Principles of Antidepressant Prescribing in Pregnancy and Postnatal Period

PRINCIPLES OF PRESCRIBING IN PERINATAL AND POSTPARTUM PERIOD - GUIDELINES

1.Explain baseline risks of congenital malformations in the absence of medication.

Whenever psychotropic medication is prescribed to pregnant and breastfeeding women, informed consent should be obtained. In order to obtain informed consent for the provision of pharmacological treatment during pregnancy and breastfeeding, a risk/benefit analysis needs to be performed giving consideration to the risks for the mother as well as the risks to the foetus, and the risks to either of nontreatment. All risks need to be identified and disclosed, both proven and speculative, giving particular consideration to what is of significance to any particular patient. Details of any risk/benefit discussion and the woman’s decision should be carefully documented. [RANZCP Guidelines, 2015]

A careful risk-benefit analysis should be undertaken in planning pharmacological management of a mood disorder in a pregnant woman: specifically, the risks of harm to the developing foetus from pharmacotherapy should be balanced against potential harm to the mother because of not receiving necessary pharmacological treatment for her mood disorder. [RANZCP Guidelines, 2021]

2. Treatment of Depression in Pregnant and Breastfeeding women: [RANZCP Guidelines, 2015]; [RANZCP Guidelines 2021]

Mild-to-moderate depression:

• Offer formulation based psychological treatments such as interpersonal therapy or cognitive behaviour therapy
• Psychological interventions, particularly Interpersonal psychotherapy (IPT) and Cognitive behavioural therapy (CBT), should be the preferred treatment modality for MDD during pregnancy and postpartum.
• A recent systematic review and meta-analysis concluded that CBT monotherapy is sufficient to improve symptoms and quality of life in postnatal depression. [Huang et al., 2018]

Severe depression

• Offer antidepressant medication even though the evidence is absent regarding the efficacy of antidepressants in the perinatal period.
• For severe cases of MDD during pregnancy, antidepressant medication may be trialled with a preference for SSRIs, but paroxetine, fluoxetine and venlafaxine should be avoided where possible
• ECT has been safely used for the treatment of severe depression during pregnancy, and it may be the treatment of choice for patients with severe depression or bipolar episodes carrying a significant risk to the mother and/or the foetus
• ECT should be considered for severe refractory cases of mood disorders in pregnancy

3. Principles in Postpartum depression [RANZCP Guidelines, 2015]; [RANZCP Guidelines, 2021]

• Episodes of depression arising within the first 4 weeks postpartum tend to be melancholic in nature and require assertive management with antidepressants.
• Infants exposed to antidepressants, mood stabilisers and antipsychotics in pregnancy should be observed for the first three days postpartum for any known adverse effects
• ECT may be necessary for psychotic (delusional) depression to ensure quick recovery from the depressive episode to minimise disruption to the mother-infant relationship.
• In addition to providing treatment to the depressed mother, attention also needs to be paid to the mother-infant dyad.
• Assessment of parenting capacity and safety of the child
• Assessment of the quality of the mother-infant relationship and if issues are identified, specific interventions may be needed.

Mild to Moderate Depression

• Psychosocial treatments, such as CBT, non-directive counselling and IPT, are the first line of treatment.
• Support to address fatigue induced by sleep deprivation.

Severe depression

• Antidepressant medication is indicated [risk-benefit analysis to be considered if the mother is breastfeeding]

NICE GUIDELINES FOR PRESCRIBING IN PERINATAL AND POSTNATAL PERIOD

1. Pregnancy or Postnatal Period: 

Persistent subthreshold depressive symptoms, or mild to moderate depression:

• Consider facilitated self‑help (based on CBT principles including behavioural activation and problem-solving techniques)

History of severe depression who initially presents with mild depression:

• Consider a TCA, SSRI or SNRI.

Moderate or severe depression : 

• High‑intensity psychological intervention (for example, CBT)
• TCA, SSRI or SNRI ( if the woman understands the risks associated with the illness and medication in pregnancy and postnatal period and; she has expressed a preference for medication or; she declines psychological interventions or; her symptoms have not responded to psychological interventions)
• High‑intensity psychological intervention in combination with medication (if the woman understands the risks associated with the illness and medication in pregnancy and the postnatal period and; there is no or limited response to a high‑intensity psychological intervention or medication alone).

2. Becomes pregnant on medication 

If a woman who is taking a TCA, SSRI or SNRI for mild to moderate depression :

• Discuss stopping the medication gradually and consider facilitated self‑help

If a pregnant woman is taking a TCA, SSRI or (S)NRI for moderate depression and wants to stop her medication:

Take into account previous response to treatment, stage of pregnancy, risk of relapse, the risk associated with medication and her preference, and discuss with her the following options:

• Switching to a high‑intensity psychological intervention (for example, CBT)
• Changing medication if there is a drug that is effective for her with a lower risk of adverse effects.

If a pregnant woman is taking a TCA, SSRI or SNRI for severe depression: 

Take into account previous response to treatment, stage of pregnancy, risk of relapse, the risk associated with medication and her preference, and discuss with her the following options:

• Continuing with the current medication
• Changing medication if there is a drug that is effective for her with a lower risk of adverse effects
• Combining medication with a high‑intensity psychological intervention (for example, CBT)
• Switching to a high‑intensity psychological intervention (for example, CBT) if she decides to stop taking medication.

ANTIDEPRESSANTS IN PREGNANCY

Spontaneous abortion rates in confirmed early pregnancy are 10-20%, and the risk of spontaneous major malformations is approximately 3% (approx 1 in 40 pregnancies). [ACOG Practice Bulletin No. 200], [Abeywardana and Sullivan, 2008]

The following points have been summarised from Maudsley guidelines, RANZCP and NICE guidelines and recent research papers. [Maudsley Guidelines, 2018]

Tricyclic Antidepressants (TCAs)

• TCAs pass through the placental barrier.
• If TCAs are to be used, then nortriptyline and desipramine are recommended as they are less anticholinergic and hypotensive than amitriptyline and imipramine.
• Clomipramine is not recommended in pregnancy due to a possible link with cardiovascular defects.
• TCAs can increase the risk of preterm delivery and use in 3rd trimester can result in neonatal withdrawal.

SSRIs

• Sertraline is the SSRI that has the lowest known risk in pregnancy.
• Sertraline has the least passage through the placental barrier.
• SSRI’s taken after 20 weeks gestation may be associated with an increased risk of persistent pulmonary hypertension in the newborn (PPHN) – paroxetine is most associated. [Bernard et al., 2017]
• There is also a significantly increased risk of the infants developing a poor neonatal adaptation syndrome (PNAS) in the first week postpartum with up to 30% of infants having symptoms.

Recent Research: [Anderson et al., 2020]

• A recent study of 30,630 mothers of infants with birth defects showed that elevated adjusted odds ratios (aORs) were observed for individual selective serotonin reuptake inhibitors (SSRIs) and selected congenital heart defects (CHD)
• Fluoxetine and anomalous pulmonary venous return: aOR, 2.56 (1.10-5.93). After partially accounting for underlying conditions, this association was attenuated: aOR, 1.89 (0.56-6.42). This pattern was observed for many SSRI-CHD combinations. [Read more on the interpretation of Odds ratios]
• Associations between SSRIs and non-CHD birth defects often persisted or strengthened after partially accounting for underlying conditions (e.g., citalopram and diaphragmatic hernia: aOR, 5.11 (1.29-20.24)).
• Venlafaxine had elevated associations with multiple defects that persisted after partially accounting for underlying conditions (e.g., anencephaly and craniorachischisis: aOR, 9.14 (1.91-43.83).)

The authors concluded:

We found some associations between maternal antidepressant use and specific birth defects. Venlafaxine was associated with the highest number of defects, which needs confirmation given the limited literature on venlafaxine use during pregnancy and risk for birth defects. Our results suggest confounding by underlying conditions should be considered when assessing risk. Fully informed treatment decision-making requires balancing the risks and benefits of proposed interventions against those of untreated depression or anxiety.

Other risks: 

• SNRIs and TCAs are associated with an increased risk of preeclampsia. [Palmsten et al., 2013]
• SSRIs, SNRIs and TCAs, are associated with an increased risk of postpartum haemorrhage (study in low-income women) although a previous 2008 study did not show an association with SSRIs. [Palmsten et al., 2013]

To date, there have been no reports of mirtazapine causing major malformations. [Smit et al., 2016]

Little information is currently available regarding the safety of some of the newer antidepressants, such as agomelatine and vortioxetine. [Niethe & Whitfield, 2018]

Websites such as the Pregnancy and Breastfeeding Medicines Guide can assist in making a risk-benefit analysis for patients.

WITHDRAWING ANTIDEPRESSANTS IN PREGNANCY

• Tapering down the dose of an SSRI or SNRI in the late third trimester has been proposed as a strategy to reduce the severity of the PNAS.
• All antidepressants carry the risk of withdrawal or toxicity in neonates; in most cases the effects are self-limiting.
• Significant amounts of SSRI’s, TCAs and Venlafaxine cross the placental barrier and late pregnancy exposure can be associated with neonatal withdrawal syndromes and subtle neuro-behavioural outcomes although these do not persist into early childhood
• SSRI withdrawal occurs in 1 out of 4 cases
• All exposed babies to be monitored for withdrawal 3 days after birth
• Involve obstetricians, neonatologists and other perinatal disciplines

ANTIDEPRESSANTS AND BREASTFEEDING - KEY PRINCIPLES

• Risk-Benefit Analysis
• Imipramine, Nortriptyline and Sertraline are present in breast milk at low levels.
• Citalopram and Fluoxetine are present at high levels.
• SSRI’s and Venlafaxine pass into breast milk in small amounts, and a risk-benefit analysis should be performed
• Information about individual antidepressants and their passage through breast milk can be found on websites such as LactMed.
• Consideration needs to be paid to the medication’s side-effects and the impact upon the nursing mother, such as sedation that might interfere with night time feeds and breastfeeding.