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Parental depression, maternal antidepressant use during pregnancy, and risk of autism spectrum disorders: population based case-control study

BMJ 2013; 346 doi: (Published 19 April 2013) Cite this as: BMJ 2013;346:f2059

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Re: Parental depression, maternal antidepressant use during pregnancy, and risk of autism spectrum disorders: population based case-control study

Dear Sir,

I read with great interest the study carried out by Rai et al regarding maternal anti-depressant use during pregnancy and risk of autism spectrum disorders. And I would like to share the following in this regard.

Selective serotonin reuptake inhibitors (SSRIs), from the family of serotonin-selective antidepressants are being prescribed widely for the treatment of depression, anxiety and other related disorders. Depression has been found frequently in women of child-bearing age1 and thus antidepressants particularly SSRIs are being widely administered. Observational studies yet conducted have raised concerns regarding the neonatal outcomes following in utero exposure to SSRIs. The use of SSRIs during pregnancy has thus remained controversial.

The current literature search finds the prenatal SSRIs exposure being linked to congenital malformations, adverse pregnancy outcomes, adverse neonatal outcomes and long-term neurodevelopmental outcomes in exposed children with conflicting and biased results found among different studies. 2

The risk of congenital malformations especially cardiovascular malformations has found to be high with particularly paroxetine exposure3 The category of adverse pregnancy outcomes associated with SSRIs exposure include miscarriage, intra-uterine growth retardation and preterm delivery2, 3 These outcomes may also be linked to underlying maternal psychiatric disorder and thus may make conducted studies biased and questionable.

Yet, prenatal SSRIs exposure has been associated most strongly with adverse neonatal outcomes. Effects become increasingly evident when SSRIs are used in late pregnancy and they include irritability, tremor and poor extra-uterine neonatal adaptation which may be presented as persistent pulmonary hypertension, respiratory distress, and lethargy3

Persistent pulmonary hypertension of the newborn in which increased pulmonary vascular resistance results in right-to-left shunting of blood and severe hypoxemia has strongly been associated with prenatal SSRI exposure3, 4 Kieler H and colleagues found twofold increased risk of persistent pulmonary hypertension in neonates born to women treated with SSRIs in late pregnancy.4

The incidence of autism spectrum disorders (ASD) has heightened during past few years. Croen and colleagues have found an association between ASD and prenatal SSRIs exposure.5But they also declare a prompt need for further studies to establish the actual role of SSRIs upon pregnancy and neonatal outcomes.

Studies identified to date have shown contradictory findings regarding neonatal outcomes following SSRIs exposure. There found great uncertainty and biased risk estimates regarding prenatal SSRIs exposure and subsequent neonatal outcomes which may in part be due to factors just mentioning; mothers may not be taking proper prescribed dosages of medications dispensed, duration for which SSRIs used, timings of exposure and last but not the least mother may stop taking their medication before or during early pregnancy. The adverse effects of SSRIs which include anxiety, nausea, vomiting, diarrhea, and changes in weight, may themselves put pregnant mothers under trouble and bring adverse pregnancy outcomes, so they should also be considered.

Yet there are studies also which have found SSRIs to be pregnancy-safe, but the debate is still open and it needs us to employ the most accurate and effective ways to investigate outcomes following SSRIs exposure in order to minimize potential biases.

Doctors should prefer non-pharmacologic options where possible, for the treatment of depression in child-bearing women which mainly includes psychotherapy. Behavioral, cognitive and interpersonal psychotherapy may help mothers with mild to moderate depression but pharmacologic treatment is indeed imperative for mothers with moderate to severe depression during and following pregnancy. 6 Considering the yet non-established and controversial role of SSRIs during pregnancy, we should aim for alternate pharmacologic therapies available.
Melatonin-based therapy has recently been determined efficacious for the treatment of depression in adults as well as expectant mothers.7, 8Since it has been established that disturbance of circadian rhythm due to altered melatonin production plays an important role in the development of depression during pregnancy and postnatal period, 9, 10treatment with melatonin and its agonists seem justified. Further, it has been declared that melatonin becomes increasingly important during pregnancy due to its beneficial effects on pregnancy wellness and embryo development.11

Melatonin, a neurohormone secreted mainly by the pineal gland controls sleep-wake patterns in humans.12 Melatonin is known to influence sleep and mood patterns; act as scavenger molecule and anti-oxidant; regulate immune mechanisms and carcinogenic processes; and also control reproductive functions.12

Pregnancy brings mother under high oxidative challenge, and the presence of associated risk factors drives the mother towards an increased susceptibility of developing depression during pregnancy and afterwards.13 The immuno-inflammatory changes during pregnancy and postnatal period involves an increased inflammatory potential together with decreased anti-inflammatory compounds which precipitate an inflammatory environment, where tryptophan catabolic products particularly kynurenine stimulate the central pathways mediating depression.13 Also, a decrease in tryptophan has been found associated with decreased production of serotonin and melatonin.13This further underpins the use of melatonin for the treatment of depression during pregnancy and post natal period considering its anti-oxidant, anti-inflammatory, and yet fetus and infant-friendly nature.12 Melatonin has been known for its protective and therapeutic role in pre-term infants and other pediatric conditions12 advocating its administration to depressed expectant and lactating mothers with maximum fetus and infant, safety and healthful profile.

Since trials specifically analyzing the role of melatonin in the treatment of depression during human pregnancy have not yet been carried out, there is enough evidence available from animal models supporting a therapeutic role of melatonin and agonists in treating maternal depression during pregnancy.14, 15

As ASD in children have been specifically benefited with melatonin treatment, 12, 16 use of melatonin for the treatment of maternal depression seems to work for the best of yet unborn fetus by substantially reducing the risk of ASD even if it’s directly associated with severe maternal depression as proposed by Rai et al 17 however this still needs further scrutiny. However melatonin and its agonist, agomelatine have shown promising results in animal models in treating maternal depression in pregnancy and preventing adverse fetal outcome related to it, melatonin and agonists’ efficacy in human pregnancy is yet to be determined. Also large randomized controlled trials should be carried out to establish the efficacy of melatonin agonists in treating depression during human pregnancy for the purpose of its implementation as a standardized treatment.

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3. Diav-Citrin O, Ornoy A. Selective Serotonin Reuptake Inhibitors in Human Pregnancy: To Treat or Not to Treat? Obstet Gynecol Int 2012; 2012: 698947.
4. Kieler H, Artama M, Engeland A, Ericsson O, Furu K, Gissler M, 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 2011;344:d8012.
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11. Carlomagno G, Nordio M, Chiu TT, Unfer V. Contribution of myo-inositol and melatonin to human reproduction. Eur J Obstet Gynecol Reprod Biol 2011;159(2):267-72.
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13. Anderson G, Maes M. Postpartum depression: psychoneuroimmunological underpinnings and treatment. Neuropsychiatr Dis Treat 2013;9:277-87.

14. Morley-Fletcher S, Mairesse J, Soumier A, Banasr M, Fagioli F, Gabriel C et al. Chronic agomelatine treatment corrects behavioral, cellular, and biochemical abnormalities induced by prenatal stress in rats. Psychopharmacology (Berl) 2011;217(3):301-13.
15. Mairesse J, Silletti V, Laloux C, Zuena AR, Giovine A, Consolazione M, et al. Chronic agomelatine treatment corrects the abnormalities in the circadian rhythm of motor activity and sleep/wake cycle induced by prenatal restraint stress in adult rats. Int J Neuropsychopharmacol 2013;16(2):323-38.
16. Malow B, Adkins KW, McGrew SG, Wang L, Goldman SE, Fawkes D, et al. Melatonin for sleep in children with autism: a controlled trial examining dose, tolerability, and outcomes. J Autism Dev Disord 2012;42(8):1729-37.
17. Rai D, Lee BK, Dalman C, Golding J, Lewis G, Magnusson C. Parental depression, maternal antidepressant use during pregnancy, and risk of autism spectrum disorders: population based case-control study. BMJ 2013;346:f2059.

Competing interests: No competing interests

20 May 2013
Rafia Afzal
Dow University of Health Sciences, Pakistan
Baba e Urdu Road, Karachi, Pakistan