Postpartum depression refers to the depression after childbirth, which is a common mental disorder in women. The pathogenesis of postpartum depression is not fully understood, and may be related to a variety of factors. Prenatal depression is an important risk factor for postpartum depression. Our recent multicenter randomized controlled trial, "Effect of Low-dose esketamine on the incidence of postpartum depression in women with prenatal depression", explored the effect of immediate postpartum intravenous infusion of low-dose esketamine on the incidence of postpartum depression in women with prenatal depression. The preliminary results showed that it reduced the incidence of postpartum depression at 42 days. Since there were no studies on the effect of intravenous esketamine infusion after delivery on long-term postpartum depression, this study is a long-term follow-up of the previous randomized trial. We aim to explore the effect of low-dose intravenous esketamine after delivery on the incidence of 2-year maternal depression after delivery in women with prenatal depressive symptoms.

Postpartum depression refers to the depression after childbirth. It is a common mental disorder after childbirth. In recent years, it has attracted more and more public attention. Studies have reported an incidence of postpartum depression ranging from 10% to 29%. Our previous findings showed that the incidence of depression at 42 days postpartum was 24.3%. Postpartum depression has adverse effects on physical and mental health of women, but also may have adverse influences on offspring including nutrition health, and cognitive and behavioral development. The pathogenesis of postpartum depression is not completely clear, and may be related to many factors, such as hormone level changes after childbirth, psychosocial factors, and adverse obstetric factors. Plently of studies have shown that prenatal depression is an important risk factor for postpartum depression. One meta-analysis showed that the incidence of postnatal depression could be as high as 39% in people with prenatal depression. Therefore, it is possible to reduce the occurrence of postpartum depression by active intervention of prenatal depressed parturients.

Ketamine, an NMDA-receptor antagonist, is a classic analgesic drug with advantages of light respiratory and circulatory inhibition and good analgesic effect. Recently, it has been found to have antidepressant effect and has been widely used in the field of psychiatry. Esketamine, a S-enantiomer of racemic ketamine, has similar antidepressant effects to equivalent doses of ketamine, with a lower incidence of adverse reactions. In 2019, esketamine was approved by the US FDA for the treatment of treatment-resistant depression. At present, the results of studies on the use of esketamine in the perioperative period for the prevention and treatment of postoperative or postpartum depression are mixed.

Our recent multicenter randomized controlled trial, "Effect of low-dose esketamine on the incidence of postpartum depression in women with prenatal depression", explored the effect of immediate postpartum intravenous administration of low-dose esketamine on the incidence of postpartum depression in women with prenatal depression. The multicenter study included 364 women who were given a low dose of esketamine intravenously after delivery. Preliminary results show that it can reduce the incidence of postpartum depression at 42 days. Here we conduct a 2-year follow-up of the women enrolled in the underlying trial to figure out the occurrence of 2-year maternal depression, and to explore the effect of immediate intravenous infusion of low-dose esketamine on the incidence of chronic depression at 2 years postpartum.

All 364 pregnant women who participated in the underling trial "Effect of low-dose esketamine on the incidence of postpartum depression in women with prenatal depression: a randomized, double-blind, placebo-controlled trial" NCT04414943）and agreed to accept this 2-year follow-up.

The inclusion criteria of the underlying trial:

• Maternal age ≥18 years;
• Prenatal Edinburgh postnatal depression scale score ≥10 points.

Exclusion Criteria of the previous study:

• A clear history of mental illness (depression, schizophrenia, etc.) or communication disorders
• Severe pregnancy complications (such as severe preeclampsia, placenta accreta, HELLP syndrome, placenta previa, placenta abruption) before surgery;
• ASA grade ≥III;
• The presence of contraindications to ketamine/esketamine use (e.g., stubborn, refractory hypertension, severe cardiovascular disease [cardiac function grade ≥III], hyperthyroidism).