Pregnancy is not protective for mental health. However, more than half of women abruptly discontinue antidepressant medication upon confirming pregnancy. Up to 68 per cent of these women suffer a relapse of depression, often occurring by the second trimester.¹ The decision to continue or cease antidepressants in pregnancy ideally should be made prior to conception, by consultation with the woman, her partner and her doctor.

This decision should be a sensible balance between risk and benefit to mother, fetus and, later, the infant. It should be based on the mother’s psychiatric history, including the severity of her past and current condition, whether the condition has remitted and what treatments were required, tolerated and successful. Important factors include whether admission was required and the frequency, severity and duration of depressive episodes. No decision to continue or withhold medication is complete without a comprehensive assessment of the woman’s mental state and psychosocial circumstances.

If a woman is currently euthymic and has been for the past 12 months, she may elect to:

• Cease medication during pregnancy
• Cease and reintroduce medication if symptoms recur
• Reduce dose (not recommended)
• Change to alternate medication or therapy
• Continue current medication
• If a woman is depressed or has suffered serious and/or recurrent depression in the past, then medication should be continued throughout the pregnancy. Antidepressants should not be routinely changed for the sake of a pregnancy if the woman has been well on this medication. There are rare exceptions to this.²

Antidepressants are prescribed for a number of conditions, including depressive, anxiety and pain disorders. Antidepressants may, at times, also be prescribed in bipolar disorder. The use of antidepressants without the co-prescription of other thymoleptic medications may risk a manic or hypomanic swing.

Approximately eight per cent of pregnant women in the US take antidepressants.³ The most commonly prescribed and researched medications are selective serotonin reuptake inhibitors (SSRIs). SSRIs and selective noradrenaline reuptake inhibitors (SNRIs) are commonly prescribed for significant depression and anxiety disorders. Mild depression may be successfully treated with psychotherapies (cognitive behavioural and interpersonal therapies) and lifestyle changes including diet, exercise and sleep patterns.

Fetal exposure

Fetal exposure to antidepressants is via the placenta, amniotic fluid and the crossing of the blood brain barrier. There are potential pregnancy complications associated with antidepressants. The absolute risk for any negative outcome for the fetus (and the pregnancy) is low but not zero.⁴

Outcome studies

Distortions in any study regarding outcomes for psychotropic medication use in pregnancy may be the result of low- or medium-quality methods. Observational studies may involve databases relying on prescriptions supplied. Patient adherence and recall bias are further complications.⁵ The timing of medication in pregnancy is also important. First trimester exposure to drugs may be implicated in congenital malformation, while second and third trimester exposures may be associated with neurobehavioural and growth challenge.⁶

Tolerability

Tolerability of antidepressant agents is important, especially in pregnancy. Nausea may be exaggerated in hyperemesis with SSRI or SNRI agents. Postural hypotension, oversedation and constipation may all be unwanted side effects of antidepressant agents in pregnancy, particularly of tricyclic antidepressant drugs (TCADs). Suicidal ideation is a significant contraindication to using TCADs, as they are potentially fatal in overdose.

Pharmacogenomics

Pharmacogenomics are becoming more useful in selecting the best medications in treatment-resistant depression. While this is still a relatively new clinical tool, it may assist, especially if a woman appears either to have significant side effects at low dose (possible poor metaboliser), or no benefit from higher doses of an antidepressant (extensive or ultrarapid metaboliser).⁷

Bioavailability

Pregnancy affects the bioavailability of antidepressants through increased maternal blood volume, reduced gut motility, increased renal function and reduction in plasma protein concentrations. The dose of antidepressant may therefore need to be increased in advanced pregnancy. Changes in hepatic P450 enzymes in later pregnancy may also affect doses required. Smoking, cruciferous vegetables and chargrilled foods may further affect therapeutic levels of antidepressants.⁸ Proton pump inhibitors, dexamethasone and nifedipine are among medications that may affect certain P450 enzymes, thereby altering therapeutic antidepressant levels.⁹

Negative outcomes

There have been many associations made between negative outcomes and the use of antidepressants in pregnancy, but direct causality is yet to be established. The severity of the mother’s depression, any co-morbidities and use of other medications and substances all affect the outcome. An untreated severe major depressive episode may result in poor attendance at antenatal clinic, poor diet and low self-care. The risk of self-medication with substances is also significant. Suicide is the final risk, aside from high incidence of postnatal depression, poor attachment to the infant and long-term risk of poor child developmental outcomes through neglect.

SSRIs and SNRIs

With respect to SSRIs, the major concern for malformation relates to congenital cardiac defects. The only medication significantly implicated here is paroxetine, and even in these studies, the prevalence was only minimally greater than the background risk.¹⁰

The studies relating to preterm delivery and low birth weight with SSRIs are fraught with discrepancies in methodology. These outcomes are unlikely to be clinically significant.¹¹ Postnatal growth impairment, delayed fine or gross motor skills, and cognitive and intellectual impairment have not been shown conclusively to be a consequence of exposure of the fetus to antidepressants in pregnancy. Major depression in the mother remains a serious consideration.

The only significant potential risk for use of SSRIs and SNRIs obstetrically appears to be postpartum haemorrhage. This risk seems small, but clinically significant (four per cent in exposed women versus three per cent in non-exposed women).¹² Persistent pulmonary hypertension of the newborn (PPHN) has been reported in late pregnancy exposure to SSRIs, SNRIs and TCADs. The incidence is low (increase from 1.2 to 3 per 1000 in SSRI exposure).¹³

Poor neonatal adaptation syndrome

Poor neonatal adaptation syndrome (PNAS) can be a risk when antidepressants are taken in late pregnancy. Infants may be jittery and suffer hypotonia, respiratory distress, hypoglycaemia and seizures. The reported incidence of PNAS varies, but appears to be higher in infants exposed late in the pregnancy. Confounding variables include infant genotype.¹⁴ This condition is usually self-limiting and minor. Admission to NICU may be warranted.¹⁵

Despite the risk of PNAS, the practice of reducing the dose of antidepressants from mid to late third trimester is not recommended.¹⁶ The medication may clear the maternal compartment, thereby predisposing the mother to an increase in depressive symptoms at a time when she is most vulnerable. It does not necessarily clear the fetal compartment and the neonate may still suffer from PNAS. It is best to engage the neonatology team prior to delivery.¹⁷

Conclusion

While there are risks to the mother and infant with the use of antidepressants in pregnancy, the negative impact of an untreated major mental health disorder in pregnancy cannot be overstated. The Obstetrics Clinical Committee of the Medicare Benefits Schedule (MBS) Review Taskforce have recently reminded us of this with the launch of the new MBS item numbers recommending mental health assessments of all women, both in pregnancy and postnatally.¹⁸ Pathways to care for all pregnant women should include access to comprehensive perinatal mental health teams.

1. Cohen L, Altshuler L, Harlow B, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA 2006;295(5):499-507.
2. Cohen L, Altshuler L, Harlow B, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA 2006;295(5):499-507.
3. Huybrechts K, Palmsten K, Mogun H, et al. National trends in antidepressant medication treatment among publicly insured pregnant women. Gen Hosp Psychiatry 2013;35:265.
4. Shea A, Thi Nguyen T, Brain U, et al. Maternal and foetal factors that influence prenatal exposure to selective serotonin reuptake inhibitor antidepressants. In: Galbally M, Snellen M, Lewis A, editors. Psychopharmacology and Pregnancy. Berlin: Springer; 2014:33-46.
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6. Conover E, Forinash A. How do I weigh the risks and benefits of taking an antidepressant medication during pregnancy? [Internet]. In: Teratology Primer 3rd Edition. The Teratology Society; 2018 [cited 2018 July 20]. Available from: www.teratology.org/primer/.
7. Shea A, Thi Nguyen T, Brain U, et al. Maternal and foetal factors that influence prenatal exposure to selective serotonin reuptake inhibitor antidepressants. In: Galbally M, Snellen M, Lewis A, editors. Psychopharmacology and Pregnancy. Berlin: Springer; 2014:33-46.
8. Shea A, Thi Nguyen T, Brain U, et al. Maternal and foetal factors that influence prenatal exposure to selective serotonin reuptake inhibitor antidepressants. In: Galbally M, Snellen M, Lewis A, editors. Psychopharmacology and Pregnancy. Berlin: Springer; 2014:33-46.
9. Shea A, Thi Nguyen T, Brain U, et al. Maternal and foetal factors that influence prenatal exposure to selective serotonin reuptake inhibitor antidepressants. In: Galbally M, Snellen M, Lewis A, editors. Psychopharmacology and Pregnancy. Berlin: Springer; 2014:33-46.
10. Conover E, Forinash A. How do I weigh the risks and benefits of taking an antidepressant medication during pregnancy? [Internet]. In: Teratology Primer 3rd Edition. The Teratology Society; 2018 [cited 2018 July 20]. Available from: www.teratology.org/primer/.
11. Ross L, Grigoriadis S, Mamisashvili L, et al. Selected pregnancy and delivery outcomes after exposure to antidepressant medication: a systematic review and meta-analysis. JAMA Psychiatry 2013;70:436.
12. Palmsten K, Hernández-Díaz S, Huybrechts K, et al. Use of antidepressants near delivery and risk of postpartum hemorrhage: cohort study of low income women in the United States. BMJ 2013;347:f4877.
13. Kieler H, Artama M, Engeland A, et al. Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the newborn: population-based cohort study from the five Nordic countries. BMJ 2012; 334:d8012.
14. Boyce P, Galbally M, Snellen M, et al. Pharmacological management of major depression in pregnancy. In: Galbally M, Snellen M, Lewis A, editors. Psychopharmacology and Pregnancy. Berlin: Springer; 2014:67-85.
15. Kieler H, Artama M, Engeland A, et al. Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the newborn: population-based cohort study from the five Nordic countries. BMJ 2012; 334:d8012.
16. Boyce P, Galbally M, Snellen M, et al. Pharmacological management of major depression in pregnancy. In: Galbally M, Snellen M, Lewis A, editors. Psychopharmacology and Pregnancy. Berlin: Springer; 2014:67-85.
17. Boyce P, Galbally M, Snellen M, et al. Pharmacological management of major depression in pregnancy. In: Galbally M, Snellen M, Lewis A, editors. Psychopharmacology and Pregnancy. Berlin: Springer; 2014:67-85.
18. Austin M-P, Highet N and the Expert Working Group. Mental health care in the perinatal period: Australian clinical practice guideline. Melbourne: Centre of Perinatal Excellence; 2017.