International Journal of Pediatrics [57]. Unfortunately, the majority of available studies are limited or incomplete in their analysis and control for these potential confounders [5, 33, 49, 53–56, 60–63]. In addition, most studies fail to diﬀerentiate between exposure to heroin, methadone, or both heroin and methadone, and no studies analyse for the diﬀerential eﬀect of additional opiate exposure in the neonatal period. Much of the research also fails to adequately discuss, analyse, or control for the eﬀects of polydrug use [5, 33, 49, 53–56, 60–64]. Even the largest and most well-designed study— the landmark Maternal Lifestyle Study—failed to adequately account for the diﬀerential eﬀects of opiate as opposed to cocaine exposure [65, 66]. Overall, it appears that control for the main drug of interest (i.e., opiate versus other drug exposure) is often lost in the complexity of attempting to control for the myriad of maternal, neonatal, and social variables found in this population. In summary, the current clinical research on neurode- velopmental outcomes of opiate exposure in utero and/or the perinatal period is best limited to small studies and, at worst, methodologically ﬂawed. This highlights the urgent need for well-controlled, preferably large, studies in this area that examine the relationship between opiate use, maternal, neonatal, and social variables, and neurodevel- opmental outcomes. The need is particularly urgent given the increasing body of theoretical and animal research suggesting likely harmful eﬀects of opiate exposure on later neurodevelopment and behaviour. 6. Are There Alternatives to Opiate Treatment for Neonatal Withdrawal? The current guidelines certainly suggest that opiates are the most eﬀective pharmacological agent in reducing the symptoms of neonatal withdrawal [6, 13, 24, 26–28]. In particular, it is acknowledged that opiates compared to other pharmacological agents (e.g., phenobarbitone, diazepam, chlorpromazine) appear to reduce the duration of treatment [67–69], the need for a second agent to reduce withdrawal symptoms [8, 68, 69], and the admission rate to neonatal units [68, 69]. They also may reduce the incidence of seizures [27]. It is generally agreed that opiates are superior to other sedative agents such as chlorpromazine and diazepam in con- trolling abstinence-associated seizures, preventing treatment failure and the need for a second pharmacological agent [24, 25, 27, 28]. They are also considered to have less adverse eﬀects in the neonate compared to sedatives [6, 24]. If a second agent is required, the current recommendations are for the use of phenobarbitone [28] which, when combined with opiates, may assist in the management of seizures, improve behaviour and interaction [70], and reduce the duration of therapy required to minimise symptoms [71]. It is also recommended that, as much as possible, the pharmacological agent used to assist withdrawal should match the agent of in utero addiction (e.g., opiates for opiate addiction, phenobarbitone for amphetamine addiction, etc.) [6, 13, 25]. Another pharmacological agent, which demonstrates some promise and may have the potential to be an alternative 3 to opiates, is clonidine, an α2-adrenergic receptor agonist. Preliminary trials have suggested that clonidine compared to, or in addition to, opiates markedly reduces treatment failure, withdrawal symptoms, duration of therapy, and/or duration of opiate use and maximum dosage required [72–74]. Given the possible safety issues associated with clonidine, however, the guidelines recommend that further clinical trials are required to establish its eﬃcacy and safety in the long term [6, 28]. 7. Conclusion At this stage, we are stuck between the devil and the deep blue sea. On the one hand, methadone maintenance treatment for pregnant women who are illicit drug users has consistently been shown to reduce harmful outcomes for both the mother and newborn [3, 32, 58]. Furthermore, there are no real alternatives to pharmacological treatment with opiates and other drugs for neonatal opiate withdrawal and opiate addiction in pregnant women. On the other hand, there is increasing animal and theoretical evidence to challenge the general assumption that opiates are a benign substance to neurodevelopment and, at this stage, there is inadequate clinical research to guide our prescription of opiates for this already vulnerable and at-risk population. 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