criminal justice system. This increases vulnerability and perpetuates the vicious cycle of drug use. Many opioid-dependent users have menstrual irregularities and may not have been aware of their pregnancy, which delays contact with services.[15] It is crucial to understand the adverse consequences of drug use in pregnancy in the context of these socioeconomic and psychosocial factors. This fact was established in a recent study that

looked at individual illicit drug use in the context of various environmental factors and birth weight as an outcome.[16] In over 800 women a number of biopsychosocial, biomedical, behavioral factors, and consumption were studied in relation to birthweight. Between 70 and 90% of birthweight decrements and increased odds of low birthweight (LBW) were explained by factors associated with drug use. The authors opine that drug misuse may be more of a marker than a risk factor for LBW in the life of a pregnant drug user. Malnutrition, stress and poverty all contribute to adverse fetal outcomes.[16]

Impact on Children

The effect of this lifestyle on previous pregnancies and children (if involved) is important. Children who are exposed to drugs prenatally are also at higher risk of involvement with child protection agencies.[17] Children of drug-using parents are at increased risk of neglect, physical and emotional abuse, and up to 50% of drug users do not live with their children.[18] There is often a fear that detection of substance misuse in pregnancy will lead to the child being taken into custody by social services after childbirth. The Confidential Enquiry into Maternal Mortality in the UK noticed an increase in maternal mortality around the time case conferences were held and children taken into custody.[19] Women may sometimes not declare substance misuse if they believe that this will lead to the baby being removed by child protection services. It is also important to ascertain the status of the partners children (if relevant) and history of contact with them. The safe storage of take-home substitute medication (methadone/buprenorphine) needs to be clarified to minimize the risk of access and potential overdose by children.

Assessment Tools

The use of structured assessment tools such as the Addiction Severity Index tailored to women and pregnancy will further inform treatment planning.[20] The Addiction Severity Index is said to have predictive validity in pregnant patients.[20] Other structured protocols such as the UK Common Assessment Framework (CAF) are also used.[14]
Effects of Substance Misuse in Pregnancy Opioids

A significant percentage of pregnant drug users presenting to drug services are dependent on opioids, which include heroin, illicit methadone and buprenorphine.[18,21] All drugs cross the placenta and are secreted in breast milk. Pregnant opioid-dependent women experience a sixfold increase in maternal obstetric complications, such as LBW, toxemia, malpresentation, puerperal morbidity, fetal distress and meconium aspiration.[21] Women who are opioid dependent have higher rates of miscarriage compared with nondrug users.[8] Meta-analyses on neonatal outcomes and maternal heroin use have produced crude odds ratios for antepartum hemorrhage (odds ratio [OR]: 2.33; 95% CI: 1.324.30).[22] Among pregnant women who continue illicit intravenous heroin consumption, the risks of medical complications such as infectious diseases, endocarditis,

abscesses and sexually transmitted diseases are increased.[13] Opioid users, particularly those abusing heroin frequently, have menstrual irregularities that include oligomenorrhea and amenorrhea. The disruption is postulated to be due to the effect on the hypothalamicpituitary ovarian axis via changes in gonadotrophin levels. This can lead to unplanned or unexpected pregnancies as women may not be aware when they are ovulating.[15] Opioids, unlike alcohol, cocaine or benzodiazepines, have not been specifically linked to any teratogenic effects.[13] Neonatal complications documented include opioid withdrawal, postnatal growth deficiency, microcephaly, neurobehavioral problems and a 74-fold increase in sudden infant death syndrome.[21] Repeated use of heroin and withdrawal symptoms are associated with increased neonatal mortality, with crude OR calculated to be 3.27 (95% CI: 0.959.60).[22] High rates of intrauterine growth retardation and LBW have been reported in heroin-addicted mothers.[23] A meta-analysis of 18 studies found that, compared with nondrug-using mothers, the relative risk of LBW infants for maternal heroin use was 4.61 (95% CI: 2.787.65);[6] prematurity and smallfor-gestational-age babies and have also been frequently reported.[2,6] Maternal opioid and methadone use during gestation predisposes the infant to signs and symptoms of central and autonomic nervous system regulatory dysfunction, traditionally defined as neonatal abstinence syndrome (NAS), which frequently results in significant morbidity and prolonged hospital stays.[22] Rates of NAS vary according to studies, from 20% to 5594%.[7,24] It is characterized by irritability, gastrointestinal disturbances, sleep and feeding disturbances, and can disrupt motherchild bonding. The onset, duration and severity vary and are mainly influenced by the type of drug used, the severity of maternal drug dependence, the timing of the last drug intake and fetal metabolic factors. Onset usually occurs within 2472 h of birth, but it can be delayed by up to 710 days.[2] Some infants can present with significant NAS up to 4 weeks of life and can exhibit subacute NAS symptoms for many weeks to months after birth.[22] Methadone-maintenance therapy is associated with protracted NAS[23] but most researchers agree that NAS severity is not related to maternal methadone dose or cumulative methadone exposure in utero.[22] It is important to recognize that many opioid-exposed infants are in actuality polydrug exposed, and the contributory effect of other licit and illicit substances, including alcohol and nicotine, to the signs and symptoms of physiologic and behavioral dysregulation after birth, must be considered.[25]
Benzodiazepines

Once the most commonly prescribed class of drugs, benzodiazepines have a chequered history. Their addictive potential has become more evident in the past couple of decades. However, they are still widely prescribed as muscle relaxants, anxiolytics, antiepileptics and to treat alcohol withdrawal, among other indications. Street benzodiazepines are widely available and common drugs of abuse. They may be used to enhance or ameliorate the effects of opioids, stimulants or alcohol. In pregnancy, they individually, or in combination with other drugs, increase the risk of adverse maternal and fetal events in pregnancy. All classes of benzodiazepines readily cross the placenta and are secreted in breast milk.[26] The teratogenic potential of benzodiazepines has been documented, although some evidence has been inconsistent. A large review by Iqbal and colleagues specifically looked at the literature relating to fetal and neonatal effects of various benzodiazepines both in pregnancy and lactation.[26] The authors concluded that the evidence was not firmly conclusive for establishing the teratogenic effects of benzodiazepines; however,

they did advocate strong caution and avoidance of use where possible in pregnancy. Benzodiazepines (specifically diazepam) in the first trimester of pregnancy have been linked to oral cleft palate. In a Swedish birth cohort study, an increased risk for preterm birth and LBW was detected in the exposed population. A higher than expected number of infants with pylorostenosis or alimentary tract atresia (especially small gut) was found,[27] while benzodiazepine use towards the end of gestation may cause withdrawal in the newborn.[4] During lactation, benzodiazepines can cause sedation, lethargy and poor growth of the fetus.[26] The sedation and lethargy is reported to be due to impaired metabolism of diazepam and its metabolites in the infant.[26] A meta-analysis of cohort and casecontrolled studies examined the relationship between benzodiazepine use in pregnancy and major malformations. The cohort studies were inconclusive, however casecontrol studies showed a small statistically significant association (OR: 1.79; 95% CI: 1.132.82).[28] The sample sizes in the studies were small and so the findings should be interpreted with caution. More recently, studies have linked increased risks of preterm delivery (adjusted OR: 6.79; 95% CI: 4.0111.5) and LBW, neonatal intensive care unit admissions and low Apgar scores to antenatal exposure.[29,30] Postulated mechanisms for neurotoxicity include promoting apoptosis in the developing brain by activating aminobutyric acid.[31] Furthermore, in neonates of benzodiazepine-using mothers, NAS will occur with a prolonged course similar to that of benzodiazepine withdrawal in adults.[20] A French study specifically looking at links between congenital malformations and benzodiazepine exposure in early gestation found a significant association between lorazepam and risk of anal atresia.[32]
Cannabis

Cannabis is the most commonly used illicit drug in surveys reported in Australia (36.1%), the USA (40%) and the UK (20.9%). Consumption is said to reach a peak among teenagers and young adults (1530 years).[33,34] It has been reported that, of 7500 pregnant women in The Netherlands, 3.2% of women reported using cannabis before pregnancy and 2.9% women used cannabis both before and during pregnancy. The strongest determinant for maternal cannabis use during pregnancy was cannabis use by the biological father of the child (OR: 38.56; 95% CI: 26.1458.88).[35] Cannabis use is often comorbid with tobacco and alcohol use, and women who report regular cigarette smoking are 4.59.5-times more likely to report co-occurring cannabis misuse and dependence.[36] The active ingredient in cannabis is d9-tetrahydocannabinol (THC), and it acts on the cannabinoid 1 and 2 receptors, part of a cannabinoid system in the human brain. Crossplacental transfer of THC is approximately a third of maternal plasma levels.[33] Increasing evidence suggests that developmental exposure to cannabinoids induces subtle neurofunctional alterations in the offspring.[36] The endocannabinoid system is thought to influence neural systems governing mood, cognition and reward.[37] Most studies on the effects of cannabis in pregnancy are confounded by sociodemographic variables and the comorbidity of other drugs, especially nicotine. While labeled as a drug of abuse, cannabis has been researched therapeutically and approved to treat pain syndromes. Numerous randomized clinical trials have demonstrated safety and efficacy for Sativex in central and peripheral neuropathic pain, rheumatoid arthritis and cancer pain.[38]

Stimulants Cocaine/Crack Cocaine

The reported prevalence of cocaine use during pregnancy varies from 0.3 to 9.5%.[2] Cocaine exposure in the UK was reported to be less than 1.1% among pregnant women.[39] A crosssectional study involving 167 pregnant substance-using women referred to a specialist perinatal addiction outreach service in southeast London measured a 24% prevalence of self-reported cocaine powder or crack cocaine use. When all primary and secondary drug use was considered, the same study reported an overall prevalence of cocaine use in pregnancy of 31%.[3] In utero cocaine exposure has been reported to produce a continuum of obstetric complications and reproductive casualty. Cocaine use in pregnancy can lead to spontaneous abortion, preterm births, placental abruption and congenital anomalies.[40] In a retrospective casecontrol study of 200 cocaine-exposed maternalneonatal pairs and 200 controls from 1991 to 2000, cocaine use correlated with premature rupture of membranes (23 vs 0%; p < 0.001), fetal demise (5 vs 0%; p = 0.004) and preterm delivery (40 vs 6%; p < 0.001).[41] Cocaine-exposed infants delivered earlier (36 vs 39 weeks; p < 0.001) had lower birthweights (2450 vs 3305 g; p < 0.001), more respiratory distress syndrome (14 vs 4%; p = 0.001), congenital syphilis (12 vs 1%; p < 0.001) and longer hospital stays (10 vs 3 days; p < 0.001). Determining the relative influence of prenatal cocaine exposure on long-term child development has remained a complicated and often controversial issue, in part because of the complex interplay of numerous covariates such as the timing and the amount of cocaine use during pregnancy, polydrug use, and the quality of preand post-natal care.[42] Cocaine in all its forms specifically acts by constricting blood vessels. Consequently, one mechanism by which cocaine exerts a teratogenic influence on fetal development is through the vasoconstrictive effects of cocaine on maternal blood flow, which impair placental blood flow and may lead to maternal hyper-tension, fetal vasoconstriction and episodes of fetal hypoxia.[43,44] Cocaine also alters the developing monoaminergic neurotransmitter systems, which include dopamine, noreprinerphine and serotonin[45]. This disruption may affect brain development globally, as well as impact the structural and functional aspects of specific systems. There are a few quantitative neuroimaging studies using diffusion tensor imaging,[46] volumetric MRI,[47,48] and functional MRI[49,50] that are starting to show findings related to prenatal cocaine exposure that support long-term effects on brain structure and function.
Amphetamines & Methamphetamines

Amphetamines and methamphetamines (MA) are also psychostimulants, although their mechanism of action upon the monoaminergic system is markedly different from that of cocaine. The additional methyl group allows MA to move through lipid-permeable membranes more easily than amphetamine. Amphetamines are usually used orally or, in the case of MA, intravenously, leading to experience of an immediate ecstasy (flash), and crystal MA (blue ice) is a form of the drug that can be smoked.

Although amphetamine use and misuse has been on the increase[101] and exceeding cocaine use in many regions of the USA,[51] there has been comparatively little systematic research to establish the prevalence and the short- and long-term effects of amphetamine use during pregnancy. MA is the most commonly misused type of amphetamine in some countries.[101] In USA communities with high MA use, more than 5% of pregnant women reported using the drug at some point during pregnancy.[52] The largest study of prenatal MA use, the Infant Development, Environment, and Lifestyle (IDEAL) study found that exposed human neonates were more likely to be 3.5-fold smaller than average for gestational age and have lower birthweights than children not exposed to MA,[53] perhaps not surprising, given the anorectic effects of the drug. Other studies reported MAinduced growth restriction as evidenced by smaller head circumference, lower birthweight and decreased gestational age.[54] After adjusting for covariates, exposure to MA was associated with increased physiological stress (p = 0.043; effect size of 0.07), lower arousal (p = 0.005; effect size of 0.53) and more lethargy (p = 0.05; effect size of 0.39).[55] Others have reported changes in the structure and myelination of the optic nerve and deficits in visual system development[56,57] due to MA exposure in utero, a decreased rate of physical growth and lower birthweight.[58] Neuroimaging studies evidenced smaller striatum and hippocampus volumes, and alternations in striatal energy metabolism in children exposed to MA gestationally.[59,60]
3,4-methylene-dioxymethamphetamine

3,4-methylene-dioxymethamphetamine (MDMA) is an analogue of MA that shares structural similarities and several pharmacologic properties with amphetamines (e.g., MA) and hallucinogenic agents (e.g., mescaline).[61] It has become a widely misused drug, especially among adolescents and young adults, including women of childbearing age. Prevalence of use rates at these ages are 412% over the last decade.[51] In the EU, MDMA prevalence of selfreported use ranges from 0.6 to 14.6% of 1534-year-old individuals, depending on the country.[102] At high doses, MDMA is capable of toxicity and, akin other drugs, passes through the placental barrier to enter into the fetal circulation,[62] suggesting that MDMA use during pregnancy is capable of causing deleterious effects in the offspring.
Hallucinogens & Other Recreational Drugs

In the EU, lysergic acid diethylamide (LSD) prevalence of self-reported use reaches 7.5% (UK), with 20 out of 23 countries reporting having rates between 0.4 and 2%.[102] By contrast, in the few countries providing comparable data, the use of LSD is often exceeded by that of hallucinogenic mushrooms, where lifetime prevalence estimates for young adults range from 0.3 to 8.3%, and in 2009 prevalence estimates were between 0.2 and 12.8%.[102] There is little evidence of the effects of LSD on pregnancy. Similarly with drugs such as phencyclidine (PCP), ketamine and Khat, there is little evidence of their effects on pregnancy or fetal outcomes. Party drugs, including herbal highs (which may be legal) and methadrone, have become popular over the last few years in the UK and internationally. There is little evidence on the effect of these type of drugs on pregnancy; however it is likely that any detrimental effects occurring in the adult are likely to occur in the fetus. In addition, Wolff and Winstock have reported risks associated with the injuries resulting from the use of hallucinogens.[63]

Stimulants Cocaine/Crack Cocaine

The reported prevalence of cocaine use during pregnancy varies from 0.3 to 9.5%.[2] Cocaine exposure in the UK was reported to be less than 1.1% among pregnant women.[39] A crosssectional study involving 167 pregnant substance-using women referred to a specialist perinatal addiction outreach service in southeast London measured a 24% prevalence of self-reported cocaine powder or crack cocaine use. When all primary and secondary drug use was considered, the same study reported an overall prevalence of cocaine use in pregnancy of 31%.[3] In utero cocaine exposure has been reported to produce a continuum of obstetric complications and reproductive casualty. Cocaine use in pregnancy can lead to spontaneous abortion, preterm births, placental abruption and congenital anomalies.[40] In a retrospective casecontrol study of 200 cocaine-exposed maternalneonatal pairs and 200 controls from 1991 to 2000, cocaine use correlated with premature rupture of membranes (23 vs 0%; p < 0.001), fetal demise (5 vs 0%; p = 0.004) and preterm delivery (40 vs 6%; p < 0.001).[41] Cocaine-exposed infants delivered earlier (36 vs 39 weeks; p < 0.001) had lower birthweights (2450 vs 3305 g; p < 0.001), more respiratory distress syndrome (14 vs 4%; p = 0.001), congenital syphilis (12 vs 1%; p < 0.001) and longer hospital stays (10 vs 3 days; p < 0.001). Determining the relative influence of prenatal cocaine exposure on long-term child development has remained a complicated and often controversial issue, in part because of the complex interplay of numerous covariates such as the timing and the amount of cocaine use during pregnancy, polydrug use, and the quality of preand post-natal care.[42] Cocaine in all its forms specifically acts by constricting blood vessels. Consequently, one mechanism by which cocaine exerts a teratogenic influence on fetal development is through the vasoconstrictive effects of cocaine on maternal blood flow, which impair placental blood flow and may lead to maternal hyper-tension, fetal vasoconstriction and episodes of fetal hypoxia.[43,44] Cocaine also alters the developing monoaminergic neurotransmitter systems, which include dopamine, noreprinerphine and serotonin[45]. This disruption may affect brain development globally, as well as impact the structural and functional aspects of specific systems. There are a few quantitative neuroimaging studies using diffusion tensor imaging,[46] volumetric MRI,[47,48] and functional MRI[49,50] that are starting to show findings related to prenatal cocaine exposure that support long-term effects on brain structure and function.
Amphetamines & Methamphetamines

Amphetamines and methamphetamines (MA) are also psychostimulants, although their mechanism of action upon the monoaminergic system is markedly different from that of cocaine. The additional methyl group allows MA to move through lipid-permeable membranes more easily than amphetamine. Amphetamines are usually used orally or, in the case of MA,

intravenously, leading to experience of an immediate ecstasy (flash), and crystal MA (blue ice) is a form of the drug that can be smoked. Although amphetamine use and misuse has been on the increase[101] and exceeding cocaine use in many regions of the USA,[51] there has been comparatively little systematic research to establish the prevalence and the short- and long-term effects of amphetamine use during pregnancy. MA is the most commonly misused type of amphetamine in some countries.[101] In USA communities with high MA use, more than 5% of pregnant women reported using the drug at some point during pregnancy.[52] The largest study of prenatal MA use, the Infant Development, Environment, and Lifestyle (IDEAL) study found that exposed human neonates were more likely to be 3.5-fold smaller than average for gestational age and have lower birthweights than children not exposed to MA,[53] perhaps not surprising, given the anorectic effects of the drug. Other studies reported MAinduced growth restriction as evidenced by smaller head circumference, lower birthweight and decreased gestational age.[54] After adjusting for covariates, exposure to MA was associated with increased physiological stress (p = 0.043; effect size of 0.07), lower arousal (p = 0.005; effect size of 0.53) and more lethargy (p = 0.05; effect size of 0.39).[55] Others have reported changes in the structure and myelination of the optic nerve and deficits in visual system development[56,57] due to MA exposure in utero, a decreased rate of physical growth and lower birthweight.[58] Neuroimaging studies evidenced smaller striatum and hippocampus volumes, and alternations in striatal energy metabolism in children exposed to MA gestationally.[59,60]
3,4-methylene-dioxymethamphetamine

3,4-methylene-dioxymethamphetamine (MDMA) is an analogue of MA that shares structural similarities and several pharmacologic properties with amphetamines (e.g., MA) and hallucinogenic agents (e.g., mescaline).[61] It has become a widely misused drug, especially among adolescents and young adults, including women of childbearing age. Prevalence of use rates at these ages are 412% over the last decade.[51] In the EU, MDMA prevalence of selfreported use ranges from 0.6 to 14.6% of 1534-year-old individuals, depending on the country.[102] At high doses, MDMA is capable of toxicity and, akin other drugs, passes through the placental barrier to enter into the fetal circulation,[62] suggesting that MDMA use during pregnancy is capable of causing deleterious effects in the offspring.
Hallucinogens & Other Recreational Drugs

In the EU, lysergic acid diethylamide (LSD) prevalence of self-reported use reaches 7.5% (UK), with 20 out of 23 countries reporting having rates between 0.4 and 2%.[102] By contrast, in the few countries providing comparable data, the use of LSD is often exceeded by that of hallucinogenic mushrooms, where lifetime prevalence estimates for young adults range from 0.3 to 8.3%, and in 2009 prevalence estimates were between 0.2 and 12.8%.[102] There is little evidence of the effects of LSD on pregnancy. Similarly with drugs such as phencyclidine (PCP), ketamine and Khat, there is little evidence of their effects on pregnancy or fetal outcomes. Party drugs, including herbal highs (which may be legal) and methadrone, have become popular over the last few years in the UK and internationally. There is little evidence on the effect of these

type of drugs on pregnancy; however it is likely that any detrimental effects occurring in the adult are likely to occur in the fetus. In addition, Wolff and Winstock have reported risks associated with the injuries resulting from the use of hallucinogens.[63]

Management of Substance Misuse in Pregnancy General Priniciples

While individual treatments for illicit drugs are described later, certain broad principles apply to all women with substance misuse in pregnancy. Establishing a supportive relationship and gaining their confidence is key to the success of any future management plan. Developing a therapeutic alliance with a timely, flexible, empathetic and optimistic approach is needed.[20] Management of substance misuse during pregnancy should combine full assessment with biological, psychological and social management.[64] The multifactorial etiology of this problem and its diverse consequences requires a coordinated, multidisciplinary approach that addresses each facet of the continuum of care. Care extends far beyond parturition and breastfeeding. Many patients need to learn parenting skills and will need support and help. Providing a stabilizing environment and social service support prevents the problems from passing over to the next generation.[13] Early interventions for children with intrauterine drug exposure needs a culturally relevant family-oriented approach.[65] Three community-based interventions have been studied in the USA for pregnant drug users and their children and have yielded promising results.[65] While treating the drug misuse one must not lose sight of psychiatric comorbidity such as anxiety and depression, which are prevalent in this group. Appropriate pharmacological and psychological treatment and monitoring of drug interactions is crucial.[13,20] Referral to a specialist perinatal addictions treatment service is ideal but not available in most areas. Alternatively, cooperation between the maternity services and addictions services are vitally important to ensure improved outcomes. The perinatal outreach service that was provided in a clinic in London had good outcomes with a polysubstance-using population of pregnant women. This type of service had all aspects of care conducted by one service where treatment occurred at home, at the addictions or the maternity service depending on the patient preference and level of need.[8,66] The treatment team consisted of an addictions nurse and specialist midwife, medical input from addictions and maternity staff, in addition to liaison with other services as needed such as housing, social services, criminal justice and mental health.
Pharmacological Therapies Opioids

Opioid-maintenance Therapies. Substitution therapy with opioid agonists is effective in opioid dependence and recommended by the WHO for the treatment of opioid dependence.[67,68] Opioid

maintenance treatment has also been recommended for women with opioid dependence who are pregnant.[21,64,69] Opioid maintenance includes both methadone mixture and buprenorphine tablets, which are long-acting agonists that are consumed orally and have been licensed to treat opioid dependence in most countries. However, neither methadone nor buprenorphine have been licensed to treat opioid dependence in pregnancy. Opioid-agonist treatment objectives for pregnant patients are similar to those of their nonpregnant counterparts: to prevent opioid withdrawal signs/symptoms, to provide a comfortable induction onto the medication, and then to block the euphoric effects of illicit opioids while also attenuating the motivation (i.e., craving and social interactions) to use illicit opioids and other drugs. In addition, there are pregnancyspecific objectives of eliminating the fetal exposure to illicit opioids and other drugs and attempting to stabilize the intrauterine environment.[20] Methadone and buprenorphine have been discussed in greater detail later. Slow-release morphine has been used in some countries for the treatment of opioid dependence in the nonpregnant and pregnant population. A recent Cochrane review found no differences in outcomes between methadone, buprenorphine and slow-release morphine, but suggested that larger randomized controlled trials were needed to draw meaningful conclusions.[21]
Methadone

Methadone is a synthetically derived agonist that selectively binds to the -opioid receptor, thereby exerting morphine-like effects. Currently, methadone maintenance treatment (MMT) is the most commonly used pharmacotherapy for opioid dependence.[25] Opioid-dependent mothers prescribed MMT have consistently shown improvements in birthweight, increased engagement with services, and enhanced access to comprehensive antenatal and postnatal care.[2,6,7,18] In the context of a multiprofessional, comprehensive care system, methadone improves the pregnant womans medical condition.[13] Increasing antenatal attendance stabilizes chaotic lifestyles and may help resolve housing, employment and other social problems, all of which have an impact on fetal outcome.[70] MMT in pregnancy is significantly associated with harm reduction by reducing illicit heroin use and other negative lifestyle factors that contribute to improved neonatal outcomes.[25] Doses can be started at 1030 mg with monitoring and gradual increments using standardized opioid withdrawal scales.[20] Owing to physiological changes in the third trimester to prevent breakthrough or withdrawal symptoms, split-day dosing can be initiated.[13,20,25,64] Higher doses of methadone leads to better results.[13,25] Some clinicians are cautious about increasing the dose due to increased risks of protracted NAS. A study that compared pregnant opioid users on high doses (average: 132 mg) versus low doses (average: 62 mg) found no significant differences in duration or treatment of NAS. With an average dose of approximately 100 mg an 80% negative toxicology screen in the sample was obtained.[71]
Buprenorphine

The incidence of NAS with methadone has prompted researchers to look at buprenorphine. It is a semisynthetic thebaine derivative that selectively binds as a partial agonist to the -opioid receptor, and to the -opioid receptor as an antagonist.[25] It has a longer half-life than methadone, which permits single daily dosing throughout pregnancy. While not yet licensed in pregnancy

trials have compared it to methadone. These trials have reported a lesser incidence and duration of NAS and hospital stay compared with methadone; however, sample sizes are small.[70,72] It was initially found to be acceptable in pregnant opioid-dependent women in small trials in Austria.[71] Naturalistic cohort studies from France, where buprenorphine has been used for over a decade, have also found it to be a favorable alternative to methadone.[73] In a double-blind double-dummy comparison study where 18 women randomly received oral methadone (40100 mg) or sublingual buprenorphine (824 mg), there was greater retention in the buprenorphine group but lesser illicit use in the methadone group.[73] There are some issues specific to buprenorphine use in pregnancy. One important issue is the risk of precipitated withdrawal, particularly if the woman is currently abusing heroin or methadone.[20] The risk of diversion is also present but can be alleviated with daily supervision, which is more commonly practiced in pregnancy. While certainly not recommended in pregnancy, studies that have looked at moving people from slow-release morphine or methadone to buprenorphine in the second trimester have managed it but discovered complaints of dysphoric mood and clear-head status. Doses of buprenorphine can be variable depending on the circumstances and need to be individually tailored. Despite this, management with buprenorphine has been comparable with MMT, especially with lower incidence of NAS and safety in neonates.[25] In 2006, a study with 259 participants did not identify any major differences for perinatal outcome between methadone (57 30.4 mg) and buprenorphine (5.4 4.5 mg).[74]
Detoxification or Abstinence

The issue of detoxification or abstinence-focused treatment in pregnant women remains contentious. Pregnant women should be stabilized on methadone as soon as dependence is established to prevent further harm from illicit opioid use, particularly injecting heroin use. Some women prefer to become abstinent from opioids during pregnancy and may request detoxification. While abstinence is an ideal goal, many women cannot remain drug free in pregnancy and on resumption of drug use, continued cycles of intoxication and withdrawal can lead to fetal distress.[13,25] There are high possibilities of resuming heroin use following detoxification and the success rates of abstinence following detoxification during pregnancy has been questioned.[2,6] Abstinence can be achieved in well-stabilized and motivated individuals under close supervision with slow reduction of the synthetic opioid.[13] While detoxification is safest within an in-patient facility owing to increased monitoring, it can be undertaken safely in the community.[23] UK national guidelines suggest that in the second trimester detoxification, is undertaken in small, frequent reductions (e.g., 23-mg methadone reductions every 35 days) as long as illicit opioid use is not continuing.[64] If illicit opioid use continues uncontrolled then detoxification is not advised and should cease, and the opioid dose may need to be increased until the woman has stopped illicit opioid use and achieved stabilization.[64] Currently, USA and Australian guidelines advise maintenance on methadone throughout pregnancy.[20]
Labor, Delivery & Breastfeeding

Detailed discussions are beyond the scope of this paper and readers are advised to consult more detailed reviews. The care of pregnant women at birth is particularly important and may

determine future positive engagement with treatment services. Maintenance treatment is recommended to precipitate withdrawal during labor and delivery.[20] Women with opioid dependence present a challenge as they will often have a higher opioid tolerance and be prescribed opioids. Since most opioid-dependent patients require greater-than-typical doses of opioid analgesics for pain management, individualized pain control is needed[20] and specialist advice may also be useful.[103] Epidural rates tend to be higher and there can be problems with post-cesarean pain control.[14,75] Epidural analgesia can provide adequate pain relief in patients requiring pain relief.[20] Commonly used opiate agonist/antagonist medications such as nalbuphine are contraindicated in this patient group as they may precipitate withdrawal.[20] Currently, breastfeeding is recommended by most authors in methadone-maintained women as the benefits outweigh the risks.[76,77] Breast feeding is known to reduce the length and severity of NAS and minimize the need for pharmacological treatment.[78] Following delivery, consensus statements recommend maintaining patients on methadone doses similar to levels received prior to pregnancy, but patients frequently wish to be medication-free upon delivery of the child. Patients should be advised of the stresses of early motherhood, the likelihood of relapse during medication tapering and the desirability of continuing agonist treatment. Postpartum methadone doses are recommended to be reduced to half the dosage required in the third trimester.[20,79]
Neonatal Abstinence Syndrome

The optimal treatment of NAS is determined by using standardized scales that rate symptom severity. The Finnegan scoring system is very popular and a score of 8 or above usually necessitates pharmacological treatment.[22] The Lipsitz system has been recommended by the American Academy of Pediatrics.[22] Opium tincture, phenobarbitones, benzodiazepines and morphine have all been used.[13,22] A recent Cochrane review comparing morphine to phenobarbitones and sedatives to treat NAS suggested that morphine or a dilute tincture of opium was the preferred treatment option.[80]
Benzodiazepines

Owing to the potential risk of teratogencity with benzodiazepine use, ideally benzodiazepine prescriptions should be gradually discontinued before a planned pregnancy. As a general rule, exposure to any type of benzodiazepine during the first 3 months of pregnancy should be avoided, because the fetus is most vulnerable to the toxic effects of drugs during this period of active organogenesis.[26] A riskbenefit analysis should be undertaken and specialist advice sought at the time. While withdrawal of methadone may occur during the second trimester, the risks of benzodiazepines are believed to be higher and, therefore, withdrawal during the first trimester may be carried out with careful monitoring and following a riskbenefit analysis. High doses of benzodiazepines are a risk for overdose when combined with opioids. Care should be taken to avoid precipitating hypnosedative withdrawal as this is very detrimental to both mother and fetus.[20] UK guidelines suggest that women who are dependent on benzodiazepines should be stabilized on diazepam and, where this can be tolerated without restarting illicit use, the dose reduced.[54] Neonates whose mothers abuse sedatives during pregnancy must be monitored for withdrawal symptoms. If concomitant opioid use is being treated then methadone dose should be maintained while benzodiazepine use is being addressed.[64]

Cannabis

No licensed biological therapies are available. Psychosocial interventions remain the mainstay of treatment. These have not been specifically evaluated in our population of interest. Studies evaluating contingency management (CM), cognitive behavioral therapy (CBT) and motivational enhancement therapy (MET), either individually or in combination, have found them to increase rates of abstinence.[81,82]
Stimulants

As with all substance misuse, women planning pregnancies should be advised to cease illicit stimulant use prior to conception. However, women using these drugs may not be in treatment and not have disclosed stimulant use to their attending clinicians. Owing to the potential severe adverse effects of stimulant use on the pregnancy and fetus, patients require monitoring throughout pregnancy and the perinatal period. Currently no pharmacological substitutes have been identified to treat stimulant abuse in pregnancy or other groups. Cochrane reviews that have looked at antidepressants, anticonvulsants or dopaminergic agents for cocaine dependence have not been encouraging.[83,84] Similar reviews have looked at antidepressants in amphetamine misuse and have not found any significant benefit.[85,86] The only place for medication administered for stimulant withdrawal in pregnancy is symptomatic relief of severe agitation. Mood symptoms (and potential effects on noncompliance) that might be experienced by the mother have been ameliorated with the use of short-acting benzodiazepines, particularly during in-patient stays.[79] Although cocaine is highly addictive to the adult, fetal withdrawal symptoms in the newborn are seen much less frequently than symptoms of opioid withdrawal. Unlike opioid substitution, cocaine substitution is not beneficial and is likely to be detrimental. Cocaine can remain in breast milk for up to 48 h. Women who produce drug-free urine screens can breastfeed.[6] Since there is no pharmacological substitute identified to treat stimulant dependency, including in the population of pregnant users, psychosocial interventions remain the key approach to address stimulant addiction.
Hallucinogens & Recreational Drugs

Currently, no licensed treatments are available for these classes of drugs. While no specific treatments have been evidence based, psychosocial interventions may be useful in these patients. Education, CM and motivational techniques to stop the drug use during pregnancy may be useful.
Psychosocial Interventions

Psychosocial interventions are a broad group of nonpharmacological interventions that have become an integral part of substance misuse management in all patient populations. They range from counseling, education, relapse prevention and brief intervention to more formal methods, such as CM therapy, CBT and MET. They also include self-help groups such as Alcoholics Anonymous and Opiates Anonymous. They help in increasing engagement, relapse prevention

and improve adherence to treatment regimens. They are the mainstay of treatment for stimulants, cannabis and hallucinogens misuse. While pharmacological treatment is effective with opioid dependence, it has been found that treatment is more effective when combined with psychosocial interventions.[87] A recent Cochrane review concluded that psychosocial interventions alone for opioid dependence have not been found to be effective.[88]
CM Therapies

These are interventions in which substance-misusing individuals receive tangible, positive reinforcers for objective evidence of behavior change. For example, patients receive a voucher, exchangeable for retail goods and services, whenever they submit a urine specimen that tests drug negative.[89] They have been quite popular in the USA and have recently been adopted in the UK.[90] CM has been found in the USA to be particularly beneficial in cocaine, cocaine/opioid and MA misuse.[14,89] A meta-analysis that specifically looked at efficacy of CM and MET in pregnant out-patients abusing illicit attending clinic reviewed nine trials. CM was better than MET in study retention but did not influence abstinence.[91]
Cognitive Behavioral Therapy

This has been particularly useful in addressing comorbid anxiety and mood symptoms in this population. Group and individual sessions of CBT had both efficacy for the treatment of cannabis dependence and associated problems.[82] They improve adherence to treatment regimens by improving depression, thereby reducing drug-taking behavior.[14]
Expert Commentary

Maternal substance misuse is a complex and challenging clinical problem that has a high prevalence. In general, most illicit drugs have been linked to adverse effects in the pregnancy. Pharmacological treatments in pregnancy exist only for opioid use. Opioid-substitution therapy has made a significant difference in reducing harm and improving antenatal and postnatal care of pregnant mothers. Psychological and psychosocial treatments are the main treatment for reducing stimulant and hallucinogen misuse, and increasing the success of treating opioid use. Research into the effects of specific drugs remains difficult because there are often restrictions on conducting research with pregnant women. Neuropharmacological and neuropathological research on individual drug effects on the developing brain have mainly been studied in animal models, and they provide important insights into brain development and vulnerability. Functional neuroimaging in drug-exposed infants is helping to develop new insights into neural pathways affected. In particular, cortical and subcortical fetal brain structures show evidence of vulnerability to intrauterine drug exposure.[22] Studies conducted into teratogencity have been hindered by sample sizes, methodological limitations and ethical problems. In addition, various confounders, such as co-morbidity, polydrug use and environmental effects, further hinder the efforts to specifically link a drug to a particular adverse outcome. Increasing access, identifying problems and screening in this most vulnerable population still remains a major challenge, and minimizing harm to both mother and infant requires multiagency collaboration. Substance

misuse in pregnancy has far-reaching developmental effects and engulf successive generations in the family if appropriate early interventions are not used. Awareness of the potential harm of drug-misuse and screening tools designed to identify patients have come a long way and continue to develop. It also requires political will and public education to create awareness and health systems that deliver effective care and management.
Five-year View

Great strides have been made in the field but significant challenges remain. Research into meconium testing and other matrices to detect and monitor drug use will help to increase detection rates. As sensitivity and specificity of these methods increase they should become more applicable in clinical settings. There is a need for more fundamental research on mechanisms of drug action on the brain and this will inform the relative risk of each drug and at what time in development the fetus is most vulnerable. It would help develop novel treatments. The next 5 years will see greater use of functional neuroimaging as a noninvasive technique to map affected areas of the brain and correlate it with clinical outcomes. New treatments for stimulant addiction such as lofexide and atomexetine that target the noradrenergic system are being researched.[92] Literature supporting the role of acetylcholine in stimulant addiction is also growing, and cholinesterase inhibitors currently used to treat dementia are being studied in stimulant addiction.[93,94] Larger, more robust trials need to be conducted and novel biomarkers for MA are being investigated.[95] These will provide more accurate estimates of drug exposure and fetal effects. As newer drugs enter the market in the future the need to expand our understanding of these effects in all populations, including pregnant women, will increase. The gaps in epidemiological and social research need to be filled. Some longitudinal studies that have looked at adverse birth outcomes in the context of lifestyle and associated factors have begun to expand our understanding. Similar large-scale studies need to be conducted and need to be methodologically sound to reduce the bias of lifestyle and environment in the context of drug use. Treatment regimens that do not just target the drug of misuse but the individuals social and economic situation may have to be developed to be more successful. Studies that have evaluated community-based interventions during pregnancy and for children postpartum have shown positive effects. We hope that the next 5 years will focus efforts in this field of research and inform public-health planning, service delivery and allocation of appropriate resources. Research into child-protection measures, risk assessment for vulnerable children and the impact of this on the mother needs to be further examined; psychosocial interventions such as CM and CBT have been found to be useful in treating substance use. They will be researched more vigorously in tandem with pharmacological treatments to improve outcomes. Medical and clinical research will need to be accompanied by epidemiological and social research in large cohorts to understand the pathways to pregnant drug users and look at ways to engage and support them in a more patient-centered manner. Only when all of these work together can we look at a bright future for the pregnant drug user and her offspring.

Key Issues

Drug misuse in pregnancy is a challenging and complex health problem, which is increasing in prevalence worldwide. Maternal drug use in pregnancy is associated with a wide spectrum of maternal and fetal complications. Opioid misuse in pregnancy is associated with complications such as low birthweight and neonatal withdrawal syndrome. Methadone is the choice for opioid substitution therapy in pregnancy and improves outcomes. Buprenorphine has been studied as an alternative and has demonstrated comparable efficacy. Breastfeeding is not contraindicated in opioid-maintenance therapy as it has demonstrable benefits. Cannabis is widely used in pregnancy and was thought to be lower risk, but there is increasing evidence that it has subtle neurodevelopment effects. Benzodiazepines are potentially teratogenic and prescriptions should best be avoided in pregnancy. Stimulant misuse produces a continuum of obstetric and neonatal complications; however, there are currently no pharmacological treatments available. Psychosocial interventions such as contingency management and cognitive behavioral therapy have been useful in reducing stimulant misuse and help to improve engagement and compliance. Hallucinogen misuse is also prevalent but the effects are still being uncovered. Urine screening is commonly used in addition to self-report and interview. Meconium testing and confirmation is increasingly being used and newer methods are being developed to increase selection rates. Assessment of the pregnant user needs to be comprehensive, exploring drug use, psychiatric and physical comorbidity, and lifestyle effects. The management requires coordinated multidisciplinary care that extends beyond parturition. Advances in neuropharmacology and identifying new biomarkers to enhance sensitivity will improve our understanding of the effects of individual drugs and their effects. There is a need for research to improve our understanding of the context in which maternal drug use occurs and to develop appropriate treatments. Further social and epidemiological research is needed to identify the role of associated factors in the pregnant drug user.

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