In this paper, we provide descriptive data on pregnancy outcomes of duloxetine-exposed pregnancies as captured in the LSS and the AERS databases. The frequency of abnormal outcomes reported in prospectively-identified duloxetine pregnancy cases captured within the LSS is generally consistent with the historic control rates in the general population. Spontaneous abortions were reported in 18% of pregnancy cases; in the general US population, prevalence of spontaneous abortion is 12%-15% 7
. Pregnancies resulting in a premature infant, a congenital anomaly, ectopic pregnancy, or stillbirth/intrauterine death, occurred in 8%, 3%, 1%, and 1% in the present analysis, versus 12% 8
, 3% 9
, 2% 10, 11
, 0.6% 12
in the general population. It is recognized that such comparisons with population rates have limitations. These include a bias towards reporting abnormal versus normal outcomes where outcomes are reported as potential safety signals. There is also a higher prevalence of risk factors for abnormal pregnancy outcomes, including smoking and alcohol use, in depressed individuals than in the general population.
We attempted to identify patient characteristics that were associated with an increased risk of abnormal pregnancy outcomes in those receiving duloxetine. As shown in table , more patients with abnormal pregnancy outcomes had a history of using concomitant medications with positive evidence of human fetal risk (pregnancy category D or X, as classified by the FDA). In our analysis, these medications included benzodiazepines, non-steroidal anti-inflammatory drugs, anti-convulsants, as well as angiotensin converting enzyme (ACE) inhibitors and other class D drugs. Consideration was given to conducting an analysis of outcomes based on the timing of duloxetine exposure within the gestational period. However, unlike in the instances of age and concomitant illness, if trimester of exposure information was missing, the data collection method involved imputing missing values and assigning these exposures to all three trimesters. These data are thus unreliable for use in assessment of any association between the timing of duloxetine exposure and pregnancy outcomes.
Disproportionality analysis of AERS data as a signal detection method, as employed here, has been widely used 13, 14
. Findings from the analysis of the AERS data showed no apparent disproportionality in abnormal pregnancy outcomes in patients treated with duloxetine versus all other drugs or selected antidepressants.
Much of the existing published literature on the safety of antidepressants in pregnancy is focused on epidemiological study findings. The topic has been reviewed by Yonkers et al 15
. Briefly, while these studies have been an essential vehicle for increasing our understanding of antidepressant safety, their limitations are recognized; the studies rely on clinical reports or self reports, there is often a lack of information on diagnosis of depression and antidepressant use and, in some cases, there is lack of control for confounding factors. While findings from some studies do suggest an association between antidepressant use and adverse birth outcomes including miscarriage, low birth weight infants, preterm deliveries, congenital abnormalities (particularly heart defects), pulmonary hypertension of the newborn and adverse effects on neonatal neurobehavior, other studies have found no such associations. Considering all published findings to date, a causal relationship between antidepressant use and adverse pregnancy outcomes has not been established.
Importantly, potential risks of treatment should be weighed against the risks of untreated depression (i.e., benefit of treatment) to mother, fetus, neonate and infant. The literature on this topic is heterogeneous and suffers from similar limitations to those outlined above. Antidepressant discontinuation may increase the risk of a new or worsening episode of major depressive disorder in pregnant women 16
, although this has not been found in all studies 17
; discontinuation of antidepressant treatment may in turn increase exposure to risk factors for adverse pregnancy outcomes (inadequate nutrition, increased exposure to additional medications, and increased alcohol and tobacco use in the mother). In some studies, untreated maternal depression has been associated with adverse pregnancy outcomes, including miscarriage, low birth weight infants, and preterm delivery (reviewed by Yonkers et al 15
). Maternal depression has also been documented to negatively impact a child's emotional development. Newborns of women with untreated depression during pregnancy cry more and are more difficult to console 18
. Children of mothers with depression have poor adaptive skills, are at risk of emotional and behavioral problems and are more prone to suicidal thoughts and behavior 19, 20
There are some limitations to the databases used in this paper. For cases not captured in the clinical trial setting, details surrounding a pregnancy or pregnancy outcomes that might help in assessing possible association with a suspect drug (e.g., potential confounders) are often incomplete. Although it is probable that the majority of pregnant women taking duloxetine are doing so to treat a depressive disorder, this cannot be confirmed; duloxetine has other approved uses in addition to treatment of major depressive disorder, including management of diabetic peripheral neuropathic pain and fibromyalgia, and may also be used in an off label manner; these individual diseases are likely to be associated with different levels of risk for abnormal pregnancy, which cannot be addressed in this study. Calculating the incidence of abnormal pregnancy outcomes is problematic, even for prospectively-identified cases, with a recognized bias towards reporting abnormal outcomes over normal outcomes. Further bias exists as a result of more diagnostic tests being employed in women with depression, such that there is increased potential for detecting anomalies that would not necessarily be detected in women who are not depressed 21
. Additional factors can influence whether or not an AE will be reported and thus the calculated incidence of the event (e.g., length of time product has been available in the marketplace, publicity surrounding the specific AE). In the case of the AERS database, challenges exist in determining the time at which an exposure occurred in relation to when an AE was observed and reported and thus identification of prospective versus retrospective cases is not possible.
Despite these limitations which restrict their use in the determination of causality or the incidence of an event, post-marketing surveillance data do have strengths over those from clinical trials. They are from a naturalistic setting rather than the controlled environment of a clinical trial, and the number of patients exposed to a medicine after it is commercialized can be considerable compared to that feasible in clinical trials, particularly in situations where drugs have been marketed for some time.
In conclusion, while limitations of these data are recognized, the information available to date from these two data sources suggest that the frequency of abnormal outcomes reported in duloxetine pregnancy cases is generally consistent with the historic control rates in the general population. It is recognized that numbers are small, and the monitoring of the safety of duloxetine in pregnancy will continue. As data continue to accrue, our understanding of the safety of duloxetine use in pregnancy will increase. Patient and healthcare provider reports to manufacturers and to the FDA through MedWatch 22
are valuable for continuing data gathering. Information relating to use of drugs in pregnancy may also be reported through pregnancy registries, including the Cymbalta Pregnancy Registry 23
, designed to collect prospective data about potential risks of duloxetine exposure during pregnancy. As with all medications, duloxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.