Antidepressants. Professor Ian Jones May /WalesMentalHealth

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1 Antidepressants Professor Ian Jones May 2017 /WalesMentalHealth

2 We identified pregnancies exposed to an antidepressant at some point during pregnancy. The rate of exposure increased from 0.2% in 1997 to 3.2% in 2010 Kjaersgaard et al, PLoS One. 2013

3 Problems with interpreting the data Case reports or small case series in past now studies of over 120,000 exposures and 102 papers published in 2015 Retrospective bias Data from non psychiatric disorders Increased vigilance for malformations in women taking medication Little information on the severity of malformation Residual confounding Depression, other medications, other risk factors

4 Questions 1. Are ADs associated with an increased risk of congenital malformations? 2. Are there long term implications of taking ADs? 3. What are the implications of stopping ADs in relation to pregnancy? 4. Do ADs impact on pregnancy outcomes? Yes, small effects on gestational age, birth weight and APGAR scores (Ross et al, JAMA Psychiatry, 2013) 5. Are ADs associated with neonatal complications? Yes, increased risk of postnatal adaption syndrome (PNAS) OR over 5 (Grigoriadis et al, 2013)

5 1) ADs and risk of congenital malformations Before 2005 no teratogenicity demonstrated for antidepressants (TCIs and SSRIs) BUT..Many studies small cohorts with insufficient power to detect anything other than very large effects 2006 two large studies reported x increased risk of cardiac defects with paroxetine exposure Cardiac defects 2/100 compared with 1/100 Many further studies in large numbers

6 Two Meta analyses Meta analysis of 16 (out of 115) studies: Fluoxetine (OR 1.14, 95% CI ) and paroxetine (OR 1.29, 95% CI ) associated with increased risk of major malformations Paroxetine associated with increased risk of cardiac malformations (OR 1.44, 95% CI ). Myles et al, ANZJP, 2013 Overall, antidepressants do not appear to be associated with an increased risk of congenital malformations, but statistical significance was found for cardiovascular malformations. Given that the RRs are marginal, they may be the result of uncontrolled confounders. Although the RRs were statistically significant, none reached clinically significant levels. Grigoriadis et al, 2013

7 Finish registry study The influence of confounding Major congenital abnormalities OR 1.24 ( ) Not significant when controlled for confounders OR 1.08 ( ) ADs less likely to be married, twice as likely to smoke, 20 times more likely to take other psychiatric medication, Fetal alcohol syndrome OR 9.6 ( ) Malm et al, Obstetrics and Gynecology, 2011

8 Further evidence of confounding 2.3 million births 36,772 SSRI exposures Cardiac defect adjusted OR =1.15 Sibling controls OR lower and not significant (0.92) Although the prevalence of septal defects and right ventricular outflow tract defects was higher in the exposed infants, the lack of an association in the sibling controlled analyses points against a teratogenic effect of these drugs Furu et al, BMJ, 2015

9 Do SSRI s increase risk of PPHN? 377 PPHN cases OR 6 1% N Eng J Med 2006;354:579-87

10 Further studies risk lower? Wichman et al 2007 case note review of 25,214 deliveries no association Kallen et al ,324 infants risk doubled 0.15% Andrade et al SSRI and 1104 controls case note review no association Reis and Kallen 2010 RR 2.56 for late exposure 0.2% Kieler et al, 2012 Scandinavian registries 1.6 million infants 30,000 SSRI exposures 0.3% (OR 2.1)

11 Largest study risk increase more modest JAMA. 2015;313(21): ,950 women who filled a prescription for antidepressants in late pregnancy (3.4%) Absolute risk small and risk appears more modest than suggested in previous studies OR = 1.51 ( ) Adjusted OR = 1.10 ( )

12 So...what has been shown Lack of consistency re malformations and drugs All commonly used SSRIs implicated plus clomipramine Multiple testing Residual confounding Not controlled for depression, obesity, drugs and alcohol, tobacco, use of folic acid, detection bias Absolute risk for any pregnant women low

13 2) Long term implications Croen et al, Arch Gen Psych, ASD kids 1507 controls 6.6% vs 3.3% at least 1 prescription or an antidepressant in the year prior to delivery OR 2.2 ( ) attrib risk 2.1% Highest risk in first trimester (OR 3.8, ) Numbers small 20 ASD kids with AD prescription Adequacy of controlling for confounders?

14 A number of further papers.

15 Two meta analyses Meta-analysis of 4 studies Pooled crude OR = 2.13 Adjusted OR = 1.81 two studies employing the same Danish data had conflicting results some signal exists.six out of eight reviewed articles confirm an association must still be cautiously interpreted

16 Long term impact Using a sibling design, we showed that prenatal antidepressant use was specifically associated with increased anxiety symptoms after adjusting for maternal familial factors and confounding by indication.

17 Possible Positive Impact of AD in pregnancy

18 AD exposed children do better than those with mothers with untreated depression

19 Impact of stopping AD Bad News!!! 201 euthymic women with history of MDD 68% recurrence in those who discontinued AD 26% recurrence in those who remained on AD History of severe mood disorder mean duration 15.4 years, 44% had 5 or more episodes Cohen et al., JAMA. 2006;295:

20 Or.being on AD s makes little difference Yonkers et al, Epidemiology, pregnant women with a history of major depression No effect of Antidepressant treatment Hazard Ratio 0.88 ( )

21 Summary and Conclusions Decisions about medication complex and difficult No longer can we say that we lack data on antidepressants in pregnancy small teratogenic risk still difficult to determine if due to drug or to confounding Emerging evidence of potential positive impacts Data on reproductive safety must be considered in light of full risk benefit analysis

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23 Drugs used in the treatment of ADHD Methylphenidate (atomoxetine) A Danish register study found the rate increasing 5 to 533 per 100,000 person years between 2003 and 2010 (Haervig et al., 2014) Increased risk of miscarriage (Haervig et al., 2014) Further study no risk of miscarriage but low Apgar score at delivery (not seen in babies born to women with ADHD not on treatment) 186 exposures (Bro et al., 2015) Neonatal withdrawal symptoms

24 Conflicting data in animal and human studies Study in Mice The group treated with MPH presented significant external (polydactyly P < 0.01), skeletal (incomplete ossification of the skull P < 0.01) and visceral (dilated ventricles P < 0.05) malformations. Behavioural effects (motor activity, memory of habituation and anxiety) were not observed in both male and female offspring evaluated at postnatal days 22, 35 and 75. The results suggest that MPH is an embryotoxic and teratogenic drug Costa Gde A et al. Reprod Biomed Online. 2016;32(2):170 7 Study in Humans 382 methylphenidate exposed pregnancies No evidence of teratogenicity Diav Citrin et al. J Clin Psychiatry. 2016;77(9):

25 BAP Guidelines. There are limited data regarding the risks of in utero exposure to methylphenidate and very little regarding atomoxetine. Current data do not suggest a link between methylphenidate exposure and congenital malformations. Methylphenidate may be associated with an increased risk of miscarriage, but this may be a result of confounds related to the diagnosis of ADHD. Methylphenidate exposure in utero close to delivery may be associated with a neonatal syndrome with low Apgar scores and stimulant withdrawal syndrome. Risks associated with atomoxetine are undetermined. It is not known if it is appropriate to extrapolate from the data related to SNRIs and SSRIs.