In utero drug and alcohol exposure in infants born to mothers prescribed maintenance methadone
- 1Neonatal Unit, Royal Hospital for Sick Children, Glasgow, UK
- 2Neonatal Unit, Department of Neonatology, Princess Royal Maternity, Glasgow, UK
- 3Department of Forensic Medicine and Science, University of Glasgow, Glasgow, UK
- Correspondence to Dr Laura McGlone, Neonatal Unit, Department of Neonatology, Royal Hospital for Sick Children, Dalnair Street, Glasgow G3 8SJ, UK;
- Received 3 April 2013
- Revised 28 May 2013
- Accepted 31 May 2013
- Published Online First 8 July 2013
Aims To describe the prevalence of in utero alcohol and illicit drug exposure in infants born to mothers prescribed methadone in pregnancy, and to compare the accuracy of maternal interview with infant toxicology.
Methods Urine and meconium samples were collected from 56 infants born to mothers prescribed methadone during pregnancy and a confidential interview conducted soon after delivery. Samples were screened for drugs of misuse and meconium samples analysed for the presence of fatty acid ethyl esters (FAEEs) to detect prenatal alcohol exposure.
Results 91% of infants had been exposed to illicit drugs in utero, including opiates (73%), benzodiazepines (70%) and cannabinoids (59%). 47% of infants had elevated FAEEs. Meconium was more sensitive at detecting in utero drug exposure than urine toxicology (p<0.01 for opiates, benzodiazepines, cannabinoids) or maternal interview (p=0.03 for opiates, p<0.01 for cannabinoids).
Conclusions The majority of infants born to mothers prescribed methadone during pregnancy are exposed to polysubstance misuse, and almost one-half additionally exposed to excess alcohol.
What is already known on this topic
The true extent of alcohol and illicit drug misuse during pregnancy in women prescribed maintenance methadone is unknown, and likely to be under-reported.
What this study adds
The majority of infants born to mothers prescribed methadone during pregnancy are exposed to polysubstance misuse, and almost one-half are additionally exposed to excess alcohol. Alcohol consumption in pregnancy is particularly under-reported.
Methadone maintenance is currently the recommended management strategy for opioid misuse in pregnancy.1 Although prescription of methadone in pregnancy stabilises maternal lifestyle and reduces the incidence of preterm delivery, it does not prevent ongoing use of illicit drugs.2 The latter is likely to be under-reported, and so the extent of ongoing drug misuse in methadone-maintained pregnant women is not known.2 Furthermore, despite well publicised government and Royal College of Obstetric and Gynaecology guidelines, it is likely that significant numbers of women continue to drink excessive quantities of alcohol in pregnancy. Lack of a validated technique for routine assessment of such alcohol consumption as well as under-reporting mean that the true prevalence of excessive alcohol consumption in pregnancy is also unknown. Excessive alcohol use during pregnancy in women who use illicit drugs has been postulated to be even higher than in the general population, but there are few data to support this.3
The aims of this study were to describe the prevalence of in utero alcohol and illicit drug exposure in infants born to drug-misusing mothers prescribed maintenance methadone in pregnancy, and to compare the accuracy of confidential postnatal maternal interview with comprehensive postnatal toxicology.
As part of a prospective cohort study undertaken to investigate the visual and developmental outcomes of infants exposed to methadone in utero, paired urine and meconium samples were collected soon after birth from infants born to drug-misusing mothers prescribed maintenance methadone during pregnancy, and delivered at the Princess Royal Maternity in Glasgow. All women had been managed within an obstetrically led, community-based multidisciplinary service for women with social problems including substance misuse.
Exclusion criteria were birth before 36 completed weeks’ gestation, congenital ocular abnormality and/or significant neonatal illness. This 2-year cohort study recruited 100 infants born to mothers prescribed methadone during pregnancy; mothers gave informed consent, postnatally, for collection of both meconium and urine samples from the newborn as well as access to results of routine maternal urine testing in pregnancy.
As soon as possible after obtaining informed consent, urine was collected via a urine bag applied to the infant's perineum, and meconium collected directly from the nappy; samples of each were frozen at −20°C prior to being analysed in batches. Urine samples were screened using enzyme-multiplied immunoassay techniques run to Substance Abuse and Mental Health Services Administration guidelines on an Abbott Architect Analyser (Abbott, Abbott Park, Illinois, USA); assays included methadone, opiates, benzodiazepines, amphetamines, cannabinoids and cocaine metabolites. Meconium samples were screened for the same drugs using ELISA and selected positive samples were further analysed using solid-phase and liquid-liquid extraction followed by GC-MS or LC-MS-MS.
The detection of elevated fatty acid ethyl esters (FAEEs) as a biomarker for significant prenatal alcohol exposure was achieved using LC-MS-MS using a cut-off level of ≥10 000 ng/g of meconium.4 This level of cumulative FAEEs has been shown to be highly predictive of an alcohol consumption in pregnancy of greater than two units of alcohol per day, or binge drinking of greater than five units per episode.5 We defined significant prenatal alcohol exposure as a history of greater than seven units of alcohol per week, clearly above Department of Health recommendations.
Maternal urine toxicology results were obtained retrospectively; most women had urine collected routinely at their booking hospital visit, and again at approximately 36 weeks’ gestation. In addition, urine toxicology was undertaken in some of those mothers suspected of illicit drug use during their pregnancy.
A confidential interview was conducted (LMcG) with all mothers within 3 days of delivery regarding their drug and alcohol use during pregnancy. This was a semistructured interview using validated techniques.6 All women were asked the same questions relating to the use of individual drugs and alcohol in pregnancy, and frequency of use. The interviewer was not blinded to maternal history or toxicology in pregnancy.
Ethics committee approval was obtained prior to study commencement, and informed written parental consent obtained for all participants, including infant urine and meconium toxicology.
One hundred and fourteen infants were screened for inclusion in the study, of whom 12 were excluded. Of the 102 mothers approached regarding consent, 100 agreed to participation in the study (98% consent rate). Paired urine and meconium samples were successfully obtained for 56 infants within 3 days of birth, all of whose mothers underwent a confidential interview. All infant urine and meconium samples were analysed for drugs of misuse; 44 meconium samples were sufficient to analyse additionally for the presence of FAEEs. The results of urine samples (n=62) collected from 45 mothers during pregnancy were available for analysis.
Results from confidential interview (n=56), maternal urine toxicology (n=62), infant urine toxicology (n=56) and meconium toxicology (n=56) were combined to provide an overall pattern of in utero drug exposure for each study infant. A positive result from either maternal interview or any toxicology test was taken to indicate exposure in pregnancy.
Ninety-one per cent of infants (51/56) had evidence of having been exposed to illicit drugs in utero, including opiates (73%), benzodiazepines (70%), cannabinoids (59%), amphetamines (7%) and cocaine (14%) (figure 1). There was a high degree of overlap in the pattern of in utero drug exposure, with the most common combination being opiate, benzodiazepine and cannabis (n=15).
Forty-seven per cent (21/44) of infants tested had elevated FAEEs (>10 000 ng/g meconium), indicating significant alcohol exposure during pregnancy. By comparison, only three (5%) women admitted during confidential interview to drinking greater than seven units of alcohol per week.
Meconium analysis yielded significantly more positive results than infant urine (illicit opiates p<0.01, benzodiazepines p=0.01, cannabinoids p<0.01) and confidential interview (illicit opiates p=0.03, cannabinoids p<0.01) (table 1). Compared with the combined toxicology results, meconium was more sensitive than either urine toxicology or maternal interview (table 2).
While it is recognised that many women prescribed methadone during pregnancy continue to use illicit drugs, the extent of this has never been quantified in the UK using a combined toxicology approach, and there are no data regarding coexistent excessive alcohol consumption in this population.
Within this relatively small cohort of infants born in the West of Scotland to mothers prescribed methadone during pregnancy, the vast majority were exposed to polysubstance misuse, and almost one-half were additionally exposed to excess alcohol in utero. This has significant implications for the longer-term outcome of this vulnerable cohort of babies, as well as for interpretation of research studies investigating possible adverse effects of in utero methadone and/or illicit drug exposure.
Meconium analysis was more sensitive at detecting in utero drug exposure than maternal interview or infant urine toxicology, in keeping with previous studies.7 It is well recognised that pregnant women under-report illicit drug and alcohol use in pregnancy, often due to a fear of legal and custodial repercussions.
Despite the high incidence of polydrug exposure identified, it is still possible that this study under-reports the true incidence of in utero drug exposure in this population. Urine toxicology is limited by the short half-life of many drugs of misuse, and collection of meconium was sometimes thwarted by samples being discarded or soaked into the nappy. While meconium toxicology reflects fetal drug exposure during the second and third trimesters of pregnancy, the sensitivity of this technique is lower for drugs which are used episodically, such as stimulants, compared with drugs used more regularly, such as cannabis. We recognise that meconium toxicology is not available to all units managing drug misuse in pregnancy; furthermore, since results take several days at least, meconium analysis is not likely to influence acute management of individual cases. We do recommend, however, that geographical regions consider defining their own pattern of in utero drug exposure to guide both the neonatal management of these infants and their longer-term follow-up requirements. In this study, urine toxicology was actually inferior to maternal history in determining prenatal drug exposure.
FAEEs are non-oxidative ethanol metabolites produced by the esterification of ethanol and free fatty acids. Cumulative FAEE levels in meconium have been found to have 100% sensitivity and 98% specificity for excess alcohol exposure in pregnancy.5 We believe, therefore, that these results are an accurate reflection of drinking patterns among our pregnant drug-misusing population. Recognising that the pattern of drug and alcohol misuse will vary from region to region, that our data may not be representative of the UK population as a whole, and that there is some evidence of reducing alcohol consumption in pregnancy,8 it seems likely, nevertheless, that excessive alcohol consumption is more commonly associated with drug misuse in pregnancy than is generally recognised.
Follow-up studies of infants born to drug-misusing mothers must take into account the pattern of alcohol and drug misuse in pregnancy, which cannot be reliably deduced from maternal report.
We wish to acknowledge Mr Bill Borland who analysed the urine toxicology samples for the study. We wish to thank the midwives at the Princess Royal Maternity.
Contributors LMcG was involved in study design, recruited the patients, collected the samples and patient data and drafted the manuscript. HM contributed to original idea, study design and edited the manuscript. GC and HH contributed to study design, analysed the toxicology samples and edited the manuscript. All authors have approved the final version of the manuscript.
Funding Yorkhill Children's Foundation, Tenovus Scotland, grant number S08/15.
Competing interests None.
Ethics approval West of Scotland research ethics committee.
Provenance and peer review Not commissioned; externally peer reviewed.