Parental depression, maternal antidepressant use during pregnancy, and risk of autism spectrum disorders: population based case-control study
BMJ 2013; 346 doi: https://doi.org/10.1136/bmj.f2059 (Published 19 April 2013) Cite this as: BMJ 2013;346:f2059
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As a parent, i found this article very useful and informative to some questions that have concerned me in the post few years with my son. I liked the way the article was tested and had arguments for both sides if the issues. Thank you! www.voice4autism.org
Competing interests: No competing interests
To the Editor:
Rai and colleagues conducted a case-control study on the association between antidepressant use during pregnancy and autism spectrum disorders in offspring with great number of samples (1). Compared with the past case-control study (2), there is an advantage of using variable on intellectual disability for their sub-analysis.
In contrast, Hviid and colleagues described no significant association between maternal use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy and autism spectrum disorder in the offspring by a cohort study over one decade of follow-up (3). In their sub-analysis, a significant association between maternal use of SSRIs before pregnancy and autism spectrum disorder was observed. They analyzed the data with enough number of events with use of SSRIs during pregnancy. I think that the quality of information on the use of SSRIs and diagnostic procedure of autism spectrum disorder are superior to those by Rai and colleagues.
Andrade reported the statistical problems of the above-quoted two case-control studies (4). Namely, they were summarized into type II error by the lack of statistical power and type I error by the lack of adequate adjustment by confounders. Although there are some limitations in a case-control study by Rai and colleagues, intellectual disability seems important to affect the relationship between antidepressant use during pregnancy and autism spectrum disorders in offspring. So I strongly recommend using "intellectual disability" as a key variable for cohort studies in the future.
References
1 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.
2 Croen LA, Grether JK, Yoshida CK, Odouli R, Hendrick V. Antidepressant use during pregnancy and childhood autism spectrum disorders. Arch Gen Psychiatry 2011;68:1104-12.
3 Hviid A, Melbye M, Pasternak B. Use of selective serotonin reuptake inhibitors during pregnancy and risk of autism. N Engl J Med 2013;369:2406-15.
4 Andrade C. Antidepressant use in pregnancy and risk of autism spectrum disorders: a critical examination of the evidence. J Clin Psychiatry 2013;74:940-1.
Competing interests: No competing interests
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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1. Noble RE. Depression in women. Metabolism 2005;54:49-52.
2. Udechuku A, Nguyen T, Hill R, Szego K. Antidepressants in pregnancy: a systematic review. Aust N Z J Psychiatry 2010;44:978-96.
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.
5. Croen LA, Grether JK, Yoshida CK, Odouli R, Hendrick V. Antidepressant use during pregnancy and childhood autism spectrum disorders. Arch Gen Psychiatry 2011;68:1104-12.
6. Yonkers KA, Vigod S, Ross LE. Diagnosis, pathophysiology, and management of mood disorders in pregnant and postpartum women. Obstet Gynecol 2011;117(4):961-77.
7. Hickie IB, Rogers NL. Novel melatonin-based therapies: potential advances in the treatment of major depression. Lancet 2011;378(9791):621-31.
8. Chen YC, Sheen JM, Tiao MM, Tain YL, Huang LT. Roles of Melatonin in Fetal Programming in Compromised Pregnancies. Int J Mol Sci 2013; 14(3): 5380–5401.
9. Parry BL, Meliska CJ, Sorenson DL, Lopez AM, Martinez LF, Nowakowski S, et al. Plasma melatonin circadian rhythm disturbances during pregnancy and postpartum in depressed women and women with personal or family histories of depression. Am J Psychiatry 2008;165(12):1551-8.
10. Parry BL, Martínez LF, Maurer EL, López AM, Sorenson D, Meliska CJ. Sleep, rhythms and women's mood. Part I. Menstrual cycle, pregnancy and postpartum. Sleep Med Rev 2006;10(2):129-44.
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.
12. Afzal R. Melatonin: Miracles far beyond the pineal gland. Indian J Endocrinol Metab 2012; 16(4): 672–674.
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
Dear Editor
Please find enclosed a letter of comments on the article: Rai D., Lee B. K., Dalman C., Golding J., Lewis G., Magnusson C. (2013) Parental depression, maternal antidepressant use during pregnancy, and risk of autism spectrum disorders: Population based case-control study. B.M.J. 346: 1-15.
First, we wish to recognize the importance of retrospective population studies on the subject of factors that could be implicated in Autism Spectrum Disorder (ASD). As underscored in the study, retrospective population studies remain the main source of data because the absence of non-clinical markers of ASD renders prospective studies ethically unacceptable. However, the biases and confounders of such studies need to be properly assessed. This begs for some comments on the interpretation of the results provided in this study. The first two concern the absence of information regarding co-prescription medicines in addition to SSRIs.
(1). It is a known fact that over 30% of patients receiving an antidepressant are also prescribed and take a tranquilizer and/or hypnotic drug, essentially BZD [1]. The prescription of BZD has not been explored in connection with ASD. Nor for that matter has the joint effect of BZD with SSRIs. Furthermore, such a co-prescription, could be associated with certain forms of depression (with more or less irritability, or suicidal ideation) which, in and of themselves, may involve different transmission of neurodevelopmental impact on the developing fetus.
(2). Women with severe mental disorder were excluded from the study (cf. section Parental history of depression), but no information is provided on the existence or co-existence of obsessive compulsive disorder (OCD). OCD is associated with depression and its psychotropic treatment is often based on a specific SSRI medication. Therefore, IRSS prescription could actually be linked to both diagnoses individually and/or to co-morbid diagnosis. The subgroup of women with OCD ought not be overlooked as studies have shown that ASD and OCD may have common symptoms (mechanisms) [2].
One last separate comment concerns a surprising result bearing on the maternal population i.e. mothers of ASD cases are more often of local origin. This is surprising since migration is considered a globally stressful factor that increases risk of psychiatric disorder, specifically depression, both in adults and their offsprings. Conversely, mothers of ASD cases were older (this is common in all infants with pathological risk) but there is no information concerning assisted reproductive technique (ART): Older mothers have a higher risk of use of ART with or without gamete donation; this could also be a potential confounder in any interpretation of results.
We do agree with the main conclusion of the authors that it is necessary to enhance and implement more retrospective research on large population (perhaps with international pooling) on potential links between prescription of psychotropic medication, diagnosis of mental disorders during the peripartum and subsequent ASD symptomatology in offspring. However, up until now management of maternal affective health (mood disorder) during the peripartum still needs to be guided by current updated knowledge and case by case tailored management, navigating between Charybdis and Scylla [3].
References
[1] Ververs T, Kaasenbrood H, Visser G. et al. Prevalence and patterns of antidepressant drug use during pregnancy. Eur J Clin Pharmacol. 2006:62; 863-870.
[2] Russell AJ, Jassi A, Fullana MA, Mack H, Johnston K, Heyman I, Murphy DG, Mataix-Cols D. Cognitive behavior therapy for comorbid Obsessive-compulsive disorder in High-functioning autism spectrum disorders: A randomized controlled trial. Depression and Anxiety 2013 DOI 10.1002/da.22053.
[3] Rubinow D. (2006). Antidepressant treatment during pregnancy: between Scylla and Charybdis. Am J Psychiatry. 2006:163(6). 954-6.
Competing interests: No competing interests
We thank Glukhov (1), Morgan (2), Grant (3), and Bratt (4) for their comments on our paper (5).
There are unique challenges in human research related to long term offspring outcomes of in-utero exposures, particularly when exposures and outcomes are relatively rare and measured several years apart. As discussed in the paper, robust and adequately powered experimental data in humans are unlikely to be ever available on this topic and the only alternative is to use observational data.
Our study was nested within a longitudinal design in a population based sample, covering all known pathways of autism diagnosis and care in Stockholm County, where free and universal access to care is offered. This reduces the possibility of selection bias. Since the data were recorded prospectively, before the birth of the child, the possibility of recall and attribution biases is also eliminated. The design suggested by Bratt (5) may be prone to such biases.
It is also important to mention that a low statistical power in our study was not because of the lack of ‘affected individuals’, it was because the exposure was very rare despite relatively large numbers (we had 4429 individuals had an autism spectrum disorder in our main sample, of which 1679 had data on maternal medication use during pregnancy but antidepressant use during pregnancy). Therefore the database with 700 families that Bratt suggests (4) is unlikely to be able to address this limitation since it is less than half the size of our subsample with medication data. Glukhov also wondered if one of the p-values in Table 1 was incorrect (1)- we can confirm it is accurate, and as noted in the table footnote, was derived after conditioning on age and sex to account for the matched design.
Confounding is a major problem in observational studies. We considered a number of potential confounders and adjusted where possible. Morgan correctly mentions that this adjustment may not be very effective given the low power (2). Of more concern is the possibility of residual confounding by factors that cannot be measured or adjusted for and the possibility of confounding by indication. Glukhov suggests the possibility of ascertainment bias concerning health service use (1) and we note other potential limitations in our discussion (5).
As a result we do not claim any causal associations. On the contrary, we expressly warn against jumping to such conclusions, particularly when making clinical decisions (5).
One area of harmonious consensus between all correspondents (1,2,3,4) and authors is that there is much more work required to understand these associations. We sincerely hope our paper will prompt others to attempt to replicate, refute or improve understanding of these findings. The last word has certainly not been said, and Croen et al’s (6) and our study should be viewed as just the beginning in the understanding of this topic in human populations.
References
(1) Glukhov V. http://www.bmj.com/content/346/bmj.f2059/rr/642022
(2) Morgan T. http://www.bmj.com/content/346/bmj.f2059/rr/642417
(3) Grant ECG. http://www.bmj.com/content/346/bmj.f2059/rr/643182
(4) Bratt AM. http://www.bmj.com/content/346/bmj.f2059/rr/643508
(5) 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
(6) Croen LA, Grether JK, Yoshida CK, Odouli R, Hendrick V. Antidepressant use during pregnancy and childhood autism spectrum disorders. Arch Gen Psychiatry 2011;68:1104-12
Competing interests: No competing interests
Maternal antidepressant use and autistic spectrum disorder: Fetal reprogramming or pre-conception epigenetic phenomenon, conferring what real-world magnitude of risk?.
Alison .M. Bratt BSc. (Hons), PhD: Lecturer in Pharmacology, Medway School of Pharmacy, Universities of Kent & Greenwich at Medway, Central Avenue, Chatham Maritime, Kent, ME4 4TB.
Comment on the article: Rai D, Lee B K, Dalman C, Golding J, Lewis G, Magnusson C. (2013) Parental depression, maternal antidepressant use during pregnancy, and risk of autism spectrum disorders: Population based case-control study. B.M.J. 346: 1-15.
Rai et al, (2013) very recently published results of their research study testing the hypothesis that antidepressant drug use during pregnancy was associated with increased risk of autistic spectrum disorder (ASD) in the offspring. This large case controlled study conducted in Stockholm, Sweden between 2001-2007, found that in utero exposure to both SSRI’s and monoamine oxidase inhibitors was associated with a two-fold risk for birth of a child with ASD. These findings corroborate earlier independent results collected by Croen at al., (2011) in the USA which found any exposure to SSRI’s while pregnant gave a 2.2-fold increase in risk of ASD diagnosis, with first trimester exposure raising the risk 3.8-fold.
Preclinical research has demonstrated that homeostatic serotonergic tonus within the central nervous system is necessary for normal brain morphogenesis in utero (Oberlander, 2012). Indeed exposure of pregnant rats to clinically relevant doses of antidepressant drugs (ADD’s) disturbs both the architecture and functioning of the young rat brain causing aberrant behaviours, (Darling et al., 2011; Homberg, 2009; Simpson et al., 2011), which have some degree of translational relevance to the clinically diverse presentation of autism. The two major brain circuits affected by prenatal ADD exposure in rats appear to be the somatosensory cortex and dorsal raphe nucleus (DRN)- medial prefrontal cortex (mPFC)-amygdaloid corticolimbic circuit, underpinning sensory appreciation and stress-mediated behaviours respectively, (Darling, 2011)
Both the Rai and Croen studies could be criticised for being too small and inadequately powered, by including too few affected individuals, and clearly it is necessary to amass data from a larger population to strengthen and further these findings. One possible way to achieve this might be to utilise such national databases as the Autism Spectrum Database U.K. funded by Autistica. This growing database currently has approximately 700 families registered and is growing rapidly throughout the U.K. Data could be extracted from this database regarding previous incidents of depressive episodes and psychopharmacological treatment exposure from both parents of children with ASD, allowing a comprehensive capture of a variety of possible biological, experiential and contextual confounding variables.
There are several noteworthy points of interest that require further investigation arising from the study by Rao et al., 2013. Guidelines for clinical practice both in terms of informing prescribers and in final prescribing practice of ADD’s in pregnancy should be considered. Given the apparent ambiguity in the literature regarding any superior efficacy of SSRI’s in comparison with some non-drug therapies, (Khan et al., 2012), it would be prudent to advise treating pregnant women with ADD’s only when non-drug interventions fail, and when symptoms are sufficiently severe. Untreated depression during pregnancy of course carries its own risks, for both the mother and the foetus, but these should be rigorously monitored and treated with individualised intensive therapies on a case by case basis.
At present the British National Formulary (BNF) gives the following guidance for the prescription of SSRI’s in pregnancy, that “Manufacturers advise against use in pregnancy unless the potential benefit outweighs the risk. There is a small increased risk of congenital heart defects when SSRI’s are taken during early pregnancy. When SSRI’s are used during the third trimester there is a risk of neonatal withdrawal symptoms”. It might be prudent, especially in light of growing evidence, to consider an amendment to BNF wording to inform of an association between antidepressant use in pregnancy and possible resultant ASD.
It would be interesting to consider the possibility that the children associated with prenatal ADD exposure may constitute a phenotypically distinct subgroup of children with ASD? The Rai et al, 2013 paper showed that these children did not present with intellectual impairment, and were considered more “high functioning” on the autistic spectrum, mirroring characteristics of the group of autistic children which latest demographic data on diagnostic trends have shown to be increasing in number throughout the USA (Autism & Developmental Disabilities Monitoring Network 2012) and worldwide. Whether these children experience specific clusters of symptoms, such as more affective (high anxiety or irritability) or sensory dysregulations would have implications for how best to support them in home and educational settings.
Controversially, consideration should be given to whether exposure to SSRI’s during a “pre-conception” period confers any additional risk for ASD? The serotonin specific transporter SLC6A4 has been found to be present in mouse oocytes and appears to play a role in follicular growth and meiotic maturation, (Amireault & Dube, 2005). This raises questions surrounding whether serotonin guides the same reproductive processes via the same mechanisms in man and if SSRI exposure could potentially damage early embryogenesis?
Considering the challenges faced by individuals and their families living with autism, whatever the real-world risk maternal antidepressant use carries, it is a risk worth understanding.
Amireault P, Dube F. (2005) Serotonin and its antidepressant-sensitive transport in mouse cumulus-oocyte complexes and early embryos. Biol. Reproduct. 73: 358-365.
Autism Spectrum Database U.K. : http://www.asd-uk.com/
Croen L A Grether J K, Yoshida C K, Odouli R, Hendrick V. (2011) Antidepressant use during pregnancy and childhood autism spectrum disorders. Arch. Gen. Psychiatr. 68(11): 1104-1112.
Darling R D, Alzghoul L, Zhang J, Khatri N, Paul I A, Simpson K L, Lin R C S. (2011) Perinatal citalopram exposure selectively increases locus coeruleus circuit function in male rats. J. neurosci. 31(46): 16709-16715.
Homberg J R, Schubert D, Gaspar P. (2009) New perspectives on the neurodevelopmental effects of SSRI’s. Trends in Pharmacol Sci. 31(2): 60-65.
Khan A, Faucett J, Lichtenberg P, Kirsch I, Brown W A. (2012) A systematic review of comparative efficacy of treatments and controls for depression. PLoS ONE 7(7):
Oberlander T F. (2012) Fetal serotonin signalling: Setting pathways for early childhood development and behaviour. J. Adolescent Health 51: S9-S16.
Prevalence of autism spectrum disorders-Autism and Developmental Disabilities Network, 14 sites, United States, 2008. MMWR Surveill Summ (2012) 61: 1-19
Simpson K L, Weaver K J, de Villiers-Sidani E, Lu J Y F, Cai Z, Pang Y, Rodriguez-Porcel F, Paul I A, Merzenich M, Lin R C S. (2011) Perinatal antidepressant exposure alters cortical nerwork function in rodents. P.N.A.S. 108(45): 18465-18470.
Competing interests: No competing interests
The increased risk of autism with maternal antidepressant use during pregnancy may relate to previous use of progestins.1
Progesterone or progestins can cause depression by increasing monoamine oxidase levels in the late secretory phase of a normal cycle or during medication with a powerful progestin.2 Monoamine oxidase inhibitor drugs are antidepressants.
In 2010 Ann Brit Wirehn and colleagues studied nearly a million Swedish women.3 In all age groups progestin-only takers had significant increased risks of antidepressant use but the highest risk was in 16-19 year olds. Combined hormonal contraceptives also increased antidepressants use in 16-19 year-olds. The risk of antidepressants use for past hormone takers was not assessed. As past takers also have increases in depression, adding these women to never taker controls minimized the increased risk of antidepressant use for hormone ever- takers.
The RCGP study enrolled Pill takers and controls between 1968 and 1972 when depressive neurosis increased by 1.3 (p<0.01) in takers and by 1.28 (p>0.01) in ex-takers. Hospital admission for depression increased by 3.61 in ex-takers (p>0.01) and suicide was the commonest cause of death in takers.4 In 1984 the relative risks for attempted suicide was 1.42 for current takers and 2.12 for former takers compared with controls.5 Mortality in the RCGP study was under recorded as a quarter of the women originally enrolled were lost to follow-up before deaths began to be flagged on the NHS Central Register in 1977. The 2010 RCGP mortality study still found higher rates of violent deaths for ever-takers of oral contraceptives.6
There are already reasons to suspect a link between maternal hormonal contraceptive use and autism with increased toxic DNA adducts found in some women taking hormones and also in some autistic children.7 Now there is also a link with maternal antidepressant use.
1 Rai D, Leer BJ, 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.
2 Grant ECG. Pryce Davies J. Effect of oral contraceptives on depressive mood changes and on endometrial monoamine oxidase and phosphatases. BMJ 1968;3:777-80.
3 Wiréhn AB, Foldemo A, Josefsson A, Lindberg M. Use of hormonal contraceptives in relation to antidepressant therapy: A nationwide population-based study. Eur J Contracept Reprod Health Care. 2010;15:41-7.
4 Royal College of General Practitioners. Oral Contraceptives and Health. 1974 Pitman Medical, London.
5 Royal College of General Practitioners, Oral contraception study: some recent observations 1984;11 759-86.
6 Hannaford PC, Iversen L, Macfarlane TV, et al. Mortality among contraceptive pill users: cohort evidence from Royal College of General Practitioners' Oral Contraception Study. BMJ 2010; 340: c927
7 Grant ECG. McLaren-Howard J. Re: The effects of toxic metals in autistic children. http://bmj.com/cgi/eletters/329/7466/588-b#74117, 13 Sep 2004.
Competing interests: No competing interests
The authors concluded, based upon 9 cases and 27 controls, that there is a 3.34-fold increase in risk of autism among children whose depressed mothers took antidepressant medications. They purported to adjust the raw association for "history of psychiatric disorders other than depression, parental ages, income, education, occupation, migration status, and parity." While it is mathematically possible to make such a statistical adjustment, the result is essentially meaningless. There are too many variables, not enough cases. The authors should have acknowledged that they were unable to control their study for confounding variables, due to limited sample size, and therefore, the observed association was not established as causal. Further research in larger studies is required in order to determine whether or not a robust, causal association exists between maternal antidepressant use and autism. The association observed in this study is necessarily tentative, and the weakness of evidence should be taken into account when women and their physicians make decisions about pharmacotherapy of depression during pregnancy.
Competing interests: No competing interests
The article unfortunately adds virtually nothing to our understanding of causes of autism.
Approximately two third of cases which can be diagnosed as autism remain undiagnosed and untreated1. It is established that both autism and depression are often under- and misdiagnosed. Probabilities of an under- or misdiagnosis are not known with confidence. Therefore, statistical inference regarding correlations between depression and autism ultimately depends on this uncertainty.
Authors do not make any effort to exclude or at least evaluate the likelihood of diagnosed maternal depression and diagnosed autism being co-related via a third factor. An example of such factor is the following. Mother who is interested in or concerned about her own mental state and is likely to trust doctors to be able to fix it, is more likely to pay close attention to her child's mental development and trust doctors to evaluate and fix it.
Science is prediction. Using the results presented in the paper it is virtually impossible to answer an elementary scientific question: what is the likelihood of the child to be autistic if the mother has mental depression.
In the absence of the causation model, for example a mechanism by which SSRIs or depression in general are affecting fetal development, statistical results alone are useless, however small are the reported p-values.
Also, there seems to be either a typo or an error in the table 1. Paternal depression in the case of autism with ID. 0.5 (presumably %) versus 0.3 for controls. The probability that the proportion of diagnosed paternal depression is greater for the autism cases than for controls is 0.93, which indicates that the p-value in the table (0.293) is likely to be wrong by almost an order of magnitude.
1. Prevalence of autism spectrum disorders in a total population sample. Kim YS, Leventhal BL et al, Am J Psychiatry. 2011 Sep;168(9):904-12. doi: 10.1176/appi.ajp.2011.10101532. Epub 2011 May 9.
Competing interests: No competing interests
Re: Parental depression, maternal antidepressant use during pregnancy, and risk of autism spectrum disorders: population based case-control study
A recent systematic review and meta-analysis of previously published relative studies concluded that maternal affective, depressive or bipolar disorders were associated with a higher risk of autistic spectrum disorder in offspring.
Reference
https://www.sciencedirect.com/science/article/pii/S0165032718309716
Competing interests: No competing interests