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Midweek Medicine: Antidepressants in pregnancy

Treating depression during pregnancy – the current state of play

The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. Yonker KA et al – General Hospital Psychiatry 31 (2009) 403–413

Depression is a serious illness, characterised by a pervasive and persistent loss of interest and pleasure, and/or lowered mood – together with a cluster of associated symptoms including disturbances of sleep, appetite, energy, motivation, concentration and memory, and by changes in the nature of one’s thinking: becoming negative, helpless, hopeless, and often preoccupied with guilt, death and suicide. It is relatively common: The Epidemiologic Catchment Area and National Comorbidity Survey data from the USA describe a 12 month prevalence (the proportion of people who meet diagnostic criteria at some point within a given 12 month period) of between 4 and 10%, and a lifetime prevalence of 14 to 23%.

Antidepressant medication is one effective form of treatment for depression, and is probably more important the greater the severity. Tricyclic Antidepressants (TCAs) are the oldest; Selective Serotonin Reuptake Inhibitors (SSRIs would be the most commonly prescribed now; Mono-Amine Oxidase Inhibitors (MAOIs) are not now used a lot, because various dietary restrictions are needed; and there are various newer antidepressants such as venlafaxine, duloxetine, mirtazapine, that vary in their mode of action and side effects.

Pregnancy is a high-risk time for women in a number of respects, depression being one: either the development of a new depressive disorder or the relapse of a pre-existing one: according to a study by Gaynes et al in 2005, 14 to 23% of women will experience a major depressive episode during pregnancy.

Understandably however many women are hesitant about taking medications during pregnancy, fearing possible adverse effects on the developing foetus. However, the risks of an untreated depression (bearing in mind that medication is not always the only appropriate option for treatment) must be considered as well. Finding the balance needs to be done on an individual, case-by-case basis, and is often not easy. A new publication from the American Psychiatric Association and the American College of Obstetricians and Gynaecologists attempts to provide some guidance for doctors helping women with depressive disorders and planned or current pregnancy. The methods section in the abstract suggests a systematic approach to the review (going as far as to include their search terms), but the methods section in the text is absent. Having read it, I think it’s a good summary, and potentially helpful – though it stresses that (a) the literature is nowhere near as clear as we would like, and (b) decisions need to be made with the individual woman, taking her particular case into account.

Essential take-home points:

In essence, there is little to no clear evidence of harm from antidepressants, but some suggestive evidence there might be. Proper treatment of depression during pregnancy is important, and can include antidepressant medication as well as careful planning and monitoring, and psychotherapy.

The authors noted that most of the reports looking at associations between antidepressant treatment and birth outcomes did not include information on the mother’s psychiatric illness, and that in the studies they reviewed there was variable controlling for various important confounding factors that occur in a higher rate among depressed than among non-depressed women: poor ante-natal care, and drug, alcohol and/or nicotine use. Also of note is that depressed women are more likely to suffer complications such as nausea, hyperemesis gravidarum, or pre-eclampsia during pregnancy.

Detailed information:

The paper is broken into a number of sections: adverse reproductive outcomes of maternal depression itself; the impact of antidepressants on birth outcomes; ECT; diagnosis of depression in pregnancy; algorithms for treating a depressed pregnant woman; and finally their answers to six frequently asked questions. I’ll omit the latter two sections here, as they are more specifically aimed at prescribers. I think that the full text of the article should be available here

Can maternal depression itself have adverse effects?

The authors looked at miscarriage, growth effects (Low Birth Weight – LBW and Small for Gestational Age – SGA), pre-term delivery (PTD), neonatal effects, and long-term effects on offspring. There is little evidence around depression and miscarriage, and methodological problems with existing studies. Current evidence is inconsistent, and does not support or refute associations between maternal depression and LBW (low birth weight), SGA (small for gestational age), or pre-term delivery.

They identified no studies linking maternal depression with any congenital neonatal abnormalities. However some abnormalities of infant behaviour have been identified, with increased risk for irritability, and decreased activity, attentiveness, and facial expression. They also note from some small studies, physiological abnormalities in infants born to depressed mothers: increased cortisol, decreased peripheral dopamine and serotonin, a relative increase in right frontal electroencephalogram (EEG) activity, and lower vagal tone (impulses from the vagus nerve, which keep the heart rate down at its resting rate).

There is some suggestion that maternal depression might be associated with delays in development at 18 months, but studies are contradictory, and not methodologically rigorous. More investigation is needed to clarify whether there truly is such an association.

Diagnosing Depression in Pregnancy:

Screening tools do not replace clinical diagnosis, but can identify women who might need further investigation. However, commonly-asked about depressive symptoms such as fatigue, and changes in sleep and appetite are common in (non-depressed) pregnant women. It can be helpful to use a screening tool validated in a pregnant population, such as the Edinburgh Postnatal Depression Scale.

Impact of Antidepressants on Birth Outcomes:

The authors note that more than 80% of women take at least one dose of medication during pregnancy, and women who take an antidepressant are more likely to take another prescription medication as well. Thus it is difficult to be sure what medication – or combination – might be responsible for any given outcome.

Miscarriage, pre-term delivery, low birth-weight/small for gestational age

There is a reported increase in the risk of spontaneous abortion with various antidepressants in early pregnancy. However, no studies controlled for psychiatric illness, and control for confounding factors such as smoking, drug use, and age, was variable. Thus more rigorous study is needed to determine whether there is an association, and if so, how strong.

There is a reported increase in LBW and SGA deliveries in women taking SSRIs, though not all studies agree. It is not clear whether foetal growth is more affected by the time of exposure to an SSRI, the duration of exposure, or by the severity of maternal illness.

Studies of antidepressant (SSRI or TCA) use and preterm delivery (PTD) are contradictory, with some finding an association, and some not. Studies that found an effect generally reported a decrease in the order of a week or less. Effects of SSRIs on PTD appear to be related to longer duration of exposure during the pregnancy.

Structural malformations

In the majority of studies, TCAs have not been shown to be associated with structural malformations.

Current data show no consistent association between SSRI use in pregnancy and structural malformations. There are some reports (from small studies) of higher rates of cardiac malformations with paroxetine, but these have not been replicated by other (including larger) studies. There is suggestion of an increased rate of congenital heart defects in babies exposed in utero to an SSRI in combination with a benzodiazepine (but not an SSRI alone). Again, confounding factors include health habits and other medication use, and studies in this area are methodologically difficult as a consequence.

Less data are available for antidepressants other than SSRIs or TCAs, but there is currently no evidence of congenital malformations with these agents.

Neonatal neurobehavioural outcomes

TCA use during pregnancy can be associated with increased jitteriness, irritability, and rarely convulsions in neonates.

15 to 30% of neonates whose mothers took SSRIs in late pregnancy have been reported to have a transient cluster of symptoms termed ”poor neonatal adaptation”, including: tachypnoea (rapid breathing), hypoglycaemia (low blood sugar), temperature instability, irritability, weak or absent cry, and seizures. These symptoms typically resolve within 2 weeks or sooner. The mechanisms are not determined, though various hypotheses have been proposed. These include a “discontinuation” syndrome similar to that some people experience on stopping their SSRIs, an interaction between the SSRIs and genes, toxicity directly related to levels of the medication, or some sustained changes in brain function.

Other perinatal complications

SSRIs in pregnancy have been associated with Persistent Pulmonary Hypertension in the neonate. This occurs in between 0.5 to 2 per thousand births, and is fatal about 10% of the time. Use of SSRIs is estimated to raise this risk to between 3 and 6 per thousand. This association has not been shown with antidepressants other than SSRIs – though the authors note the fact that SSRIs are used more commonly might affect that. Note: the increase, while a trebling of risk, is at most 4 more cases per thousand live births.

Long-term effects on offspring

There is little information about longer-term effects on offspring: the authors identified 2 reports (from 1 study) that did not show a link between either SSRIs or TCAs and neurocognitive or behavioural outcomes.

Electro-Convulsive Therapy (ECT) in Depression:

There is little evidence to suggest harm to mother or foetus from ECT. It is a highly effective treatment for depression, and is particularly appropriate where the depressive disorder is treatment-resistant or life-threatening.

In summary:

While we do not know enough about the effects of either depression or antidepressant use on pregnancy and infant development, it can be seen that in general these medications appear to be relatively safe; at least they should not be stopped in a knee-jerk fashion when a depressed woman becomes pregnant, nor should they be thoughtlessly avoided when depression is diagnosed during pregnancy.

However, there are some possible adverse effects (congenital heart defects, low birth weight/small for gestational age with SSRIs), and some definite but low frequency adverse effects (increased jitteriness, irritability, and rarely convulsions in neonates with TCAs, and ”poor neonatal adaptation” and persistent pulmonary hypertension with SSRIs)

Other than these, this paper – published by the American Psychiatric Association and the American College of Obstetricians and Gynecologists – does not describe any clear concerns around the use of antidepressants in pregnancy – though it must be noted that most of what little we do know relates to TCAs and SSRIs, and there is even less information about the newer antidepressants.

As is always the case in medicine, it comes down to a risk/benefit analysis, addressed in a clear and open way with the individual patient, to identify what evidence-based treatment is the best choice for that person at that time. None of this post is meant to assume or imply that medication is the only option for treating depression; in the general population it might well be that antidepressants are resorted to too easily, where psychosocial approaches might in fact be sufficient. However in depressed pregnant women, anecdotal experience certainly suggests the opposite is true, which risks a lot of suffering, and potentially very bad outcomes for mother and baby.

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1 Comment

  • It seems to me this risk is just too high as one going throught long term withdrawal from antidepressants I would say forget it there has to be a better way.There are a lot of people sufferring from withdrawal from antidepressants and I suspect the majority don't even know that withdrawal is what is wrong with them as it often takes a long time to kick in many times wks after the drugs are stopped. Doctors do not know what to do about it even if they believe you as they have been trained to expect no withdrawals as that is what the drug companies drugs testing claimed they are wrong….so horribly sadly WRONG! I cannot even imagine a new born baby having to go through withdrawal and how would anyone know what a new born is feeling? I will say that all of they effects listed above are part of what I and many others have experienced in withdrawal. There are many more things not on that list.

    I can only hope that some sense comes to the medical comunity soon to stop this needless sufferring.

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