Prospective multicenter observational study of 260 infants born to 259 opiate-dependent mothers on methadone or high-dose buprenophine substitution

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Abstract

Specialized prenatal care and substitution programs improve the perinatal prognoses of pregnant drug-abusers and their infants. Although methadone is well documented, little is known about high-dose buprenorphine (HDB). This prospective, multicenter (n = 35) observational study included 259 women on maintenance during pregnancy: 39% on methadone and 61% on HDB. Major findings were: 46% of them received good prenatal care; 62% had peridural analgesia; 12.3% delivered prematurely (<37 weeks); mean gestational age, 38.6 weeks; mean birth weight, 2822 g. Three-quarters of the newborns developed neonatal abstinence syndrome (NAS) beginning at a mean age of 40 h, with the mean maximum Lipsitz score of 9.1 at 72 h; half of them were treated, mainly with morphine hydrochloride. No baby died. Newborns were discharged with their mothers (96%) or placed in foster care (4%). Comparing methadone with HDB, respectively, mean age at the maximum Lipsitz score was 81 h versus 66 h (P = 0.066). The perinatal medical and social prognoses for these 259 drug addicts and their infants appeared to be improved by specialized prenatal care and was similar for methadone or BHD substitution during pregnancy.

Introduction

The coexistence of pregnancy and drug addiction is a common situation. In France, the estimated number of opiate addicts varies between 150,000 and 300,000; 25–30% of them are women, among which an overwhelming majority is of childbearing age. At present, pregnant drug addicts in France are, usually polysubstance abusers, and are particularly dependent on opiates: heroin and/or methadone or high-dose buprenorphine (BHD) in the framework of a substitution program or illegal drug trafficking. This opiate use is almost always associated with tobacco use and more-or-less marked consumption of alcohol and/or marijuana, and/or cocaine or crack, and/or medications, especially benzodiazepines.

The perinatal prognoses for pregnant opiate-dependent women and their infants are clearly improved by specialized management of their addictions, including the prescription of substitution therapy, accompanied by medical–psychological–social support and early monitoring of the pregnancy (Hulse et al., 1997, Kandall et al., 1999, Lejeune et al., 1997a, Lejeune et al., 1997b, Randal, 1991, Ward et al., 1999).

In their editorial, Ward et al. (1999) noted the beneficial effects of methadone substitution during pregnancy, when the dose is adequate: protection of the fetus against the deleterious effects of sudden opiate-concentration changes; better medical monitoring of the pregnancy; prevention of prematurity and low birth weights; prevention of backsliding to use of heroin and other addictive substances.

HDB efficacy as substitution therapy, for drug addicts in general, and its good tolerance have been established (Kintz and Marquet, 2000), provided that the recommendations are respected concerning the administration modalities and the proscription of high doses of benzodiazepines.

Although studies on the use of HDB during pregnancy are much rarer than those on methadone, the prognoses of these pregnancies also seem to be improved (Fisher et al., 1998, Fisher et al., 2000, Jernite et al., 1999, Johnson et al., 2001, Johnson et al., 2003, Lacroix et al., 2004, Lejeune et al., 2001, Lejeune et al., 2003, Mazurier et al., 1996, Schindler et al., 2003). The neonatal abstinence syndrome (NAS) of infants born to mothers on methadone or HDB can be relatively severe (Jernite et al., 1999, Kandall, 1999), and even more intense on methadone than heroin. Johnson et al. (2003) recently published their review of 21 published reports that included a total of 309 women taking HDB substitution during their pregnancies. They concluded that this treatment was very well tolerated, with few perinatal pathologies, particularly a relatively low rate of prematurity for this setting. The doses given varied widely, from 0.4 to 24 mg/day. NAS, considered to be less severe than under methadone, occurred in 68% of the newborns; 48% of them required treatment for it.

However, because no comparative data were available on the outcome of pregnancies under either substitute, no consensus existed as to which agent should preferentially be prescribed to pregnant addicts. The objective of this study was to compare the perinatal morbidity and NAS of infants born to women taking methadone or HDB during their pregnancies. Recently, a preliminary report of double-blind and double-dummy study, HDB (n = 9) versus methadone (n = 11) have been published (Jones et al., 2005); no differences were found between the two groups for NAS severity.

Although high-dose buprenorphine (HDB) (Subutex®) was not officially authorized for use during pregnancy in France, the limited number of places in methadone clinics and the less restrictive rules for HDB prescription mean that numerous pregnant drug addicts are currently taking HDB in France.

Certain particularities of the French medical system need to be explained: (1) at the time these data were collected, methadone could only be prescribed by a authorized specialized center, while HDB could also be prescribed by a private practitioner or a hospital; (2) all pregnant women, even those without medical insurance or illegal immigrants, can be followed free-of-charge in public hospitals ‘Protection Maternelle et infantile’ (Maternal and Child Health Protection Centers); almost all socioeconomically disadvantaged women and/or illegal immigrants obtain medical coverage ‘Couverture Maladie Universelle’ (Universal Medical Coverage), and ‘Aide Médicale Etat’ (National Medical Assistance).

Section snippets

Framework

This prospective study was conducted by GEGA, from 1 October 1998 to 30 September 1999. During the study period, the 35 participating French perinatal centers of public hospitals included all live births to mothers receiving drug substitution that had started before or during this pregnancy within the framework of a maintenance protocol prescribed by a specialized center or a general practitioner and had been continued until delivery.

The following information was prospectively collected from a

Overall findings

Six percent of the women were HIV seropositive and 63% were hepatitis C virus (HCV) positive. Almost half of the women had benefited from good prenatal monitoring (first consultation before 15 weeks of amenorrhea and the number of visits correct for the gestational age, i.e., seven consultations for a term delivery) (Table 2), with 75% having had at least three ultrasonographies.

The rate of premature delivery was 10% for women with good prenatal care versus 16% for the women with poor prenatal

Discussion

To the best of our knowledge, this was the first prospective, but not double-blinded or randomized, study to compare the outcomes of infants born to mothers on methadone or HDB substitution. Although not officially authorized in France for use in pregnant women, HDB is routinely prescribed during pregnancy. This situation is probably explained by the significantly higher rate of HDB use initiated prior to conception than methadone. When substitution is started during a pregnancy, methadone

Acknowledgments

The analysis of this cohort was financed by the Observatoire Français des Drogues et des Toxicomanies (OFDT), 105, rue La Fayette, 75010 Paris, France.

GEGA members responsible for data collection in the 35 participating French centers: Araujo E. (Versailles), Bastian H. (Bichat, Paris), Berthier M. (Poitiers), Boissinnot C. (Robert-Debré, Paris), Bolot P. (Aulnay-sous-Bois), Bouderlique C. (Angers), Bouillie J. (St-Antoine, Paris), Brossard V. (Rouen), Cahuzac-Lhermitte C. (Creil), Chabrolle

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