Pharmacologic Interventions for Pregnant Women Enrolled in Alcohol Treatment
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
This review will examine the effectiveness of pharmacological treatments in pregnant women enrolled in alcohol treatment programmes when compared to other pharmacological treatments, placebo, non‐intervention, psychosocial interventions.
Background
Only ten countries were found to have recommendations on alcohol use in pregnancy, all provide the guidance that women avoid alcohol while pregnant. Three of these countries; Australia, Switzerland and the United Kingdom; also provide broader guidelines in the case that a woman decides to drink while pregnant. They state that if a woman decides to drink she should have no more seven standard drinks a week and not binge drink (ICAP 2007). Recommendations of complete abstinence are contrary to the fact that the use of alcohol during pregnancy is a common practice (Doggett 2006). In the US, 11.8% of pregnant women reported recent use of alcohol (ONDS 2006). 75% of pregnant women in Australia reported alcohol use in the last twelve months (NSDUH 2006; NSDUH 2007). In the UK, 61% of mothers continued to drink alcohol while they were pregnant. The majority (71%) of those who continued to drink consumed less than 1 unit of alcohol per week and only 3% had drunk more than 7 units a week (NSDUH 2006; NSDUH 2007). However, these figures are related to 'regular' use of alcohol and therefore are not necessarily at levels where there is evidence of associated harm. Some countries including Australia, Spain, the United Kingdom provide broader recommendations on alcohol use during pregnancy and state that if a woman decides to drink she should have no more one to two drinks a week and not binge drink (ICAP 2007).
Women who choose to drink alcohol during pregnancy were advised to drink no more than one to two units of alcohol once or twice a week. Even though there is no safe level of alcohol consumption in pregnancy, there is no conclusive evidence that low level of alcohol consumption has any adverse effects to the unborn child (NICE 2008). However, excessive alcohol use during pregnancy has been associated with increased risk of miscarriage, a reduction in foetal growth and impaired neurodevelopment (AAP 2000; Taylor 2006).
Description of the condition
Along with these detrimental effects to both the mother's and the baby's health there are innumerable costs to the economy. Alcohol misuse is estimated to cost the economy in the region of £20 billion (Strategy Unit 2003). In developed countries, alcohol is the third leading cause of ill health after smoking and raised blood pressure. Current estimates are that for one pound spent on effective substance use treatment, five pounds is saved in health and social care costs (Raistrick 2006).
Alcohol use during pregnancy is associated with a wide range of adverse effects both on the mother's health and her baby's. Alcohol is associated with a continuum of birth damage, which can be very serious (Barrison 1985). These effects can include a combination of developmental delay, growth retardation, neurological abnormalities and characteristic facial dysmorphology referred to as the Foetal Alcohol Syndrome (FAS). Adolescents and adults with FAS have varying degrees of psychosocial and behavioural problems (Weintraub 1998). Less severe effects of alcohol use during pregnancy include mild to moderate mental and physical growth retardation, referred to as Foetal Alcohol Effects (FAE) (Sanchez 1979). Alcohol consumption during pregnancy has a vast impact on society and is the most commonly recognised cause of mental retardation, with as many as 5% of all congenital anomalies being attributed to prenatal alcohol exposure (Pietrantoni 1991). Children can also be at risk of reduced developmental goal attainment as a result of either a direct effect of alcohol use or from the associated lifestyle factors connected to alcohol use (Belcher 1999; Eriksson 2000; Faden 2000; Frank 2001; Jacobson 2002; Singer 2002). Increased child abuse and neglect have been documented in some populations, as a result of alcohol use during pregnancy (Bessinger 1999; Nair 1997), along with child deaths (Jaudes 1997). Other major factors which are compromised by alcohol use during pregnancy include the mother‐infant attachment and responsiveness, along with post‐natal depression and possible domestic violence within the household. Mothers also tend to be less likely to attend health facilities for education, medical treatment and social support (Doggett 2006).
Description of the intervention
There are many pharmacological drugs available to assist with alcohol treatment. These drugs are given to both lessen the effects during the withdrawal period and to help maintain abstinence. Drugs given during detoxification include Benzodiazepines (BZs), phenothiazines and chlormethiazone among others (Mann, 1996). These drugs are used in severe cases of alcoholism to suppress the patient's anxiety and insomnia to increase the chances of completing detoxification.
While many drugs including MAOIs and anti‐depressants in addition to those listed above have been used to treat alcoholics in the post‐withdrawal phase only three drugs have been approved by the United States Federal Drug Administration (FDA) for the treatment of alcohol dependence and abuse following detoxification; disulfiram, naltrexone and acamprosate (FDA 2007, Jaffe, 1992). Each drug uses a different mechanism of action to influence alcohol abstinence. Disulfiram works by causing an adverse reaction when a person taking the medicine consumes alcohol; naltrexone attenuates the "high" of alcohol consumption; and acamprosate decreases the cravings for alcohol in abstinent alcohol dependent persons (Mann, 1996, Kenna, 2004, Kenna, 2004a). Naltrexone and acamprosate have been shown to be effective in reducing the frequency of drinking days and increasing the time to relapse and time to first drink (Garbutt 1999, Kranzler 2001). Trials of disulfiram have shown inconclusive results on the drug’s overall effectiveness, but being the oldest available drug it does appear to be useful in delaying time to first drink from fear of the reaction ( Garbutt 1999) but not necessarily effective in long term abstinence from alcohol (Kranzler 2001). These reviews have included both adult males and females, but provide no specific evidence for the effectiveness of these treatments in pregnancy. Each of these drugs holds a class C pregnancy category in the United States which means that there is evidence of adverse effects in animal studies but no adequate or well‐controlled human studies and either a B2 or B3 category in Australia which means “the drugs have been taken by a small number of pregnant women with no increase in the frequency of malformation or harmful effects to the fetus and studies in animals have shown evidence of harmful effects but the the corollation to humans is uncertain (TGA 2007 , FDA 2007 ). In short, the effects of these drugs in pregnancy has not been fully ascertained. Due to the short duration of pregnancy and the importance of this time period, it may be especially important to find treatments that work effectively, even for short periods of time.
How the intervention might work
Specific interventions need to be put in place to assist pregnant women and postpartume women who have alcohol problems. Interventions should be aimed at harmful alcohol use, pregnancy care, health surveillance and promotion, counselling, social support, education, facilitation of mother‐infant interaction and promotion of parenting (Doggett 2006). The purpose of this is to facilitate earlier and more intensive pregnancy care, improve pregnancy and neonatal outcomes, reduce alcohol use, aid the mother‐infant interaction and improve the home environment. This should then improve longer‐term outcomes such as reducing child neglect, reducing mother‐infant separation, improving neurodevelopmental outcomes, increasing successful schooling performance and decreasing problems in adolescence and young adulthood (Olds 2002).
Why it is important to do this review
Pregnant women in alcohol treatement are an important population to determine the most effective intervention in order to reduce the number of infant born with foetal alcohol syndrome. A systematic review is necessary in this area as, to our knowledge, there are none to date.
Objectives
This review will examine the effectiveness of pharmacological treatments in pregnant women enrolled in alcohol treatment programmes when compared to other pharmacological treatments, placebo, non‐intervention, psychosocial interventions.
Methods
Criteria for considering studies for this review
Types of studies
We will review all randomised controlled trials (RCTs) or quasi methods of participant allocation. Studies comparing pharmacological treatments versus either psychosocial intervention or placebo or no intervention or with another pharmacological treatment will be eligible for this review.
Types of participants
Trials that enrolled pregnant or postpartum women in alcohol treatment programmes will be included in this review. No minimum level of alcohol use will be required for inclusion, so long as the authors stated the women are receiving alcohol treatment. Studies will be excluded if the participants are illicit drug (i.e. cannabis, heroin, cocaine, amphetamine etc) users and are treated for their illicit substance use disorders. Studies that did not report participants' alcohol use will not be included.
Types of interventions
Experimental intervention:
This review will include any pharmacological treatments that are used for the treatment of alcohol dependence. In order to be eligible, a study must include at least one group where only some pharmacological treatments will be given.
Control Intervention:
This review will compare the experimental intervention to: other pharmacological treatment alone or in association with psychosocial treatment, placebo, non‐intervention, psychosocial intervention.
Types of outcome measures
Each trial must, at minimum, report at least one retention, birth or abstinence outcome.
Primary outcomes
Birth outcomes:
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birth weight.
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gestational age at birth.
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placental abruption.
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foetal alcohol syndrome (FAS).
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admission to and length of time spent in hospital (i.e. neonatal intensive care unit [NI
Secondary outcomes
Abstinence outcomes:
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alcohol abuse measured by: maternal toxicology, maternal self‐report, newborn toxicology and any biological markers provided in the original studies.
Retention outcomes
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treatment attendance as measured by the proportion or count of treatment visits attended.
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treatment attendance as measured by the proportion or count of individuals who complete treatment.
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prenatal care attendance as measured by the proportion or count of prenatal visit attended.
Each trial must, at minimum, report birth, abstinence or retention outcomes.
Search methods for identification of studies
We will undertake both electronic and manual searches to identify the studies of review.
Electronic searches
We will search the following electronic databases:
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Cochrane Drug and Alcohol Group trials register (April 2008)
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MEDLINE (1950 to April 2008)
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PsycINFO (1806 to April 2008)
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EMBASE (1974 to April 2008)
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CINAHL (1982 to April 2008)
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SPECTR
Databases will be searched using a strategy developed incorporating the filter for the identification of RCTs (Higgins 2008) combined with selected MeSH terms and free text terms. The MEDLINE search strategy will be translated into the other databases using the appropriate controlled vocabulary as applicable. For MEDLINE search strategy see Appendice 1
The search strategies will be developed in conjunction with a librarian (Leeds Partnership Foundation Trust). We will not apply any language restriction to the review.
Searching other resources
We will search:
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the reference lists of all relevant papers to identify further studies.
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some of the main electronic sources of ongoing trials (Current controlled trials meta register of controlled trials (mRCT): clinicaltrials.gov; The International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) Clinical trials portal: www.ifpma.org/clinicaltrials.html).
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conference proceedings likely to contain trials relevant to the review.
We will contact investigators seeking information about unpublished or incomplete trials.
Data collection and analysis
Selection of studies
Two reviewers will read all titles and/or abstracts resulting from the search process and eliminate any irrelevant studies. We will obtain full copies of all the potentially relevant studies. Two reviewers acting independently will classify these as included, excluded or unclear. Decision will be based upon inclusion criteria outlined in the protocol. Differences in opinion will be resolved through consensus or referral to a third reviewer.
Data extraction and management
Data will be extracted by two reviewers independently using a data‐extraction form that will be developed to assess the following data: study location, methods, participant details, type of intervention, and outcomes. One reviewer will enter data into RevMan 5, and a second will confirm correct data entry.
Assessment of risk of bias in included studies
Assessment of methodological quality
The reviewers will asses the studies as per the Cochrane Collaboration Handbook . Appraisal of the included studies will be carried out independently by two reviewers. Any differences will be negotiated by a third reviewer to reach consensus. We will evaluate the methodological quality of the studies for potential biases by qualitatively assessing the study design; randomization method; allocation concealment and blinding based on the criteria described below.
Selection Bias
We will assess method of allocation to control or intervention by ensuring that all study participants had an equal chance of receiving the control or intervention.
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A. Adequate allocation concealment: central randomization(e.g. allocation by a central office unaware of subject characteristics), pre‐numbered or coded identical bottles or containers which are administered serially to participants, drug prepared by the pharmacy, serially numbered, opaque, sealed envelopes, on‐site computer system combined with allocations kept in a locked unreadable; computer file that can be accessed only after the characteristics of an enrolled participant have been entered or other description that contained elements convincing of concealment.;
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B. Unclear allocation concealment: when the authors either did not report an allocation concealment approach at all or report an approach that did not fall in the category A or C.
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C. Inadequate allocation concealment: alternation or reference to case numbers, dates of birth, day of the week. Any procedure that is entirely transparent before allocation, such as an open list of random numbers or other description that contained elements convincing of not concealment
Performance bias
We will assess those providing and receiving the intervention should be blinded so that they do not know which group the participants have been allocated to. With psychosocial interventions it is not always possible to do so. Key questions to be considered here will be:
"Were participants unaware of the assigned intervention?
"Were those providing the care unaware of the assigned intervention?
Depending on the study design the following criteria will be used.
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A Double blind
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B Single blind (blinding of participants)
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C Unclear (when is not specified but could be blinded for the kind of intervention compared, i.e. pharmacological intervention with the same way of administration)
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D No blinding (when it is clear that is not blinded but it could have been for the kind of intervention compared, i.e. pharmacological intervention with the same way of administration)
Detection bias:
We will consider blinding of the outcome assessor as studies which blind outcome assessors will be less open to bias.
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A Blind to treatment allocation at outcome assessment (if explicitly stated or if the study is double blind and it is clear that the outcome is assessed by the provider of the intervention)
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B Not blind to treatment allocation at outcome assessment (when specified that is not blind)
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C Unclear (when is not specified)
Studies with adequate allocation concealment will be classified as A: low risk of bias, studies with unclear allocation concealment will be classified as B: moderate risk of bias and studies with inadequate allocation concealment will be classified as C: high risk of bias.
Intention to treat analysis will be considered:
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A Intention to treat analysis performed
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B Intention to treat analysis not performed
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C Unclear
Measures of treatment effect
Dichotomous outcomes will be analysed calculating the Relative risk (RR) for each trial with the uncertainty in each result being expressed by their confidence intervals. Continuous outcomes will be analysed calculating the WMD (weighted mean difference) with 95%CI.
Unit of analysis issues
We will not use data presented as number of positive urine tests over total number of tests in the experimental and control group as measure of substance abuse. This is because using tests instead of the participants as the unit of analysis violates the hypothesis of independence among observations. In fact, the results of tests done in each participant are not independent.
Dealing with missing data
In this study population it is plausible that there will be missing information for participants for different study points, sensitivity analysis will be performed as needed. Studies will not be excluded based on missing data for study subjects, as retention is one of the outcomes of interest for this reveiw.
Assessment of heterogeneity
Due to the nature of the studies in this review, it is anticipated that there will be some degree of heterogeneity in the study interventions, outcome measures reported and methodological quality therefore it may not be appropriate to combine these studies. A P‐value of the chi‐square test less than 0.05 indicates a significant heterogeneity.
Assessment of reporting biases
Funnel plots will be used to assess the potential for bias related to the size of the trials, which could indicate possible publication bias.
Data synthesis
Meta‐analysis and narrative review will be performed where appropriate for each of the nominated outcomes. Where possible, we will pool results of similar studies.The RR or the WMD from the individual trials will be combined through meta‐analysis where possible (comparability of intervention and outcomes between trials) using a fixed effect model unless there will be significant heterogeneity, in which case a random effect model will be used. A P‐value of the chi‐square test less than 0.05 indicates a significant heterogeneity.
The RevMan software package will be used to perform the meta‐analysis for continuous and dichotomous outcome measures.
