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WP5 - SSRIs and Anti-asthmatics



Work Undertaken (Deliverables)

  • Report to CHICOS WP1 regarding potential of birth cohort data for drug teratogenicity studies (Deliverable 18)
  • Case-malformed control study on risk of specific CA in relation to anti-asthmatics (Deliverable 19)
    • Literature review on risk of specific CA in relation to anti-asthmatics
  • Case-malformed control study on risk of specific CA in relation to SSRIs (Deliverable 20)
    • Literature review on risk of specific CA in relation to SSRIs
  • Population linkage study on risk of sepcific CA in relation to SSRIs (Deliverable 21)
  • Population linkage study on risk of specific CA in relation to anti-asthmatics (Deliverable 22)


WP5 Results and Foreground


The main objective of WP5 was to assess the relationship between anti-asthmatics, SSRIs and congenital anomalies. WP5 also explored the potential of the European birth cohorts participating in the FP7 funded CHICOS project for drug teratogenicity studies. 

Evaluation of other databases - birth cohort studies


An online survey was conducted regarding the congenital anomaly data and medication exposure data currently available in European birth cohorts participating in the FP7 funded CHICOS project. Twenty-seven cohorts were invited to complete the survey, 24 responded of which 12 cohorts had both medication and congenital anomaly data and were potentially interested to join a collaborative effort. These 12 cohorts cover 238,000 births, 87% of which are from two large cohorts (The Danish and Norwegian cohorts close to 100,000 births each). The report of this survey was made available to the CHICOS project in February 2012 (Deliverable 18).

A second additional phase of the survey was done in addition to the deliverable. In this phase the 12 cohorts with medication and congenital anomaly data were invited to submit their congenital anomaly data for evaluation of its quality (coding precision, completeness of ascertainment), as well as the prevalence in the cohort of three exposures in the first trimester of pregnancy (anti-depressants, anti-asthmatics, fever). Of the 12 cohorts, 6 have sent the requested data and 1 has sent partial data which have been analyzed and assigned EUROCAT subgroups. 5 cohorts have declined to continue in the study or have been unreachable. For those participating, it was found that there was much to be done to standardize the coding and classification of congenital anomalies to allow further analysis, with suggestions given for study protocols.  


Risk of congential anomalies in relation to anti-asthmatics use: case-malformed control design

The literature review detected 9 signals for first trimester fetal exposure to beta-2-agonists and 4 signals for fetal exposure to corticosteroids. Beta-2-agonists were associated with spina bifida, cleft lip and palate, cleft palate, severe CHD, Tetralogy of Fallot, esophageal atresia, anal atresia/stenosis, gastroschisis and omphalocele. Corticosteroids were associated with cleft lip and palate, cleft palate, anal atresia/stenosis and hypospadias. The case-malformed control study including data from 13 registries confirmed the association for cleft palate and gastroschisis with fetal exposure to inhaled beta-2-agonists. None of the 4 signals for inhaled corticosteroids were confirmed.


Conclusions from the study: Even though the increased risk of cleft palate and gastroschisis associated with exposure to inhaled beta-2-agonists is statistically significant, it does not present a large added risk for each individual pregnancy. Cleft palate has a prevalence of about 1 case per 1000 births, gastroschisis of 2-3 per 10,000 births. Even with a five-fold increased risk (as compared to the less than twofold increase in odds observed) the risk for the individual pregnancy would still be below 1 in 100. 

We did not find any statistically significant increase in risk of congenital anomalies after exposure to inhaled steroids. This is reassuring, as maternal asthma and asthma exacerbation have been associated with an increased risk of congenital anomaly and of other negative pregnancy outcomes for both mother and infant. Use of prophylactic inhaled steroids to prevent asthma exacerbations and reduce the need for beta-2-agonists may be the best solution for treatment of asthma in pregnancy.

Risk of congenital anomalies in relation to SSRIuse: case-malformed control design


The use of selective serotonin reuptake inhibitors (SSRI: ATC code N06AB) has risen over the past few decades. The safety of these drugs when used in pregnancy has been questioned, including their effect on fetal organogenesis when taken in the first trimester of pregnancy. SSRI are often co-prescribed with other types of medication: antidepressant medications (4% in our data) and with psycholeptic medications (16% in our data). We therefore expanded our study to include all antidepressants (ATC code N06A) and psycholeptic medications (N05A) including anti-psychotics (ATC code N05A), anxiolytics (ATC code N05B) and sedative/ hypnotic type medications (ATC code N05C).  


The literature was reviewed, identifying 16 signals, where at least one study had found a statistically significant association between an antidepressant used in the first trimester of pregnancy and congenital anomaly: Congenital Heart Defects (CHD), Neural Tube Defects (NTD), Anencephaly (a specific NTD), Eye anomalies, Ear/Face/Neck anomalies, Respiratory anomalies, Digestive System anomalies, Ano-rectal malformations, Gastroschisis, Omphalocele, Renal dysplasia, Limb reduction anomalies, Lower limb reduction anomalies, Clubfoot, Craniosynostosis and Cleft palate.


We used data from 14 EUROCAT congenital anomaly registries in 12 countries covering a total population of over 3 million births.  Four of the registries provided data enhanced through data linkage to maternal medication prescriptions (see Workpackage 3), contributing 50% of the antidepressant/psycholeptic exposures. SSRI use recorded for babies with congenital anomaly is shown in Figure 5.1

Figure 5.1 Breakdown of SSRI use as proportion of babies with CA, per EUROmediCAT registry
Final Report Figure 5.1

We confirmed that there is evidence of a small excess risk, of borderline statistical significance, of CHD associated with SSRI use in the first trimester of pregnancy, particularly severe CHD. We found new evidence that this relates to citalopram which has recently been more commonly prescribed in the European population than paroxetine and fluoxetine.  We found a statistically significant excess risk of Ebstein’s anomaly relating not only to SSRI but all antidepressants and psycholeptic groups studied, of particular interest given previous evidence relating to lithium and benzodiazepines. We also found that there is evidence of excess risk of non-CHD signal anomalies associated with use of SSRI or specific SSRI, specifically for NTD, anophthalmos/micropthalmos, respiratory anomalies, gastroschisis, hypospadias, renal dysplasia and club foot.  We found no evidence to confirm signals in the literature for craniosynostosis, omphalocele or limb reduction anomalies with SSRI exposure consistent with the signals found in the literature.  Our study had less statistical power for non-SSRI antidepressants or psycholeptics which were less frequent exposures, but some associations based on a small number of cases are worthy of follow-up.  We did not find evidence of large excess risks associated with antipsychotics or other psycholeptics, nor with non-SSRI antidepressants. There was some evidence that combinations of SSRI and of SSRI and non-SSRI antidepressants were associated with higher risks of CHD and non-CHD anomalies which requires further research. Unfortunately, dose information was not available.


Conclusions from the study: There was no clear evidence that one type of SSRI is preferable to another in terms of safety, but rather evidence that congenital anomaly risk is found across all SSRI types studied. The increased risk, if causal, is small for individual mothers, but reinforces the need to assess appropriate use of these medications to make sure that benefits outweigh harm (Deliverable 20.

Risk of congenital anomalies in relation to SSRI use: cohort linkage design

We investigated the putative teratogenicity of SSRI exposure in the quarters preceding and following 1st day of last menstrual period (LMP) by analysing prospectively collected electronic healthcare data including prescriptions for all pregnant women linked to three population based congenital anomaly registries which are members of EUROCAT – Norway (2004-2010), Wales and Funen (2000-2010), Denmark (2000-2010).

We identified 519,117 deliveries with data covering pregnancy and the preceding quarter, and 462,641 with data covering pregnancy and one year either side. Prescription of SSRIs 91 days either side of LMP was associated with: a non-significant increase in the overall prevalence of congenital anomalies (3.09% [400/12,962] vs. 2.67% [13,536/506,155] odds ratio (OR) 1.09, 95% confidence interval 0.99 - 1.21); marginal difference in all congenital heart defects (CHD) (0.93% [121/12,962] vs. 0.89% [4503/506,155] OR 1.03, 0.86-1.24) and an increased risk of severe CHD (34/12,962 [0.26%] vs 865/506,155 [0.17%] OR 1.50, 95%CI: 1.06 - 2.11). Prescription of high dose tablets or capsules or >1 prescription further increased the risk of severe CHD, to 0.49% (7/1429, meta-regression OR 1.49, 1.12-1.97)) and 0.31% (20/6392, OR 1.98, 1.26 - 3.10), consistent with an SSRI-exposure related risk. Exploration of confounding by indication (underlying depression) or associated socioeconomic or lifestyle exposures found no evidence that these explained the excess risk of severe CHD.


Conclusions from the study: By employing a population cohort linkage approach, we have shown that the overall risk of CA is very small, but that the excess risk of severe CHD with SSRI exposure is a robust finding (Deliverable 21).



Risk of congenital anomalies in relation to anti-asthmatic use: cohort linkage design

The study included data from Wales, Norway and Funen County in Denmark using the same databases as in Deliverable 21. The study confirmed the association of inhaled steroids with anal atresia found in the literature and found potential new associations with combination treatment (inhaled long-acting beta-2-agonists and inhaled corticosteroids): severe CHD and common AV canal. The study is not able to distinguish between the effect of maternal asthma and asthma medication use. The potential new associations should be interpreted with caution due to the large amount of comparisons performed in this study (Deliverable 22).