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Drugline nr 9616

Publicerat 1993-01-11


What are the outcomes of children of mothers maintained with methadone during pregnancy?


Methadone substitution therapy during pregnancy occurs in association with treatment of heroin addiction, and has been given in an attempt to provide better social and obstetric care for pregnant addicts.

Methadone is a synthetic opioid agonist similar to morphine, but with a longer duration of action. The chief metabolic pathways, which probably occur in the liver, are mono- and di-N-demethylation. The metabolites are free from pharmacological effects. With regular oral doses of 100-200 mg daily, plasma concentrations rise from trough levels of approximately 500 mcg/L to a peak of about 900 mcg/L in 4 hours. The concentration in cord blood is about half the maternal level. The half-life following a single oral dose is 12-18 (mean 15) hours. With regular doses, the tissue reservoir is already partly filled, and so the half-life is extended to 13-47 (mean 25) hours (1).

Methadone substitution in heroin addicts during pregnancy enhanced intrauterine growth, and acute wihtdrawal within the last trimester raised the incidence of preterm deliveries (2). Therefore, it is not recommended that methadone dosage be reduced during pregnancy because of the resultant impaired fetal growth (3).

The effects of prenatal opioid exposure on the behaviour of newborn infants are dramatic. During the first week after birth, most opioid-exposed infants show a well-documented neonatal withdrawal syndrome that includes a variety of behaviours associated with central and autonomic nervous system hyperarousal, such as tremors, hypertonus, hyperactive reflexes, high pitched crying, poor sleeping and feeding, fever, and rapid respiration (4). When withdrawal symptoms occur, they usually start within 48 hours after delivery, but a small percentage may be delayed up to 7-14 days (5). These signs attenuate dramatically during the first month of life, and by one month of age only subtle differences can be observed between exposed and unexposed infants (4). Withdrawal syndromes occur in approximately 60-90 per cent of the infants (5-7). The neonatal withdrawal syndrome may be explained by postnatal understimulation of central alpha-2-adrenergic receptors whose number increases in utero due to fetal opiate exposure (8).

To date, the few studies that have been done in an attempt to compare clinical withdrawal with methadone concentrations have produced conflicting results. The intensity of the neonatal withdrawal syndrome has been found to relate to the total dose of methadone ingested by the mother during the last 12 weeks of pregnancy, the maternal dose of methadone at delivery and the intrapartum serum methadone levels (9). One study concluded that the intensity of withdrawal was increased if the daily maternal dosage exceeded 20 mg (7). Another study reported that the incidence and severity of neonatal methadone withdrawal was not related to postnatal plasma concentration, but to individual plasma half-life which was shorter in infants with severe withdrawal (10). Blinick et al measured methadone in maternal plasma and urine, as well as amniotic fluid, cord blood, fetal urine and breast milk. They could not find any relationship between these levels and the intensity of the withdrawal syndrome (11). Mack et al reported that there was no correlation between neonatal serum levels and the intensities of withdrawal symptoms, and they found no relationship between maternal and neonatal methadone concentrations (12).

Methadone withdrawal seems to be more intense than that occurring with heroin (5). Less than one-third of symptomatic infants require therapy (5-7).

Postnatal apnoea after prenatal opiate exposure can be treated with naloxone 0.01 mg/kg body weight intravenously (13). In newborns with clinical signs of withdrawal, these symptoms can be quantified, and oral phenobarbital therapy has been given (loading dose 10-20 mg/kg, maintenance dose 4-6 mg/kg daily, adjusted to serum level). If the withdrawal symptoms are severe enough, morphine can be given parenterally (0.02-0.05 mg/kg every four hours) (13).

A high incidence of preterm deliveries have been reported in opiate addicts, which may be due to drug withdrawal attacks. Infants of drug-addicted mothers are often small for gestational age. In some series, one-third or more of the infants weigh less than 2500 gram (5,6). An increased stillborn and neonatal mortality rate has also been reported (14). Infants of methadone-maintained mothers may have an increased risk of developing sudden infant death syndome(SIDS). Although one study of 313 infants of methadone-addicted mothers reported two cases(0.6 per cent) of SIDS, an incidence rate similar to the overall experience of that location, another study showed that a correlation between drug addiction and SIDS has been suggested with 20 cases (2.8 per cent) in a group of 702 infants; however, the confounding effects of smoking or other drugs were not mentioned (15).

Breast feeding may or may not alleviate withdrawal symptoms, depending on the amount of methadone that passes through the breast milk. Methadone enters breast milk in concentrations approaching plasma levels and may prevent withdrawal symptoms in addicted infants. The amount of methadone that a nursing infant would ingest in a day is on average 0.7-4.7 per cent and at maximum 6.4 per cent of the weight-adjusted maternal daily dose (11). Methadone ingested in breast milk has been claimed to contribute to the death of an infant (16). However, a recent report claimed that methadone enters breast milk in such low quantities that it would be clinically insignificant (17). The American Academy of Pediatrics considers methadone to be compatible with breast feeding, with no adverse effects reported in the nursing infant when the mother was consuming less than 20 mg/day (18).

Rosen and Johnson studied the first 18 months of life of children born to methadone-maintained mothers. The infants showed reduced head circumference and raised systolic blood pressure. At follow-up over 18 months these children had a higher incidence of otitis media, reduced head circumference, and abnormal eye findings when compared with drug-free controls (19).

Olofsson et al have reported the outcome at one to ten years of 72 children exposed in utero to a variety of drugs (heroin, methadone or tranquillizers). Based on screening tests and interview data, they reported impaired psychomotor development in 21 percent of the sample and behavioural abnormalities (lack of concentration, hyperactivity, aggressiveness and lack of social inhibition) in 50 per cent (20).


Methadone maintenance therapy is now regarded as the accepted form of management of narcotic addiction during pregnancy. The sequel methadone exposure in utero is the so-called neonatal withdrawal symptoms experienced by the infant following delivery. Since these addicts usually consume a wide variety of drugs, it is not easy to differentiate the effects of methadone from the effects of other drugs. Neonatal withdrawal syndrome and low birthweight are immediate problems in the infants of women receiving methadone during pregnancy. Breast feeding is safe provided the maternal dose is low (less than 20 mg/day), and the mother is warned to seek medical advice if her infant appears sedated. Long-term effects on the behaviour and gross motor development skills are not known.

Roh HK
Bergman U


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