Drug Abuse

16 Pregnancy and parenting in drug treatment

Guidelines for treatment improvement
Moretreat-project
MUW Vienna Austria
October 2008
(This protocol includes parts of the manuscript for WHO guidelines and therefore may not be published before the publication of these WHO guidelines; the reference always has to be stated)

The content of this report does not necessarily reflect the opinion of the European Commission. Neither the Commission nor anyone acting on its behalf shall be liable for any use made of the information in this publication.

Content

1. Introduction
1.1 Definitions

2. Evidence base
2.1 Multiple substance abuse during pregnancy
2.2 Treatment of drug use during pregnancy
2.3 Neonatal abstinence syndrome (NAS)
2.4 Psychiatric co-morbidity in pregnancy
2.5 Overview of European literature

3. Recommendations
3.1 Maintenance treatment during pregnancy
3.2 Treatment of NAS
3.3 Blood borne viruses
3.4 Access to treatment
3.5 Breastfeeding

References

1. Introduction

1.1 Definitions

Evidence-based treatment options in the field of substance dependence and pregnancy and parenting are limited since trials are difficult to conduct in this area. Many of these women are poly-drug users, and so standardization and interpretation of the study results is complex. As long as women continue to abuse opioids and other drugs, we will be faced with challenges in the management of pregnant addicts. Getting these women into multidisciplinary treatment as early as possible, where they can be maintained on medication and monitored regularly, is beneficial to both mother and child, in both the short and long term, and should be standard practice. Abstinence of opioids during pregnancy is difficult to maintain, but it presents the ideal goal. Opioid maintenance therapy is the recommended treatment approach during pregnancy and there appear to be few developmental or other effects on these children in the long term. In addition to standardized approaches towards pregnancy, equivalent attention needs to be given to the treatment of the neonatal abstinence syndrome (NAS), which occurs frequently also after opioid medication. Further research in this area would be welcomed, although this obviously presents serious methodological problems.

1.1.1 Effects on mother, fetus and neonate

Substance abuse during pregnancy affects the pregnant women, the fetus and neonate in two different ways: they suffer from direct consequences due to substance use or abuse as well as from indirect ones resulting from the influence of their living environment. Substance dependent women often face difficult domestic circumstances such as violence, sexual abuse or substance abuse by a responsible family-member. Regarding the impact of the experience of violence and abuse during childhood, a strong correlation between childhood trauma and later drug dependence is reported (Schnieders et al. 2006). Furthermore, based on the multifactorial genesis of addiction, genetic influence becomes increasingly important (Lessov et al. 2004; Uhl 2006). Therefore, the need for a stable environment for the developing child, including assistance by health authorities, becomes evident in order to prevent addiction in the second generation.

2. Evidence base

2.1 Multiple substance abuse during pregnancy

All of the published literature on the topic of opioid dependence and pregnancy refer to the consequences of either heroin or methadone and more recently to buprenorphine. Other substances co-abused by the target population, tend to be neglected in the analyses. The additional use of other substances represents a potentially confounding factor that may be responsible for a variety of clinical features. We have included these below:

2.1.1 Cannabis

Marijuana abuse is very common in pregnant women (Hurd et al. 2005). However, the facts documenting the direct effects of prenatal cannabis exposure to fetal development are very limited. Hurd et al. report decreased mid-gestational fetal growth (Hurd et al. 2005). Ostrea et al. examined the incidence of SIDS associated with cannabis abuse during pregnancy and found no increased risk (Ostrea et al. 1997). The validity of these results is limited by the fact that only 11 cases of SIDS were investigated. Scragg et al. conducted a nation-wide case-controlled study in New Zealand with 393 cases and 1592 controls, which shows that cannabis abuse as a weak risk factor in SIDS (Scragg et al. 2001). Further research in this domain is indispensable, but in a real-world situation, solely cannabis-abusing pregnant women are difficult to recruit for prospective studies.

2.1.2 Cocaine

Following a major increase in cocaine use in the US over recent decades, the United Nations Office on Drugs and Crime (UNODC) has reported increasing figures for Europe, Asia and Australia – the prevalence ranges between 0.1% and 2.7% (World Drug Report, 2005).

Cocaine abuse represents an increasing and serious health problem, yet there is no proven medication for an effective pharmacological treatment. Cocaine abuse in pregnant women may have teratogenic effects on the fetus and lead to life-threatening complications like cardiac and cerebral ischemias, malignant hypertension, stroke and sudden death (Vascia et al. 2002; Brownlow et al. 2002; Egred et al. 2005). Preclinical studies suggest that the reinforcing effect of cocaine that promotes its abuse is mediated by blockade of the presynaptic dopamine transporter (Carrera et al. 2004). Presently, support for cocaine-dependent women comprises education about the risks and the consequences of ongoing substance abuse for mother and fetus. Cognitive behavioural therapy and contingency management (CM) is the standard for the treatment of the cocaine-dependent pregnant women, with the aim of cocaine abstinence (Breza et al. 2002).
Physiological changes in pregnancy have a direct effect on the metabolism of cocaine: cholinesterase slows cocaine’s metabolism in the pregnant woman as well as in the fetus. Cocaine crosses the placenta rapidly by diffusion due to its lipophilic properties, which gives rise to increased plasma concentrations in the fetus (Farrar et al. 1989; Dempsey et al. 1998; Dempsey et al. 1999).

2.1.3 Amphetamines and Metamphetamines

Handmaker et al. report a larger cranial to body growth ratio in amphetamine-exposed neonates (Handmaker et al. 2006). In 2004, Chang et al. identified several possible consequences for neonates exposed to methamphetamine prenatally. Their results showed smaller subcortical volumes and associated neurocognitive deficiencies. These findings suggest a neurotoxic effect in the developing brain of the fetus related to metamphetamine abuse during pregnancy (Chang et al. 2004).

2.1.4 Benzodiazepines

Benzodiazepines are common drugs used for the treatment of anxiety, insomnia and epilepsy. Despite the fact that benzodiazepines have been on the market for more than 40 years, the safety of their use during pregnancy remains controversial because conflicting results regarding their teratogenicity have been reported (Dolovich et al. 1998; Eros et al. 2002). In addition to the postulated teratogenic component, benzodiazepines have postnatal consequences for the infant. In spite of the apparent equivalence in potentially harmful effects, benzodiazepines are still administered to avoid prescribed opioids during pregnancy (Kandall et al. 1977; Laegreid et al. 1990; Kohen, 2004; Einarson, 2005; Swortfiguer et al. 2005). Dolovich et al. conducted a meta-analysis and found studies that examined major malformations following benzodiazepine consumption in pregnancy: 11 of the studies reported oral cleft only and three cited other specific malformations (Dolovich et al. 1998). Although Dolovich et al’s meta-analysis could not show a direct association between fetal exposure to benzodiazepines and the risk of malformations or oral cleft alone in pooled data from cohort studies, the authors outline a significantly increased risk in data from case-control studies (Dolovich et al. 1998). Eberhard-Gran et al. reported that benzodiazepines may cause adaptation problems in the newborn, concluding that the possible adverse effects of fetal exposure must be balanced against the adverse effects of an untreated maternal mood disorder (Eberhard-Gran et al. 2005). Moreover, NAS has a prolonged course after intrauterine benzodiazepine exposure, which resembles adult withdrawal symptoms (Lagreid et al. 1992; Coghlan et al. 1999). Besides the liberal prescription of benzodiazepines, including prescription to opioid-maintained patients, there is a tendency among these patients towards buying this medication on the ‘black market’. These patients often take very high doses of benzodiazepines which, require slow detoxification in order to avoid preterm labour or exacerbation of psychiatric symptoms (Swortfiguer et al. 2005; Eberhard-Gran et al. 2005).

2.1.5 Alcohol

Due to its teratogenic potential, alcohol affects the development of the foetal nervous system which may lead to severe lifelong consequences. One of these is the so called foetal alcohol syndrome (FAS) which is characterized by a dose-dependent severity, growth retardation, craniofacial abnormalities and a permanent nervous system damage (Garcia-Algar et al. 2008).

2.1.6 Opioids

The continuous abuse of illicit opioids during pregnancy leads to adverse consequences in the mother, fetus and neonate. However, in comparison to alcohol, cocaine or benzodiazepine abuse during pregnancy, opioids do not have teratogenic or cytotoxic effects (Chasnoff et al. 1984). The main risk factor is caused by the fluctuation of opioid concentration in the maternal blood, which may cause withdrawal symptoms in the neonate as well as symptoms of overdose, in addition to difficult psychosocial environmental conditions (Finnegan et al. 1992). Heroin use in pregnancy is often related to malnutrition of the pregnant women as well as a poor outcome in neonates (Finnegan et al. 1992). Johnson et al. indicate the inadequacy of antenatal care programmes for women misusing illicit substances, as they often remain in a violent environmental situation and receive poor medical and social care (Johnson et al. 2003). In addition, more than 50% have a co-addicted partner, and successful treatment is only possible if the partners are enrolled in adequate psychosocial and medical care as well (Fischer et al. 2000). Despite major methodological flaws in published reports about the effects of heroin use during pregnancy (e.g.. no control for nicotine dependence), a significant reduction in birth weight has been reported when compared to neonates of non-smoking methadone-maintained mothers (Hulse et al. 1997).

2.2 Treatment of drug use during pregnancy

2.2.1 Pharmacological treatment

Methadone in the context of comprehensive care is associated with more prenatal care, increased fetal growth and less neonatal morbidity and mortality than continued opioid abuse (Finnegan and Kaltenbach, 1992; Council of Europe, 2000; Johnson et al. 2003; Jones et al. 2005; Fischer et al. 2006). Investigations of oral methadone therapy as part of a multi-professional care system during pregnancy have highlighted many benefits over recent decades and the results are well documented: improvement of the medical condition in the pregnant woman, standardized pre-delivery care, prevention of premature birth and prevention of underweight babies (Fischer et al. 1998; Fischer et al.
2000; Daley et al. 2001; Ashley et al. 2003; Jones et al. 2005). These studies also show that higher dosing yields to better results (Kaltenbach et al. 1998). Very often the once daily dose of methadone needs to be split and administered twice daily, taking into account the physiological changes in pregnancy relating to enzyme-induction during the last trimester (Pond et al. 1985; Drozdick et al. 2002). Although methadone is clearly beneficial, it has been estimated that 60–87% of the infants born to methadone-maintained mothers need treatment for NAS (Finnegan and Ehrlich, 1990; Lacroix et al. 2004; Jones et al. 2005; Lejeune et al. 2006; Fischer et al. 2006; Sarkar et al. 2006). Buprenorphine, approved in Europe since 1999 for the treatment of non-pregnant opioid-dependent adults, may reduce the incidence and/or severity of NAS. Buprenorphine demonstrates safety for mother and child, and shows effectiveness in the treatment of opioid-dependence during pregnancy, although limited controlled data are published so far (Kayemba-Kay’s et al. 2003). To date, the scientific literature includes data on more than 450 babies prenatally exposed to buprenorphine. Results generally suggest that treatment with buprenorphine provides the same benefits to the mother as methadone but, more importantly, may attenuate NAS (Johnson et al. 2003; KayembaKay’s et al. 2003; Jones et al. 2005; Lejeune et al. 2006). The majority of information has been gained through French publications, where buprenorphine has been available for more than 10 years; as a result of the office-based prescription policy in France, many patients, including pregnant women, have been treated with buprenorphine. These naturalistic data indicate that the use of buprenorphine in pregnancy is safe; and data regarding buprenorphine use during conception has also been collected (Jernite et al. 1999; Lejeune et al. 2001; Kayemba-Kay’s et al. 2003; Lacroix et al. 2004; Lejeune et al. 2006). Limited data from prospective open-label controlled studies of neonates born to buprenorphine-treated mothers are available. Nevertheless, such data support the use of buprenorphine in pregnancy; their results suggest no NAS or a mild NAS, with only a small portion of neonates requiring treatment (Fischer et al. 2000; Johnson, Jones, & Fischer, 2003; Johnson et al. 2001). A prospective report regarding buprenorphine use at the time of conception is available: newborns show low NAS scores and are in good health (Schindler et al. 2003). Buprenorphine represents a possible alternative to methadone in maintenance therapy and is described as a safe drug for maintenance therapy of opioid-dependent women (Kayemba-Kay’s et al. 2003). Two randomized double-blind double-dummy controlled trials using similar methodology (ie Jones et al. protocol shared with Fischer et al.) were designed to obtain safety and efficacy data comparing methadone and buprenorphine in pregnant women (Jones et al. 2005; Fischer et al. 2006). Both of them indicate the safety of both substances for the mothers-to-be and the comparability in efficacy for retaining patients in treatment and in regard to concomitant consumption of illicit drugs. A major influencing factor appears to be the incidence of concomitant consumption which can be reduced through contingency management approaches (Schottenfeld et al. 2005; Carroll et al. 2005; Kirby et al. 2006). Monetary vouchers were given to patients for opioid-and cocaine-negative urine tests in a study exploring the effectiveness of contingency management in patients with co-occuring cocaine and opioid-dependence by Schottenfeld et al. There may be an improvement in treatment outcome in combining buprenorphine or methadone with contingency management (Schottenfeld et al. 2005). Interpretation of data on both medications during pregnancy has often entailed a number of problems. The lack of blinded designs and random assignment has left results of many studies subject to potential bias. Concomitant drug use has been prevalent in many study samples, confounding results. Small sample sizes have limited the statistical power of such studies, making it difficult to draw clear conclusions. Attempts to combine results across studies have been difficult due to substantial differences in methodology. A minority of studies included the issue of nicotine dependence, which might have crucial influence on outcome parameters. Another medication used for maintenancy therapy is slow-release morphine, although data on this treatment option during pregnancy is derived from small-scale studies and the medication is registered for treatment in general only in a few countries (Geistlich et al. 1998; Fischer et al. 1999; Eder et al. 2005; Kraigher et al. 2005).

2.2.2 Opioid detoxification/abstinence

Abstinence throughout the course of pregnancy is the ideal clinical aim. However, this is often unachievable and overemphasis on gaining abstinence can be futile. The quest for abstinence may place the mother under a enormous stress, and studies have shown that most opioid-dependent women cannot stay drug-free for the duration of their pregnancy (Dashe et al. 1998; Luty et al.2003; Fischer et al. 2006). This indicates that many women relapse to opioid use and a resulting continuous cycle of intoxication and withdrawal. This causes wide variations in blood opioid levels, which lead to fetal stress. Nevertheless, abstinence is feasible. In well-motivated individuals under close medical supervision and with appropriate treatment – i.e. slow reduction of a synthetic opioid, not later than week 32 in pregnancy to avoid preterm delivery – abstinence can be achieved. However, the prospect of abstinence often discourages opioid-dependent mothers from seeking help and refraining from using treatment services. The course of action to be taken needs careful discussion between doctor and patient to confirm that the appropriate treatment is given on an individual basis.

2.2.3 Psychosocial intervention/counselling during prenatal care

Services should be provided in a supportive, culturally sensitive, and non-judgmental environment by all healthcare personnel, from the receptionist to the physician. Literacy-and reading-level information will affect patient education efforts and the ability to obtain informed consent so an assessment should be made of the woman's literacy and reading level. The woman may enter prenatal care in different stages of pregnancy and from a variety of settings, including hospital emergency rooms, community health centers, family planning clinics, abortion clinics or social service offices. It is essential to be able to offer assessment, triage, case coordination and referral services from any or all of these settings. Case management services that coordinate the care of the pregnant, substance-using woman and her family are critical. Ideally, case conferences and referral to appropriate services should be managed by one healthcare professional who oversees the multidisciplinary team. An outreach worker who visits the woman in her home should be part of this team. The most difficult issue to resolve, given the financial and staffing constraints experienced by most health care and service providers, is the identification and designation of a case manager. Counselling about and obtaining written informed consent for medical procedures and treatment are important, as is the clear explanation of confidentiality, privacy and other patient rights. Equally important seems the involvement of the patient’s partner. The earlier in pregnancy that opioid-dependent pregnant women have access to psychosocial support, the higher the likelihood of establishing an appropriate living environment for the new family and of settling juridical and financial problems (Kaltenbach et al. 1998; Finnegan, 1991; Grella et al. 2006).

2.3 Neonatal abstinence syndrome (NAS)

An important aim and challenge in the treatment of pregnant opioid-dependent women is avoiding the development of NAS or minimizing its severity and duration. The incidence of NAS in neonates of opioid-dependent women varies between 70% and 95%. NAS is characterized by a variety of symptoms of variable intensity: sneezing, yawning, hyperactive Moro reflex, sleeping after feeding, tremor, increased muscle tone, myoclonic jerks, high pitched crying, excoriation, mottling, generalized seizure, convulsions, fever, sweating, nasal stuffiness, tachypnea, retractions, nasal flaring, poor feeding, excessive sucking, vomiting, diarrhoea, failure to thrive, excessive irritability and, in very rare cases, convulsions (Finnegan and Kaltenbach, 1992). NAS may start any time during the first 24 hours up to 10 days postnatally, dependent on the medication administered during pregnancy or substance abused. The withdrawal syndrome of heroin in the neonate sets in during the first 24 hours. With methadone, the symptoms don’t develop until after 48 hours (Fischer et al. 2006). An even later onset of withdrawal symptoms can be observed if the neonate was exposed to buprenorphine, benzodiazepines or barbiturates in utero. Generally, dosage of opioid-medication (methadone, buprenorphine, slow-release morphine) does not correlate with withdrawal or NAS (Kaltenbach and Finnegan, 1986; Brown et al. 1998; Berghella et al. 2003; Jones et al. 2005; Fischer et al. 2006; Lejeune et al. 2006). A limited number of recent scientific reports refer to a positive correlation of maternal dose and severity of NAS, however, some of these are confounded by additional consumption (Doberczak et al. 1993; Malpas et al. 1995; Marquet et al, 2002; Dashe et al. 2002). Importantly, higher dosing seems to lead to better results for the mother during the course of treatment (Kaltenbach et al. 1998). Different standardized and validated scoring systems are used to assess the severity of NAS. The majority of publications refer to the Finnegan Score (Finnegan, 1979; Finnegan, 1985): this score comprises 21 items and a maximum of 45 points. Treatment is initiated at a Finnegan Score greater than 10 points while a reduction in medication starts at a rating of 10 and less. The Finnegan Score should be assessed six times a day. However, many scientists and physicians working with NAS and related scorings use an adaptation of the Finnegan score (different items, different scorings, different threshold for treatment initiation) (Sarkar et al. 2006). This fact complicates the comparability in scoring of NAS in different medical centers in relation to duration and intensity. This also limits the comparability of publications. Another scoring system, which has been used more widely for NAS is the Lipsitz score (Lipsitz, 1975). The heterogeneity of rating and treatment approaches is stressed by Sarkar et al (2006).

2.3.1 Treatment of NAS

It is not easy to determine which substances are the most beneficial in the treatment of NAS, as there are currently no double-blind controlled studies available. Until 1998, the drug of choice was paregoric in the USA, a substance consisting of 44–46% alcohol with opium, benzoic acid, camphor and glycerin. Now, however, some clinicians prefer using phenobarbital, benzodiazepines or morphine (Kaltenbach and Finnegan, 1986; Chiang and Finnegan, 1995; Kandall, 1995; Rohrmeister et al. 2001; Lejeune et al. 2006). Phenobarbital and paregoric seem equally effective, but studies tend to favor paregoric because it is associated with better sucking behaviour (Kron et al. 1976). The American Academy of Pediatrics recommends the use of a tincture of opium for opiate withdrawal; and phenobarbital should be the drug of choice for sedative-hypnotic withdrawal (AAP Committee on Drugs, 1998). A combination of phenobarbital and diluted tincture of opium (DTO) has been favored because of shorter hospital stay and less severe withdrawal symptoms; it should be stressed that the neonates were tapered from phenobarbital on an outpatient basis for an average duration of 3.5 months, which may have been a confounding factor in this study (Coyle et al. 2002). The effectiveness and safety of opiate treatment in neonates has been dealt with in a recent Cochrane Review, which concludes that opiates represent the preferred initial therapy for NAS, particularly for infants of mothers taking opioids during pregnancy (Osborn et al. 2005). Various reports underline the utility of morphine in this respect. Jackson et al. show the superiority of morphine sulphate in the treatment of NAS, although 83% of patients had positive urinalyses for concomitant drug consumption at the time of delivery (Jackson et al. 2004). Theis et al. show that diazepam is clearly inferior in the treatment of neonatal withdrawal syndrome (Theis et al. 1997). In a comparison study, Langenfeld et al. recommend morphine drops as an alternative treatment of NAS (Langenfeld et al. 2005). However, in all these reports, no standardized information about urine toxicologies during pregnancy in regard to concomitant consumption have been available. According to a short report by Pacifico et al. morphine hydrochloride is described as the best therapy in the treatment of NAS, but no details are indicated (Pacifico et al. 1989). Shaw and McIvor declare oral morphine for being a successful treatment alternative in neonates born to methadone-maintained mothers; 37% of the infants enclosed in their study received that medication for withdrawal with a median length of treatment of six days (Shaw and McIvor, 1994).

2.4 Psychiatric co-morbidity in pregnancy

In the majority of cases, pregnant heroin dependent women suffer additionally from severe psychiatric and somatic illnesses or multiple substance dependences (Marsden et al. 2000; Willenbring, 2005; Galletly et al. 2006; Kurz, 2006; Winklbaur et al. 2006; Whicker et al. 2006; Watkins et al. 2006; ICD-10; DSM-IV). Therefore, we would emphasize the importance of quality assured diagnosis (applying the ASI for diagnostic procedure) and the requirement for using a broad bio-psycho-social treatment approach that takes psychiatric and somatic co-morbidities into account (Fischer et al. 1998; Kraigher et al. 2001). Women of childbearing age suffer quite often from psychiatric disorders and are frequently prescribed psychotropic drugs. However, despite the fact that most recent studies have documented the relative safety of these medications during pregnancy (although almost all results are based on a retrospective evaluation), a high level of anxiety regarding their safety persists among patients and healthcare providers alike (Einarson et al. 2005). Teratogenic effects, postnatal behavioural disorders and perinatal syndromes are of particular concern to psychiatrists. Burke et al. explored the risk of the development of depression in women and found a lifetime risk of 10–30%. Women of childbearing age are at an increased risk with a heightened prevalence of depression (Burke et al. 1991). Given the high risk for depression in women of reproductive age, treatment providers more often have to cope with opioid-dependent women of reproductive age, who additionally receive pharmacotherapy such as antidepressants. While pregnancy seems to afford a protective phase regarding the first manifestation of a psychiatric disease (O´Hara et al. 1984), others (e.g.. Evans et al. 2001) report a higher risk of depressive disorders associated with pregnancy. The occurrence of a self-limited neonatal behavioural syndrome observed after in utero exposure to serotonin reuptake inhibitors (Moses-Kolko et al. 2005) further complicates the considerations in the care of reproductively active opioid-dependent women presenting with co-morbid depression.

2.4.1 Management of psychiatric co-morbidity in pregnancy

All psychiatric pharmaceuticals cross the placenta barrier. Selective Serotonin Reuptake Inhibitors (SSRIs) are prescribed for the treatment various disorders such as major depression, anxiety and chronic pain. SSRIs are frequently administered by physicians during pregnancy and the postpartum period (Lattimore et al. 2005). Although early investigations on the effects of SSRIs in pregnancy were misleading, we know today that they include serotonergic overstimulation and withdrawal syndromes, as well as long-term effects on neurobehaviour and performance. Fluoxetine and its active metabolite norfluoxetine are among the common SSRIs and have been investigated more than sertraline, paroxetine and fluvoxamine. Even though early results showed that, during the first trimester of pregnancy, SSRIs did not seem to increase the risk of neonatal malformations, contradictory data have been published for paroxetine (Kulin et al. 1998; Ericson et al. 1999). Some research has failed to show a higher risk for spontaneous abortions with fluoxetine (Chambers et al. 1996), while a literature review has revealed a possible link between fluoxetine and miscarriage (Baum and Misri, 1996). Pastuszak et al. explored a controversial outcome around the same issue (Pastuszak et al. 1993). Neonates exposed to fluoxetine in the third trimester of pregnancy are at a higher risk for developing neonatal complications like hypoglycaemia, hypothermia, respiratory distress, increased bilirubin, decreased Apgar Scores and increased incidence of prematurity. These symptoms may be originate from either a toxic serotonergic effect, abrupt drug withdrawal or a combination of both (Nordeng et al. 2005). Chambers et al. performed a trial to explore the possible association between SSRIs in the third trimester of pregnancy and persistent pulmonary hypertension (PPHN) of newborns, a disorder that is associated with infant mortality and morbidity. They found that SSRI-linked PPHN may result from the lung acting as a reservoir for antidepressant drugs leading to an accumulation of antidepressant in the lungs (Suhara et al. 1998 and Lemberger et al. 1985). Increased levels of serotonin in the lungs of the newborn may result in the proliferation of smooth muscle cells typical of PPHN (Chambers et al. 2006). Newborns exposed to any kind of SSRIs have an elevated risk of convulsions and NAS. A total of 93 neonates (64 with paroxetine, 14 with fluoxetine, 9 with sertraline and 7 with citalopram) were found with a neonatal withdrawal syndrome relating to maternal treatment with SSRIs (Sanz et al. 2005). If a mild form of depression occurs during pregnancy a non-pharmaceutical treatment like psychotherapy should be the first line approach. If major depression is diagnosed and risk of suicide is found in addition to psychotic symptoms, treatment with psychotropic drugs and inpatient care are indicated (Knoflach-Reichart et al. 2003). No study has compared neonatal outcomes and the possible long-term complications among depressed women not using medication, depressed women using SSRI medication and unexposed healthy women (Lattimore et al. 2005). Lattimore et al. suggest that women with depression should not be withheld adequate pharmacological treatment in late pregnancy but the neonate should be monitored for possible complications after birth. In the light of the dual diagnosis of affective disorders and opioid dependence in a pregnant patient, the diagnosis must be well evaluated and appropriate treatment of both disorders initiated as an opioid-maintained patient with untreated depression may relapse and may then be difficult to stabilize. However, such treatment requires an informed risk-benefit assessment. In addition, healthcare providers need to be vigilant for drug-drug interactions. Enzyme induction may either reduce or increase the opioid plasma level (eg fluvoxamine increases plasma levels of methadone) and appropriate dose adjustments are required in order not to destabilize either the mother-to-be or her fetus (Bertschy et al. 1994; Alderman et al. 1999; De Maria et al. 1999).

2.5 Overview of European literature

Only few studies including pregnant women have been conducted in the countries of the European Union. Most trials on maintenance treatment of opioid dependence exclude pregnant women by definition, since these require specialised management and treatment programmes to minimize harm to the fetus. Most of the scientific literature within the European Union on opioid dependence and pregnancy comes from workgroups in Austria and France. The majority of data from France has a naturalistic character while randomized controlled trials are still very rare among pregnant addicts. French data focuses on therapy with buprenorphine, since buprenorphine has been widely available there through office-based prescription for over 10 years. Work from Austria has focused on comparative trials of buprenorphine and slow-release morphine with methadone as well as on management of NAS. One of the only two double-blind double-dummy randomized controlled trials on the comparison of buprenorphine and methadone maintenance therapy during pregnancy and conception also comes from Austria.

2.5.1 Maintenance treatment during pregnancy

Methadone is currently the gold standard treatment for opioid dependence in pregnancy. There is widespread evidence in European and international scientific literature that methadone is associated with improved maternal medical status and a reduction of fetal and neonatal morbidity. Approximately 60-80% of neonates exposed to methadone require postnatal treatment of NAS (Fischer et al. 2006, Fischer et al. 2000). Okruhlica et al. 2003 reported in a naturalistic trial on 7 women stabilized on methadone treatment during their pregnancies in Bratislava, Slovakia. The mean methadone dose was 144 mg per day, all conceptions were successful and the neonates were healthy with a mean birth weight of 3033 g, mean head circumference of 34 cm and a mean Apgar score of 9/10/10. Buprenorphine is gradually becoming a valuable alternative to methadone as the research foundation steadily increases. The predominantly retrospectively gathered data indicates the safe use of buprenorphine in pregnancy. A large multi-site randomized double-blind double-dummy study comparing the efficacy of buprenorphine to methadone treatment is still ongoing and first results are being published at the moment (Jones et al. J Subst Abuse Treat 2008). Until now, there have been only two prospective double-blind double-dummy randomized controlled trials comparing buprenorphine with methadone in pregnancy. Both studies, one from Europe (Fischer et al. 2006) and one from the US (Jones et al. 2005), used similar methodology to show the safety and comparability of both substances. Data from two prospective studies conducted by the group from the Medical University in Vienna was extracted for MoreTreat. Fischer et al. (2006) included 18 pregnant opioid dependent women using a prospective double-blind double-dummy controlled design, comparing methadone with buprenorphine in pregnancy. Mean methadone dose was 47.5 mg and mean buprenorphine dose was 13.5 mg per day, while doses where slightly increased during the last trimester (+ 5 mg for methadone, + 0.5 mg for buprenorphine). No significant differences between both groups were observed in neonatal outcome. Overall 43% of the neonates did not require NAS treatment. NAS occurred 12 hours later (mean) in the buprenorphine group and the mean duration of NAS treatment was 4.8 days in the buprenorphine and 5.3 days in the methadone group. No difference was seen in the dose of medication needed to manage NAS. Retention was better in the buprenorphine maintained women, as eight women of the buprenorphine and six of the methadone group completed the study. Methadone, however, was significantly more effective in prevention of additional opiate consumption, while both groups showed low concomitant consumption of cocaine and benzodiazepines. Fischer et al. (2000) conducted an open-label, flexible-dosing, buprenorphine maintenance study of 15 opioid-dependent pregnant women. Buprenorphine was well tolerated during induction (Wang score < 4) and all mean birth outcome measures were within normal limits (gestational age at delivery 39.6 +/-1.5 weeks, Apgar score 8.9/9.9/10, birth weight 3046 +/-346 g, length 49.8 +/-1.9 cm and head circumference
34.1 +/-1.8 cm). NAS was absent in 8 neonates, mild in four cases and moderate (requiring treatment) in three neonates. The mean duration of NAS treatment was 1.1 days. A consecutive case report by Schindler et al. (2003) analyzed 2 buprenorphinemaintained pregnant women and their neonates in a prospective manner. It was the first report detailing the pregnancies of women treated with buprenorphine at the time of conception and investigated in a prospective study. Both newborn babies were healthy (length 51 cm and 49 cm, birth weight 3430 g and 2800 g, Apgar score 9/10/10 respectively) and had no NAS requiring treatment. These results represented a positive echo of the preceding open-label buprenorphine maintenance trial conducted by Fischer et al. in 2000. In 1999 a study by Fischer et al. investigated neonatal outcome in babies born to methadone or slow-release morphine maintained opioid-dependent pregnant women. A total of 48 pregnant women were randomized in an open trial, 24 receiving methadone and 24 receiving slow-release morphine maintenance treatment. No difference was found in the number of days that NAS was experienced by neonates born to methadone or morphine maintained mothers (mean = 16 and 21 days, respectively). All children were born healthy and no serious complications arose. Fewer benzodiazepines (p < 0.05) and fewer additional opiates (p < 0.05) were consumed by the morphine-maintained women compared with those who took methadone, but no difference was seen in cocaine consumption. Nicotine consumption was reduced significantly in both groups during pregnancy (p < 0.02). Nevertheless the results of this trial have to be discussed critically, since only a small patient sample and a non-blinded design were used. Methadone still remains the golden standard for maintenance treatment in pregnancy while buprenorphine seems to be a good alternative.

2.5.2 Management of the neonatal abstinence syndrome

A recent study by Ebner et al. in 2007 compared prospectively the effects of opioid maintenance treatment with methadone, buprenorphine and slow-release morphine regarding the occurrence and timing of NAS, additionally comparing two different NAS treatments, phenobarbital and morphine hydrochloride. Of the 53 newborns included, 22 were born to mothers maintained on methadone, 14 to mothers maintained on buprenorphine and 17 to mothers maintained on slow-release oral morphine throughout pregnancy. 68% of neonates in the methadone-maintained group (n=15), 82% in the slow-release oral morphine-maintained group (n=14), and 21% in the buprenorphinemaintained group (n=3) required treatment for NAS. The mean duration from birth to requirement of NAS treatment was 33 hours for the morphine-maintained group, 34 hours for the buprenorphine-maintained group and 58 hours for the methadone-maintained group. Further on treatment of NAS using morphine hydrochloride and phenobarbital was compared. In neonates requiring NAS treatment, those receiving morphine required a significantly shorter mean duration of treatment (9.9 days) versus those treated with phenobarbital (17.7 days). Although a non-randomized study design was used, these results indicate a benefit of neonates born to buprenorphine-maintained mothers with regard to the development of NAS requiring treatment. Furthermore, the results suggest a benefit of morphine in comparison with phenobarbital in NAS treatment.

2.5.3 Conclusions

The available evidence suggests that methadone as well as buprenorphine represent a safe treatment for pregnant mothers and their newborn children with no significant differences in neonatal birth parameters. Nevertheless buprenorphine may be able to reduce the severity and frequency of NAS (Winklbaur et al. 2008). To safely assess treatment in pregnancy, stronger evidence is needed (randomized trials with powerful sample sizes). An effort in this direction represents an ongoing multicenter NIDA-supported study, called MOTHER, which is a double-blind, doubledummy, randomized, stratified, parallel group study comparing the efficacy of methadone versus buprenorphine. It should be noted that the protocols are dynamic and may be modified, based on the collective experiences of the sites. Modifications made in the protocols are done to enhance comfort for and retention of the patients.

3. Recommendations19

Strength of evidence: **** Strong evidence: High quality meta-analyses, systematic reviews including one or more RCT with a very low risk of bias, more than one RCT a very low risk of bias *** Moderate evidence: Limited systematic reviews, one RCT with a low risk of bias or more RCTs with a high risk of bias ** Some evidence: one RCT limited by research factors or more case-control or cohort studies with a high risk of confounding
* Expert opinion ? insufficient evidence/unclear/unable to assess

3.1 Maintenance treatment during pregnancy

Rec. Methadone maintenance therapy is the gold standard pharmacotherapy. There is a growing body of evidence regarding the use of buprenorphine while it was shown effective in recent studies. Rec. Women who are in treatment should be encouraged to remain in treatment during pregnancy. Opioid agonist maintenance with methadone is seen a resulting in best combination of outcomes, taking into consideration affects on the fetus, neonatal abstinence syndrome, impact on ante-natal care and on parenting young children. Although many women want to cease using opioids when they find out they are pregnant, opioid withdrawal is a high risk option because any relapse to heroin use could result in disastrous consequences for the newborn. Severe opioid withdrawal symptoms may induce a spontaneous abortion in the first trimester and induce premature labour in the third trimester. Relapse to heroin use during pregnancy can also result in poorer ante natal outcomes. Opioid agonist maintenance is thought to have minimal, if any, long term developmental impact on children and this risk is outweighed by the impact of opioid agonist maintenance on reducing the risk of relapse to heroin use and resulting harms. Methadone is the gold standard treatment during pregnancy because there is more evidence on the safety of methadone than buprenorphine in pregnancy. If women are being well treated with buprenorphine then the risks of transferring to an alternative treatment should be weighed against the certainty of methadone effects.
While abstinence during pregnancy is the ideal clinical outcome, it incorporates the risk of opioid use relapse, which can be of great danger for the fetus. **** Strong evidence

3.2 Treatment of NAS

Rec Clinicians should use opioids or barbiturates for the management of NAS. Untreated NAS can cause considerable distress to infants and in rare cases seizures. Cochrane reviews indicate that opioids and barbiturates are more effective than placebo or benzodiazepines. Of the two, opioids are probably more effective than barbiturates. **** Strong evidence

3.3 Blood borne viruses

Rec. Pregnant female drug users should be routinely tested, with their informed consent, for HIV, hepatitis B and hepatitis C, and appropriate clinical management provided including hepatitis B immunisation for all babies of drug injectors. Once infected with HIV or hepatitis C, most individuals will become lifelong carriers with the potential to transmit the infection to others. It has been estimated that the annual incidence of hepatitis B infection among drug injectors in the UK is around 1% per year16. However, very few become chronic carriers and therefore the number of female drug users who might infect their baby with hepatitis B is much lower than for HIV or hepatitis C. Transmission of these viruses from an infected mother to her baby can occur during pregnancy or birth or through breastfeeding. Antenatal transmission of HIV infection occurs in up to 25% of cases where the woman has not received anti-retroviral treatment, reducing to about 2% if treatment is given during pregnancy. Similar rates of infection occur after birth if the baby is breast-fed. Rates of antenatal transmission of hepatitis B are even higher, but infection can be prevented if the baby is immunised shortly after birth. Prevention of HIV and hepatitis B infection thus depends very much on antenatal diagnosis and treatment. The transmission rate of hepatitis C from mother to baby during pregnancy or birth has been found to be about 5% in general population studies17 but was 12% among drug injectors in an Italian study. Elective Caesarean section appears substantially to reduce the rate of transmission. Assuming a prevalence of hepatitis C among female drug users of 30–60% and a mother-to-baby infection rate of 5–12%, between 15 and 70 babies per 1,000 pregnancies among female drug injectors will be infected with hepatitis C. To our knowledge, there have been no studies that provide reliable information on the extent of mother to baby transmission of hepatitis C. This is clearly an issue that urgently requires more research. However, the known facts indicate that it is essential that every pregnant drug user who has injected drugs should be offered testing for all three viruses and given appropriate treatment and clinical management if found to be infected.
*** Moderate evidence

3.4 Access to treatment

Rec Every maternity unit should ensure that it provides a service that is accessible to and non-judgemental of pregnant problem drug users and able to offer high quality care aimed at minimising the impact of the mother’s drug use on the pregnancy and the baby. This should include the use of clear evidence-based protocols that describe the clinical management of drug misuse during pregnancy and neonatal withdrawals. Rec Every maternity unit should have effective links with primary health care, social work children and family teams and addiction services that can enable it to contribute to safeguarding the longer-term interests of the baby.
* Expert opinion

3.5 Breastfeeding

Rec. For women on methadone and buprenorphine, breast feeding is safe and should not be precluded. A number of opioid-maintained women express a desire to breastfeed their infants. Breastfeeding is not contraindicated in a methadone/buprenorphine-maintained patient if she is known to be free of other drug use and is known to be HIV-seronegative (McCarthy et al. 2000; Philipp et al. 2003; Jansson et al. 2004). If an opioid-maintained mother wants to breastfeed her child, this should be encouraged: it can be helpful for mother-child bonding, and it might decrease NAS symptoms (Abdel-Latif et al. 2006). If the mother is abusing multiple drugs that would expose the infant to diverse agents in varying levels, then breastfeeding may still be contraindicated. Breastfeeding is not recommended if the mother is HIV-infected. Nursing and weaning under opioid maintenance therapy needs to be under special assistance of physicians, as rapid weaning would cause withdrawal in the neonate. **** Strong evidence

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19 Reference of WHO guidelines to be added!

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