Neonatal outcome following buprenorphine maintenance during ...

Blackwell Science, LtdOxford, UKADDAddiction0965-2140© 2002 Society for the Study of Addiction to Alcohol and Other Drugs97Original ArticleShird Dieter Schindler et al.Neonatal outcome following maternal buprenorphine treatment

RESEARCH REPORT

Neonatal outcome following buprenorphine maintenance during conception and throughout pregnancy Shird Dieter Schindler1, Harald Eder1, Romana Ortner1, Klaudia Rohrmeister2, Martin Langer3 & Gabriele Fischer1 Departments of General Psychiatry1, Neonatology2 and Gynaecology3, University Hospital of Vienna, Vienna, Austria

Correspondence to: Gabriele Fischer Department of General Psychiatry University Hospital for Psychiatry Währinger Gürtel 18–20 A-1090 Vienna Austria Tel: + 43 1 40400 3552 Fax: + 43 1 40400 3500 E-mail: [email protected] Submitted 18 June 2001; initial review completed 7 August 2001; final version accepted 13 May 2002

ABSTRACT Aims To assess the effects of maternal buprenorphine treatment at conception and during pregnancy on neonates in terms of birth outcomes and neonatal abstinence syndrome (NAS). Design and setting Prospective, open-label, out-patient maintenance, case report study, conducted at the drug addiction out-patient clinic at the University Hospital Vienna. Participants Two buprenorphine-maintained pregnant women who had conceived during buprenorphine treatment. Both patients had previously given birth to healthy neonates following induction on to buprenorphine maintenance therapy in the second trimester. Measurements Mothers: urinalysis. Neonates: gestational age at delivery, Apgar scores, birth weight, length and NAS (Finnegan Scale). Findings Urinalyses were negative for both women for 25 and 38 months, respectively, during the pregnancy period. There were no complications during the course of the pregnancy. The newborns delivered by both women were healthy, birth outcomes were within normal ranges and there were no NAS symptoms requiring treatment. Conclusions To our knowledge this is the first report detailing the pregnancies of women treated with buprenorphine at the time of conception and investigated in a prospective study. The NAS noted in neonates born to buprenorphinemaintained mothers appears to be less severe than the NAS observed in neonates born to methadone-maintained mothers. These preliminary data indicate that, in our patient cohort, buprenorphine maintenance at the time of conception and during pregnancy did not seem to affect birth outcome measurements such as pregnancy complications, week of delivery, birth weight, length, umbilical pH or neurodevelopmental progress. Future prospective studies with larger study populations are warranted. KEYWORDS Buprenorphine, conception, maintenance, neonatal abstinence syndrome, pregnancy, opioid dependence.

INTRODUCTION The use of illicit substances during pregnancy can lead to a number of maternal complications and fetal problems (Finnegan 1991a). Thus, a multi-disciplinary and diver© 2003 Society for the Study of Addiction to Alcohol and Other Drugs

sified treatment approach is required in order to achieve tolerability to the prescribed maintenance therapy and ensure the safety of the mother, fetus and newborn child. Opioid maintenance treatment with methadone can help stabilize the patients, and combined with close superviAddiction, 98, 103–110

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sion (urine toxicology, supervision of compliance with medication, psychotherapeutic and social support, etc.) aids in achieving a satisfactory level of prenatal care (Chasnoff, Landress & Barett 1990). Even though abstinence will always remain the primary goal for pregnant women, detoxification therapy during pregnancy should be conducted with great care, because withdrawal can cause fetal distress syndrome. This, in turn, can severely harm the fetus or give rise to premature delivery (Kandall et al. 1999). Methadone maintenance during pregnancy leads to prenatal stabilization and normal neonatal birth weight (Blinick, Jerez & Wallach 1973; Jarvis & Schnoll 1994; Wang 1999; Fischer et al. 1999a), but often leads to the occurrence of neonatal abstinence syndrome (NAS). This syndrome occurs in about 60–80% of babies born to methadone-maintained mothers, highlighting the need for other diversified treatment alternatives (Levy & Spino 1993; Kandall 1995). Neonatal abstinence syndrome involves dysfunctions of the gastrointestinal tract and of the central and autonomic nervous systems. It is characterized by tremor, irritability, hypertonicity, abnormal crying, vomiting, sneezing, fever, poor sucking and sometimes convulsions (Finnegan & Kaltenbach 1992). Although alternative maintenance substances for use during pregnancy have been investigated, only a limited number of peer-reviewed publications are available. Oral slow-release morphine has been registered for the treatment of opioid dependence in Austria since 1998 and has also been used widely in other European countries for this indication (EMCDDA 2000). A controlled study comparing methadone maintenance therapy with slow-release oral morphine treatment showed that there were no differences between the two treatments with regard to occurrence, duration and intensity of NAS (Fischer et al. 1999a). It is worth noting that both methadone and slow-release morphine should be administered twice daily during the last trimester because of enzyme induction (Kreek et al. 1974; Jarvis et al. 1999). Buprenorphine is another centrally potent synthetic opioid with a long duration of action (72 hours) and a recommended treatment dose range of 2–32 mg/day. In France, where buprenorphine has been officially licensed for the maintenance treatment of opioid dependence since 1995, over 60 000 patients have been treated so far. Indeed, many scientific studies have shown the excellent efficacy of buprenorphine in the treatment of opioid dependence (Reisinger 1985; Strain et al. 1994, 1996; Johnson et al. 1995; Fischer et al. 1999c), and in the past few years buprenorphine has been further registered for use in other European countries and the United States. Unlike other opiates, such as methadone, morphine or heroin, children born to buprenorphine-maintained mothers show no or little © 2003 Society for the Study of Addiction to Alcohol and Other Drugs

clinically measurable NAS (Marquet et al. 1997). The partial µ-receptor agonist and κ-antagonist receptor profile of buprenorphine compared with the pure µreceptor agonist action of methadone or heroin may provide a possible explanation for this quantitative and qualitative difference in NAS (Lewis, Rance & Sanger 1983). Although the use of buprenorphine in pregnancy is considered safe, its use under such conditions should still be restricted to specialized treatment facilities (Fischer et al. 1999b). We have investigated previously the efficacy of buprenorphine maintenance given after the first trimester in a prospective study on 15 pregnant opioid-dependent women (Fischer et al. 2000). Buprenorphine was well tolerated by the women and all 15 neonates were born healthy. The mean birth weight was 3049 ± 346 g (within normal limits) and a mean Apgar score of 9/10/ 10 (within normal limits) was recorded (see also Table 1). Treatment for NAS was required in three newborns, and four newborns showed some signs of NAS that did not require treatment (increased moro reflex and tremor peaking between days 2 and 5). Eight neonates had no clinical signs of NAS. The mean duration of NAS was 1.1 days (see also Table 1). Approximately one-third of people dependent on opioids are women and, of these, the majority are of child-bearing age. It stands to reason that as the use of buprenorphine to treat opiate-dependence becomes more prevalent, conception during buprenorphine maintenance will also become more common. A review of the literature on buprenorphine in pregnancy lists 12 case reports and two research reports, including our previous study (Johnson et al. 2001). Altogether some 100 patients have been investigated, 18 prospectively. These reports provide initial safety and effectiveness data that support further studies in pregnant opioid dependent women and their infants. This current investigation is, to our knowledge, the first prospective report describing conception under buprenorphine therapy.

METHODS Standardized treatment The drug addiction out-patient clinic at the University Hospital of Vienna has established and published, for both treatment and research purposes, a comprehensive, multi-professional treatment model for the management of substance-dependent pregnant women (Fischer et al. 1998). This treatment model, which also includes details of obstetric, neonatal and neuropediatric care, is based on frequent contact (on average two to three visits per week) Addiction, 98, 103–110

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Table 1 Data of children. Study results (n = 15) Patient

Fischer et al. (2000)

Case 1 TS

Birth (week/delivery mode)

39.6 ± 1.5 10 vaginal/ 5 caesarian 8 females, 7 males 15 (days 2, 3, 5, 8) (mean: 4.3 ± 5.2 peak at day 1.6 ± 1.8)

40/vaginal

41/vaginal

38/caesarean

38/caesarean

male 6 (day 3)

female 5 (day 3)

female 6 (day 3)

male 8 (day 3)

present (days 3–4) present (days 3–4) absent



present (days 2–4)

present (days 1–4) present (days 4) present (days 2 & 4) present (day 4)

present (days 1–4) absent absent absent

absent present (days 1 & 4) present (day 3)

present

present (days 1–4) absent present (days 1 & 4) present (days 1 & 4) absent

absent

absent

present (days 2–3)

present present present 8.9/9.9/10 3049 ± 346 49.8 ± 1.9 34.1 ± 1.8

absent present (day 2) absent 9/10/10 3400 50 33

present (day 1) absent absent 9/10/10 3430 51 35

present (day 1) absent absent 9/10/10 3120 51 34

present (day 1) absent present (day 3) 9/10/10 2800 49 33

7.23 ± 0.08

7.04

7.20

7.24

7.25

7.29 ± 0.08

7.10

7.31

7.26

7.29

week 22.4 ± 1.3 no diagnosis

week 22 no diagnosis



18 ± 3.9

7

7

8

weeks 26 & 37 single umbilical artery no chromosomal abnormality 7

Sex Finnegan score (peak)

Symptoms: only if present High-pitched present voice Sleeping after present feeds Moro reflex present increased Tremor when present disturbed Excoriations present Myoclonia present Sneezing Respiration (> 60) Failure to drink Vomiting Stool/diarrhoea Apgar score Weight in grams Length in cm Head circumference in cm Arterial umbilical cord PH Venous umbilical cord PH Prenatal diagnostic screening and diagnosis

First ultrasound in week

present

with psychiatric, psychosocial and psychotherapeutic staff. Psychotherapeutic treatment of all patients consisted of a weekly 90-minute group therapy session using behavioural techniques focusing on relapse prevention, development of coping strategies and enhancing low selfesteem. Psychosocial support (for example, assistance with legal, housing and financial issues) took place twice a week. © 2003 Society for the Study of Addiction to Alcohol and Other Drugs

Case 2 GB

present (days 2–3) absent present (days 1–4)

Diagnosis and measurements The diagnosis of current opioid dependence was established according to the Structured Clinical Interview for DSM-IV (American Psychiatric Association 1994) by senior psychiatrists (GF, SDS). In addition all patients underwent standardized clinical psychodiagnostic evaluation. The Europe Addiction Severity Index (McLellan et Addiction, 98, 103–110

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Table 2 Demographic and medical data patients. Patient

Case 1 TS

Case 2 GB

Ethnicity Marital status Employment status Educational level Pregnancy history History of medical problems Hepatitis B Hepatitis C HIV Age of onset of opioid dependence (years) Age at first maintenance therapy (years) & substance first contact week of pregnancy Week of pregnancy at buprenorphine initiation (first pregnancy) Overall duration of buprenorphine maintenance (months) Delivery Conception under

Caucasian Steady partner not married Shop assistant, employed Vocational school 2 deliveries Hepatitis C, PCR pos. Negative Positive Negative 15 18 Methadone 5 21 27 1st 2nd Methadone Buprenorphine

Fagerström score at first contact Fagerström score after delivery Weight increase during pregnacy (kg) Dose at conception (mg/day) Buprenorphine dose at birth (mg/day)

3 4 10 30 8

Caucasian Steady partner not married Clerk, unemployed Vocational school 2 deliveries and 2 abortions Hepatitis C, PCR pos. Negative Positive Negative 18 23 Morphinehydrochloride 3 25 39 1st 2nd Morphine Buprenorphine hydrochloride 9 9 9 8 12 13 400 12 10 12

al. 1992) was used to assess past and current drug use and demographical data. Nicotine dependence, which is associated with sudden infant death syndrome (SIDS) and low birth weight, was evaluated applying the Fagerstrom questionnaire (Heatherton et al. 1991). Urinalysis was performed routinely on urine samples collected under supervision two to three times a week. Urine was analysed for methadone, opioids, cocaine, cannabis and benzodiazepines using the Emit®-method (Emit® Assay Troubleshooting Guide 1983). Over the last 5 years all pregnant women being treated for substance dependence at the drug addiction out-patient clinic have delivered their babies on the same ward in the gynaecology department of the University Hospital of Vienna. The neonates have undergone evaluation and treatment by the same staff from neonatology department in accordance with international standards by applying Finnegan scores (Finnegan & Erlich 1990; Finnegan 1991b) every 4 hours. The Finnegan score measures 20 possible opioid withdrawal symptoms in the neonate. Symptoms rated at least once are analysed for day of presence and used to calculate the peak score. Psychopharmacological interventions are initiated when the Finnegan score exceeds 11. The Apgar score was rated routinely. The score measures heart rate, respiratory rate, reflex irritability, muscle tone and colour at 1, 5 and 10 minutes after birth. The maximum score is 10 (Virginia Apgar 1953). © 2003 Society for the Study of Addiction to Alcohol and Other Drugs

3 5 12 6 6

Postnatal development has been assessed continuously using regular examinations by the Department of Child Neurology, Rosenhuegel Hospital (data collection ongoing). Design Both patients in the following case reports had previously delivered healthy newborns while participating in our earlier controlled prospective study, in which they were switched from methadone or morphine hydrochloride to buprenorphine maintenance therapy during the second trimester of pregnancy (Fischer et al. 2000). Both patients were living in a socially stable environment (see also Table 2). Prior to their second full-term pregnancy, the women received intensive counselling and were informed that only limited data were available regarding the effects of buprenorphine in pregnancy and that, at present, there were no controlled studies of the effects of buprenorphine at time of conception. However, because of the level of stability that had been achieved during buprenorphine maintenance therapy (both patients having been able to avoid relapse for 2 and 3 years, respectively) and the beneficial effect of buprenorphine during their first pregnancy, both women declined to be transferred to methadone treatment. Safety monitoring of both patients was in accordance with the Ministry of Health in Austria. Addiction, 98, 103–110


CASE REPORTS Case 1 The female subject, TS, is now 24 years old and lives in a stable relationship (see Table 2). The partner of the patient is employed, meets the criteria of opioid dependence DSM-IV (304.0) and has been maintained on methadone for the last 6 years. The patient started to use heroin at the age of 15 years and by the age of 16 had met the criteria for opioid-dependence according to DSM-IV (304.0), with no other Axis I psychiatric co-morbidity (American Psychiatric Association 1994). She had attempted, but not completed, two in-patient detoxification treatments (at ages 16 and 18) and one out-patient detoxification treatment (at age 17), which led to only short periods of abstinence (from 3 to 15 days). The patient began methadone maintenance therapy at 18 years of age, but while receiving methadone maintenance the patient relapsed frequently into heroin use. At age 19 the patient became pregnant while receiving methadone maintenance therapy. She then took part in the previously mentioned controlled study of buprenorphine during pregnancy and was switched from methadone 30 mg/day to buprenorphine 8 mg/day during the 21st week of pregnancy (see also Table 2). During the remaining 19 weeks of pregnancy the patient was at all times stable, keeping all appointments, taking the prescribed medications, participating in group therapy and taking part in the necessary psychiatric and obstetric examinations. Negligible amounts of heroin or morphine were detected by standardized (twice weekly) urinalysis on three occasions. In the 40th week of pregnancy the patient delivered a healthy boy, 50 cm in length and weighing 3400 g (within normal limits). The Apgar score was 9/10/10. NAS was evaluated every 4 hours on a standardized basis and no medication was required since the scoring never exceeded 11 (see also Table 1). Following the birth of her child the patient continued on buprenorphine and reduced the dosage to 6 mg/day. The patient visited the clinic twice monthly and was stable as confirmed by urinalysis. While under this treatment the patient became pregnant for a second time at age 21. As she had conceived under buprenorphine treatment and had experienced a unique period of wellbeing with no heroin relapses, the patient wanted to continue buprenorphine treatment, under close supervision, in our out-patient clinic. Throughout the pregnancy the patient received a daily dosage of 6 mg buprenorphine. All supervised urine toxicology tests were negative for illicit substances during the second pregnancy. There were no complications during the pregnancy, and spontaneous vaginal delivery occurred in the 41st week without any complications. The newborn girl had a length of © 2003 Society for the Study of Addiction to Alcohol and Other Drugs

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51 cm and a birth weight of 3430 g (within normal limits). The Apgar score was 9/10/10 and there were no NAS symptoms requiring treatment (see also Table 1). To date developmental progress in both of the patient’s children is normal and comparable to children of women with no addiction problem during pregnancy.

Case 2 The female subject GB is now 28 years old and lives in a stable relationship (see also Table 2). The patient’s partner has no psychiatric or substance-dependence problems other than nicotine dependence DSM-IV (305.1). The patient started to use heroin and other substances, including benzodiazepines and cannabis, from 18 years of age. She met the criteria of opioid and nicotine dependence according to DSM-IV (304.0, 305.1) by the age of 20. There was no other Axis I psychiatric co-morbidity, but the patient met the diagnostic criteria for histrionic personality disorder DSM-IV (301.5). An in-patient detoxification treatment at age 21 was followed by a 5week period of abstinence. The patient received morphine hydrochloride maintenance therapy at age 23, and during this time the patient did not relapse according to urinalysis. At age 24, the patient became pregnant while receiving slow-release oral morphine hydrochloride maintenance therapy. She then took part in the previously mentioned study of buprenorphine during pregnancy and was switched from morphine hydrochloride 400 mg/day to buprenorphine 10 mg/day during the 25th week of pregnancy. During the remainder of the pregnancy urinalyses were negative for opiates and other illicit substances and the patient tolerated buprenorphine well (see also Table 2). The patient delivered a healthy newborn in the 38th week of pregnancy through caesarean section, as the cervix had not dilated sufficiently after 10 hours of labour. The baby girl had a length of 51 cm and a birth weight of 3120 g (within normal limits). The Apgar score was 9/10/10, and there was no NAS requiring treatment (maximum score of 6). After this pregnancy the patient continued buprenorphine 10 mg/day. The dosage of buprenorphine was increased over the next year to 12 mg/day because of minimal withdrawal signs (increased sweating, increased craving for opiods and sleep problems), although no relapses occurred as shown by urinalysis. Under this treatment the patient became pregnant at ages 25 and 26 but terminated these unwanted pregnancies at weeks 8 and 10, respectively. The patient again became pregnant at age 27 and this time decided to continue with the pregnancy. She opted to continue buprenorphine treatment (12 mg/day) under close supervision in our out-patient clinic as conception had already occurred under buprenorphine treatment. The patient received buprenorphine over the course of Addiction, 98, 103–110

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the whole pregnancy. All supervised twice weekly urine toxicology tests were negative for all tested substances. There were no complications during the course of the pregnancy except for the ultrasound finding of a single umbilical artery. All ultrasound controls showed normal growth and normal arterial flow and no intervention was needed. Because of the history of the first pregnancy the baby was delivered by caesarean section in pregnancy week 38, following the start of labour. The newborn boy had a length of 49 cm and a birth weight of 2800 g (within normal limits). The Apgar score was 9/10/10 and there was no NAS requiring treatment (see also Table 1). In addition the patient breastfed for 6 months without any complications. To date developmental progress in both of the patients’ children is normal and comparable to children of women with no addiction problem during pregnancy.

DISCUSSION Although methadone is considered the treatment of choice in pregnant opioid-dependent women, there have been few controlled clinical trials supporting this recommendation over other treatment options such as buprenorphine. The majority of methadone investigations in pregnancy have been retrospective and therefore lack detailed information about the course of the pregnancy (Finnegan 1991a, 1991b; Kandall et al. 1999; Wang 1999). Particularly, in the absence of urine testing, there is little information available regarding illicit opioid consumption. However, it has been shown that methadone maintenance therapy leads to a positive pregnancy course through the controlled intake of an opioid and the patients’ increased medical and psychosocial contact with health-care professionals. Both pregnancies under buprenorphine treatment described in this report were without complication. Both women gave birth to healthy newborns that did not require treatment for NAS. Neurodevelopmental examinations at 6 and 12 months were normal and not different from children of mothers without a substance related disorder. Both patients were satisfied with buprenorphine maintenance therapy and have remained on buprenorphine without relapses. The treatment of pregnant patients with buprenorphine in these two cases and in our previous study did not lead to a prolonged hospital stay for the newborn, which has important benefits both psychologically and economically. A shortened neonatal hospital stay is also of psychological importance to the development of a healthy mother–child relationship. In addition, shorter hospital stays also carry the clear advantage of cost benefits. This is in contrast to neonates born to pregnant methadone© 2003 Society for the Study of Addiction to Alcohol and Other Drugs

maintained women, where treatment of NAS leads to an average hospital stay of 18 days (Kaltenbach & Finnegan 1986; Finnegan et al. 1990; Theis et al. 1997; Fischer et al. 1999a, 1999b). The potential problems of breast-feeding while undergoing maintenance therapy were brought to our attention when one of our patients (GB) decided to breastfeed. A small number of studies have recommended that breast-feeding should be encouraged in methadone treated women who are HIV-seronegative and not abusing other drugs (Treatment Improvement Protocol (TIP) Series 1993; Wojnar-Horton et al. 1997). Generally, however, the lack of information in the literature leads to the needs of the mother on maintenance therapy who wishes to breastfeed being disregarded on the grounds of safety. It has been reported that at a plasma to milk ratio of 1, buprenorphine and norbuprenorphine (the metabolite of buprenorphine) has little to no effect on breastfed infants (Johnson et al. 2001). In addition, considering the poor oral bioavailability of buprenorphine (Kaltenbach & Finnegan 1986), the amount absorbed via breastfeeding should be low, especially since buprenorphine has a similar plasma to milk ratio, therefore neonatal exposure to buprenorphine should be lower than with other opioids such as methadone (Walter & Inturrisi 1995). It is hoped that this report might encourage physicians to discuss breastfeeding with pregnant women on maintenance therapy rather than to dismiss the possibility out of hand. If other contraindications can be ruled out, it may be possible to permit the mother to follow her desire to breastfeed her child. The treatment model used in this study resulted in well-managed pregnancies and healthy births for both patients. We would recommend our ‘special care’ model to other treatment facilities, and would hope that this would allow further data to be generated on buprenorphine use during conception, pregnancy and breastfeeding. This and previous studies indicate the potential superiority of buprenorphine over other opioids for maintenance therapy of opiate-dependent pregnant women, especially with regard to decreased levels of NAS. However, there are a limited number of prospectively evaluated reports in the literature, and a larger database is needed to fully establish the safety profile of buprenorphine in these patients and their babies. The question of appropriate treatment programmes for substance-dependent women during pregnancy needs to be addressed, as in many cases concomitant consumption of illicit and licit substances will occur, which may result in NAS. Considering that in France alone, 60 000 patients have been maintained on buprenorphine, together with the increase in use in the European Union and the United States, it seems likely that more pregnancies will occur under buprenorphine treatment. We sugAddiction, 98, 103–110


gest that specialized treatment centres should be responsible for this population and we recommend that, ideally, the treatment of pregnant patients with buprenorphine should take place in specialized centres that are able to offer multi-professional care. Nongovernmental organizations (NGOs) are not the appropriate treatment place, as these patients usually need a large amount of social support. As well as the necessary medical collaboration with other departments (e.g. gynaecology and neonatology), psychosocial and psychotherapeutic interventions are also often warranted. In view of the limited data that are available on buprenorphine use in pregnancy, special attention should be focused on non-invasive prenatal diagnostics and on the follow-up of the children.

Study limitations The limitations that apply to this study are those inherent in case study design. We present only two patients, both of whom had a previous history of effective and safe buprenorphine treatment during a previous pregnancy. Given the above, the ability to generalize our findings to a larger population based on this study alone is limited.

CONCLUSION To our knowledge, this is the first report detailing the pregnancies of women treated with buprenorphine at the time of conception and investigated in a prospective study. The low NAS scores and good health of the neonates seen in these cases echo the results of our previous prospective study of 15 pregnant women maintained with buprenorphine (Fischer et al. 2000). They also serve to extend these findings, since the mothers in the earlier study had not conceived during buprenorphine maintenance. On the basis of these preliminary results, we suggest that the effects of buprenorphine maintenance during conception and pregnancy warrant further prospective investigation on a larger scale. Future studies may also seek to extend observations to evaluate the effects of breastfeeding during maintenance treatment.

ACKNOWLEDGEMENTS We are especially thankful for the assistance of our social workers, Sandra Breza, Irene Niedermayer and to Angela Herbacek for performing the weekly behaviourmodifying group therapy. We also thank our colleagues Christian Schatten (Gynecology), Manfred Weninger (Pediatrics) and Ernst Berger and Thomas Elstner (Child Neurology). © 2003 Society for the Study of Addiction to Alcohol and Other Drugs

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