Choosing an SSRI in pregnancy: Clinical context versus statistical significance

Australian & New Zealand Journal of Psychiatry, 47(12) A meta-analysis of selective serotonin re-uptake inhibitor (SSRI) medications and risks of congenital malformations published in this Journal by Myles et al. (2013) concluded that fluoxetine and paroxetine should be avoided in the first trimester of pregnancy because they were associated with small but statistically significant increases in birth defects and specifically cardiac defects following paroxetine exposure. Conversely and reassuringly, sertraline and citalopram were not found to be associated with such risks. Unfortunately, a simplistic statement of avoiding an antidepressant medication in the first trimester seems inadequate to cover the many complexities of clinical practice, including whether or not a pregnancy is planned and weighing up the risks to both mother and baby of untreated mood disorder against the potential risks of medications. Odds ratios of 1.14 (fluoxetine) and 1.29 (paroxetine) are not necessarily deal-breakers in terms of dictating best practice and it is difficult to be convinced about the clinical significance of these findings when one considers the data on which they are based. Because of obvious ethical concerns, drug companies are unable to include pregnant women in randomised controlled studies looking at reproductive outcomes following medication exposures. Therefore, data regarding pregnancy outcomes must be obtained from other sources, including prospective observational studies, retrospective case-controlled studies, case reports and series, population prescription and birth defects registries, spontaneous drug company reports as well as drug company registries. All of these methods have their pros and cons but, needless to say, none is a true ‘gold standard’. Although meta-analysis has some advantages, there are still some inherent problems because of the nature of the data being analysed. Although they were not designed to assess drug safety, databases which link prescriptions and birth defects are being increasingly used worldwide to determine pregnancy outcomes following exposures. Despite their statistical power in analysing large population datasets, these studies have significant methodological problems, including, first and foremost, the assumption that just because a prescription was filled the medication was actually taken (and in the critical first trimester) during the pregnancy. It is well recognised that adherence or compliance to prescribed medication is sub-optimal during pregnancy (Sawicki et al., 2011) and may be even lower for antidepressants. At least one study has shown that despite filling a prescription, many women chose not to actually take their prescribed antidepressant medication (Kallen et al., 2011). However, these women would have been included as ‘exposed’ on a prescription database. This suggests that exposures are likely to be over-estimated and thus makes it impossible to determine whether infants with defects were truly exposed. Given the paucity of details about the malformations reported in most of these studies, it is also very difficult to assess either their severity or clinical significance and thus contextualise the risks in a meaningful way for both patients and their healthcare providers. Some factors that can affect estimates of rates of birth defects are whether or not prenatally diagnosed anomalies (which may result in termination of pregnancy) are included, the length of follow-up from birth, specific surveillance of infants, as well as recall and ascertainment bias. Studies have shown that the rate of birth defects is around 3% when reporting is up to 12 months of age but can be as high as 6% if the period of surveillance is extended until the age of 5 years. For example, if the cut-off for reporting of birth defects is 1 year then a child with unilateral ureteric duplication would not be reported if asymptomatic until the age of 2 years. However, if reporting is until age 5 and the same child develops a urinary tract infection which requires long-term antibiotic treatment and urological intervention at age 3, then this would be reported as a major malformation. Likewise, post-natal echocardiography may be routinely ordered because of maternal exposure to an SSRI in a healthy neonate with no cardiac murmur and may detect a small asymptomatic ventricular septal defect (VSD) which would go undetected in a baby not exposed to an Choosing an SSRI in pregnancy: Clinical context versus statistical significance