Description of the condition
Depression is a highly prevalent mood disorder associated with social, human and economic costs, and public health impact worldwide. According to the World Health Organization (WHO), depression is estimated to affect more than 350 million people globally (WHO 2010a). The life-time risk of developing depression is 10% to 20% in females and slightly less in males (WHO 2010a). Despite the seriousness of depression as a disease and the availability of effective treatments, less than half of cases worldwide receive appropriate care (WHO 2010a).
Current theories on the causes of depression remain controversial, however, genetic predisposition, chronic disease and disability, environmental factors, an individual's ability to cope with difficult situations, direct biochemical changes in the brain and early childhood experiences have all been shown to potentially contribute to the onset of depression (beyondblue 2013; Black Dog Institute 2013; Passer 2008).
Depression can be diagnosed by a psychologist, psychiatrist or primary health care provider, usually in conjunction with symptom related scales such as the Beck Depression Inventory (BDI) (Beck 1961), or the Edinburgh Postnatal Depression Scale (EPDS) (also used to assess antenatal depression) (Cox 1994). However, symptom scales alone cannot be used as a direct diagnostic tool although for research purposes these tools are often used to assess improvements or decline in depressive symptoms.
Depression is one of the most common complications of the prenatal period (Gaynes 2005). Rates of depression during pregnancy range from between 7.4% and 12% and rise from the first trimester, to the second and third trimester (Bennett 2004; Gaynes 2005).
The morbidity of depression during pregnancy, as well as the negative effects of depression on subsequent fetal, infant and child development and on the family and community as a whole, have been extensively recognised (Cooper 1998; Cox 1982; Grote 2010; O'Connor 2007; O'Hara 1990; Marcus 2009a; Marcus 2009b). Antenatal depression has been associated with maternal substance use and increased risk of preterm birth and low birthweight (Grote 2010; Marcus 2009a; Marcus 2009b; Woods 2010). Prenatal depression also results in reduced total sleep time, night time awakenings, and sleep problems being identified at 6, 18, and 30 months of age in subsequent infants and is related to severity, with higher levels of prenatal maternal depression predictive of more sleep problems at 18 and 30 months (O'Connor 2007), possibly as a result of modifications to neurodevelopmental programming (Ponder 2011). In addition, disturbed infant sleep has been shown to further contribute to postnatal depression (PND) (Dennis 2005).
There is a well-established relationship between antenatal depression and the development of PND, with antenatal depression being the strongest predictor of PND (Beck 1996; Beck 2001; O'Hara 1996). PND is a debilitating and costly condition, has an immediate primary effect on child well-being, parenting efficacy, use of safe parenting practices and marital conflict. Secondary effects of increased problematic behaviours and poorer cognitive development in childhood may occur due to poorer attachment and reduced maternal engagement (Murray 1996). Moreover, it is increasingly recognised that some women who become depressed postnatally have, in retrospect, been depressed during the antenatal period (Evans 2001; Kumar 1984). Large studies have shown that rates of depression in late pregnancy in particular, are as high, or higher, than rates of postpartum depression (DaCosta 2000; Evans 2001; Josefsson 2001; Zuckerman 1989). It is therefore important to detect and treat symptoms of antenatal depression to reduce the incidence of PND.
Depressed mood during pregnancy has also been associated with poor attendance at antenatal clinics (Phillippi 2009). Despite this potential for poor antenatal attendance, the antenatal period provides an opportunity for prevention and management of depression as a result of frequent contact with health professionals. Adequate management of antenatal depression has the potential to reduce maternal substance use, prevent preterm birth and low birth weight as well as PND and its associated consequences. This information in combination with the ineffective treatment of depression, highlights a need to focus recommendations for clinical practice to treat depression in this vulnerable population of pregnant women (Muzik 2009a; Muzik 2009b).
Description of the intervention
Antidepressants are commonly prescribed to treat depression (Centre for Disease Control 2011). They include monoamine oxidase inhibitors, tricyclic antidepressants, tetracyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors and others (e.g. bupropion). Based on data from the United States, antidepressant use during pregnancy has increased from 2% of pregnancies in 1996 to 7.6% of pregnancies in 2005 (Andrade 2008).
Antidepressants can be used alone or more commonly in conjunction with psychosocial and psychological therapies such as behavioural therapy (includes behavioural activation), cognitive behavioural therapy, mindfulness-based cognitive behavioural therapy (including acceptance commitment therapy), and psychodynamic, humanistic (including motivational interviewing) and integrative therapies (includes interpersonal therapy) (Arroll 2009; Cipriani 2009; Cipriani 2010; Guaiana 2007; Magni 2013; NICE 2007). Patient responses vary markedly to different classes of antidepressants and therefore this will influence the type of antidepressant drug that is prescribed for an individual. Dosage regimes differ between the different classes of antidepressants, and also with the severity of depression. Antidepressants are typically taken daily, with the type of antidepressant determining whether or not night time or morning dosing is appropriate. The length of time antidepressants are taken for may vary, ranging from several months to several years, or lifetime use (FDA 2010; Elsevier 2013).
As with the general population, antidepressants during pregnancy can be used alone or in combination with psychological therapies (NICE 2007). Psychological therapy alone can in some cases be appropriate for some women, but others may need pharmacological treatment (NICE 2007; Yonkers 2009). Decisions surrounding the use of antidepressants during pregnancy are incredibly complex, requiring a careful balance of optimising maternal health while minimising potential risks to the developing fetus. However, data concerning the immediate risks of antidepressants to the fetus are limited, and little is known about the potential long-term risks.
There is much debate concerning the potential increased risk of congenital malformations following the use of paroxetine during pregnancy (Berard 2010; Scialli 2010; Wurst 2010), as well as for the remainder of antidepressants (despite a lack of clear evidence that they are teratogenic); due to study designs used there can be no determination of causality (Ellfolk 2010; Nguyen 2010; Pedersen 2009; Udechuku 2010). However, there is evidence that antidepressant use during pregnancy may be associated with an increased risk of a range of adverse pregnancy outcomes including spontaneous abortion (Berard 2010a; Nakhai-Pour 2010), preterm birth (Lund 2009), and low birth weight (Lattimore 2005), but separating these outcomes from the effects of depression itself during pregnancy has been challenging (Ellfolk 2010; Nguyen 2010; Udechuku 2010). Furthermore, exposure to antidepressants during late gestation is associated with an increased risk of admission to special care nurseries and neonatal intensive care units as a result of neonatal abstinence syndrome and/or poor neonatal adaptation, which are usually mild and self-limiting (Costei 2002; Heikkinen 2003; Kallen 2004; Laine 2003; Lattimore 2005; Nguyen 2010; Udechuku 2010; Zeskind 2004). Other perinatal complications include the reported increased risk of persistent pulmonary hypertension of the newborn following prenatal exposure to selective serotonin reuptake inhibitors in particular, with the greatest risk attributed to those exposed later in pregnancy (Chambers 2006; Nguyen 2010; Udechuku 2010). Finally, based on the small number of studies available, antidepressant use during pregnancy does not appear to adversely influence developmental outcomes in the offspring; however, major differences in study design, patterns of antidepressant use, age at follow-up, outcome measures used and adjustment for confounding make it difficult to reach any strong conclusions (Ellfolk 2010; Gentile 2011; Nguyen 2010; Udechuku 2010).
How the intervention might work
Antidepressants exert their action in a number of different ways depending on the specific type of antidepressant. However, all have an underlying mechanism whereby they effect monoamine transmitter deficits within the brain (Rang 2007).
Antidepressants are organised into classes for the purposes of this review as follows. Tricyclic antidepressants exert their actions through inhibiting uptake of noradrenaline, and or serotonin. Selective serotonin reuptake inhibitors exert their actions through inhibiting uptake of serotonin. Serotonin norepinephrine reuptake inhibitors exert their actions through inhibiting uptake of noradrenaline and serotonin. Noradrenergic and specific serotonergic antidepressants exert their actions through blocking the action of noradrenaline and serotonin at their receptors. Monoamine oxidase inhibitors and reversible inhibitors of monoamine oxidase A exert their actions through inhibition of one or both forms of the enzyme monoamine oxidase.
It may also be speculated that antidepressants exert some of their antidepressant effects through their negative immunoregulatory capacities (Maes 2001). Much of the research investigating the effects of antidepressants on inflammation has focused on the selective serotonin reuptake inhibitors, in particular fluoxetine. Animal studies have shown that fluoxetine may be a therapeutic agent to manage inflammatory bowel disease by significantly inhibiting activated nuclear factor kappa B signals and the up-regulated expression of interleukin-8 in intestinal epithelial cells (Koh 2011). Sluzewska 1995 reported changes in serum levels of interleukin-6 as well as levels of C-reactive protein, alpha1-acid glycoprotein and its degree of microheterogeneity before and after treatment with fluoxetine 20 mg daily over an eight-week period. Following treatment of selective serotonin reuptake inhibitors for major depression over a four-week period, O'Brien 2006 also observed a significant drop in C-reactive protein concentrations whether or not the depression resolves. These findings indicate that antidepressants can induce an anti-inflammatory response independent of antidepressant action.
Why it is important to do this review
The decision to begin, maintain or discontinue antidepressant treatment after a pregnancy is confirmed should take into account the severity of depression, the risk of relapse, and the specific drug safety data available. However, it has been shown that two-thirds of women whose depression was well stabilised and who interrupted, or discontinued their antidepressant treatment before conception, relapsed during pregnancy, compared to one quarter of women who maintained their treatment (Cohen 2006). This highlights the need to undertake, and or, continue antidepressant treatment for those women who develop depression in the antenatal period, and those women who already have a pre-existing depressive disorder prior to conception, respectively. However, with a lack of certainty in this area, a systematic review needs to be undertaken to assess the safety and efficacy of antidepressant use during pregnancy to determine potential side effects and the most effective pharmacological intervention to manage depressive symptoms in this population.
While Cochrane systematic reviews have been undertaken in the area of treatment strategies for mental health problems during pregnancy (Dennis 2007), there are currently no systematic reviews listed that address the use of pharmacological interventions to treat depression during pregnancy. This includes pre-existing depression (i.e. the mother was depressed prior to conception) and antenatal depression (i.e. the mother became depressed following conception). Cochrane systematic reviews have been presented that focus on and discuss antidepressant use for the prevention and treatment of postnatal depression (Hoffbrand 2001; Howard 2005); however, there are no reviews that target depression in the antenatal period. The proposed systematic review aims to focus on this area in particular.
Other non-Cochrane reviews that assess the use of antidepressants during pregnancy have been published. However, these tend to focus on one type of antidepressant alone. While, those that have been performed assessing all types of antidepressants appear to be lacking in their approach and are of poor quality (Simoncelli 2010).
Lack of high quality evidence surrounding the safety (as defined in this instance as a lack of adverse events) and efficacy of antidepressants during pregnancy increases therapeutic uncertainty, making it difficult to accurately balance the risks and benefits associated with treatment. This may result in decisions to cease antidepressant use during pregnancy, even in situations where treatment is considered necessary. We are however aware of the potential ethical implications of conducting randomised controlled trials during pregnancy which may impact on the ability to identify these types of studies during pregnancy. As such we have acknowledged this by expanding inclusion of studies to be assessed in this review to include non-randomised studies.
Therefore, a systematic review of the safety and efficacy of antidepressants during pregnancy is required to bring together the relevant evidence for people wishing to make a well-informed decision. This would enable strengthened safety data, support medication use during pregnancy when necessary and allow healthcare professionals and women to be adequately informed of the true risks and benefits associated with treatment.