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Selective serotonin reuptake inhibitors and congenital malformations - Editorial
 
 
  The small risk of harm must be balanced against risk of suboptimal or no treatment
 
Published 23 September 2009, doi:10.1136/bmj.b3525
Cite this as: BMJ 2009;339:b3525
 
Major depressive disorder in women is most common during their childbearing years, and about 13% of women in the United States have taken an antidepressant drug during pregnancy.1 2 In the past 20 years, selective serotonin reuptake inhibitors (SSRIs) have become a mainstay of treatment in women with major depressive disorder; however, concerns persist about safety for the developing fetus. This is counterbalanced by equally compelling concerns about the consequences of undertreatment for mother and child.3
 
In the linked population based cohort study from Denmark
 
(doi:10.1136/bmj.b3569), Pedersen and colleagues confirm a previously reported doubling of risk for septal heart defects after early exposure in pregnancy to SSRIs (odds ratio 1.99, 95% confidence interval 1.12 to 3.53).4 However, in contrast to previous studies, redemptions of prescriptions for citalopram and sertraline, but not paroxetine or fluoxetine, were significantly associated with this group of heart defects.5 6 7 8 Furthermore, unlike two previous large case-control studies conducted in the US, no association was noted with anencephaly, omphalocele, craniosynostosis, or right ventricular outflow tract defects.7 8
 
Lack of consistency across these studies with respect to specific malformations and specific drugs makes it difficult to translate the findings into clinical practice. One of the fundamental principles of teratology is that teratogenic exposures induce specific patterns of malformation, and not an increase in the incidence of every defect. In other words, if some or all SSRIs are teratogenic, we would expect to see similar findings for specific drug exposures and specific defects in all studies.
 
One explanation for this inconsistency, assuming that SSRIs do cause specific birth defects, is differences in study designs. For example, although Pedersen and colleagues linked records for 496 881 singleton live born infants, they identified only 1370 mothers who redeemed multiple prescriptions for an SSRI in the perinatal period. Therefore, the study may have been insufficiently powered to detect the previously suggested twofold to threefold increased risk for anencephaly, omphalocele, craniosynostosis, or right ventricular outflow tract defects, all of which occur at least an order of magnitude less frequently than septal defects.
 
Alternatively, these findings could be spurious and attributable in observational studies to unmeasured or inadequately controlled confounding factors, such as maternal obesity, alcohol, tobacco, or periconceptional use of folic acid supplements; confounding by the mother's underlying condition; or detection bias, in which mothers being treated for major depressive disorders are more likely to seek out or receive more comprehensive prenatal and postnatal testing of their children.
 
How does Pedersen and colleagues' study contribute to clinicians' and patients' decisions about the use of SSRIs in pregnancy, and how should this be weighed against the risks of non-treatment? The answer remains as before—if an increased risk for major congenital malformations does exist, this study and others suggest that the absolute risk for the individual pregnant woman is very low. Furthermore, each of the more commonly used drugs in this class has been implicated in at least one study, so it is difficult to conclude that one SSRI is "safer" than another.
 
We need information from larger studies of specific SSRIs, with study designs that control for maternal disease type and severity, comorbidities, and other exposures. In addition, studies of basic science might elucidate the mechanisms involved in inducing specific birth defects to support the biological plausibility of a causal association.
 
In August 2009, the American College of Obstetrics and Gynecology released a joint statement with the American Psychiatric Association on treatment recommendations for depression during pregnancy.9 Briefly, the recommendations state that women with major depressive disorder who are contemplating pregnancy or who are currently pregnant can start or continue taking their drugs. Women who prefer to avoid or discontinue drugs may benefit from psychotherapy, although this will depend on their psychiatric history. Women should be informed about the possible risks and benefits of their treatment choices, and ongoing consultation between the patient's obstetrician and psychiatrist is needed during pregnancy, to determine and carry out the most appropriate and acceptable treatment plan.
 
Most drugs taken by pregnant women have not been well studied, or studied at all with respect to safety of the fetus.10 Although research about SSRIs and pregnancy outcomes is plentiful, it does not necessarily provide definitive answers for clinical practice. Clinicians and patients need to balance the small risks associated with SSRIs against those associated with undertreatment or no treatment.
 
Christina Chambers, associate professor
 
1 Division of Dysmorphology and Teratology, Departments of Pediatrics and Family and Preventive Medicine, School of Medicine, University of California San Diego, 9500 Gilman Drive, MC 0828, La Jolla, CA 92093-0828, USA
 
chchambers@ucsd.edu
 
CC has received grant funding from pharmaceutical companies including Amgen, Abbott, Bristol Myers Squibb, Sanofi-Pasteur, Teva, Sandoz, Kali, Barr, and Apotex, some of which manufacture or distribute selective serotonin reuptake inhibitors.
 
Provenance and peer review: Commissioned; not externally peer reviewed.
Selective serotonin reuptake inhibitors in pregnancy and congenital malformations: population based cohort study
 
Lars Henning Pedersen, research assistant, visiting scholar 1,2, Tine Brink Henriksen, consultant3, Mogens Vestergaard, general practitioner and associate professor4, JŅrn Olsen, professor and chair2, Bodil Hammer Bech, associate professor1
 
1 Department of Epidemiology, Institute of Public Health, Aarhus University, Bartolin Alle 2, DK-8000 Aarhus, Denmark, 2 UCLA School of Public Health, Department of Epidemiology, 650 Charles E Young Drive South, Los Angeles, CA 90095-1772, USA, 3 Department of Paediatrics, Aarhus University Hospital, DK-8200 Aarhus, Denmark, 4 Department of General Practice, Institute of Public Health, Aarhus University, Bartolin Alle 2, DK-8000 Aarhus, Denmark
 
Correspondence to: Lars Henning Pedersen, Department of Epidemiology, Institute of Public Health, Aarhus University, Bartolins Alle 2, 8000 Aarhus C, Denmark LHP@dadlnet.dk
 
ABSTRACT
 
Objective - To investigate any association between selective serotonin reuptake inhibitors (SSRIs) taken during pregnancy and congenital major malformations.
 
Design - Population based cohort study.
 
Participants - 493 113 children born in Denmark, 1996-2003.
 
Main outcome measure - Major malformations categorised according to Eurocat (European Surveillance of Congenital Anomalies) with additional diagnostic grouping of heart defects. Nationwide registers on medical redemptions (filled prescriptions), delivery, and hospital diagnosis provided information on mothers and newborns. Follow-up data available to December 2005.
 
Results - Redemptions for SSRIs were not associated with major malformations overall but were associated with septal heart defects (odds ratio 1.99, 95% confidence interval 1.13 to 3.53). For individual SSRIs, the odds ratio for septal heart defects was 3.25 (1.21 to 8.75) for sertraline, 2.52 (1.04 to 6.10) for citalopram, and 1.34 (0.33 to 5.41) for fluoxetine. Redemptions for more than one type of SSRI were associated with septal heart defects (4.70, 1.74 to 12.7)). The absolute increase in the prevalence of malformations was low—for example, the prevalence of septal heart defects was 0.5% (2315/493 113) among unexposed children, 0.9% (12/1370) among children whose mothers were prescribed any SSRI, and 2.1% (4/193) among children whose mothers were prescribed more than one type of SSRI.
 
Conclusion - There is an increased prevalence of septal heart defects among children whose mothers were prescribed an SSRI in early pregnancy, particularly sertraline and citalopram. The largest association was found for children of women who redeemed prescriptions for more than one type of SSRI.
 
Introduction
 
Depression affects up to a fifth of pregnant women,1 2 and medical treatment must balance maternal health with potential adverse fetal effects such as congenital malformations. Until 2005, most studies on selective serotonin reuptake inhibitors (SSRIs) found no association with major malformations,3 4 5 6 7 but recent studies have indicated an increased prevalence of, for example, omphalocele,8 craniosynostosis,8 and, more consistently, heart defects.8 9 10 11 12 13 14 The results on specific types of SSRI are conflicting,8 9 10 12 13 14 but some research has suggested an increased risk of heart defects, especially with paroxetine9 12 14 but also sertraline, fluoxetine, and citalopram.6 9 13 The suspected risk of congenital heart defects was responsible for the 2005 warning by the US Food and Drug Administration related to the use of paroxetine during pregnancy.15 We evaluated associations between SSRIs during the first trimester of pregnancy and major malformations in a large population based cohort study.
 
Methods
 
We used data from four Danish nationwide registries: the medical birth registry,16 the national register of medicinal product statistics, the fertility database,17 and the national hospital register.18 The registries were linked by the use of the unique personal identifier of 10 digits assigned to all citizens at birth.
 
The medical birth registry16 stores data on all deliveries, including maternal age, maternal smoking status during pregnancy, parity, date of delivery, gestational age, birth weight, sex of newborn, and information on multiple pregnancy. Information on gestational age at birth is usually estimated from ultrasound measures during early pregnancy. In case of no ultrasound measure the last menstrual period is used. The initiation of pregnancy was calculated by subtracting day of birth by gestational age in days.
 
The register of medicinal product statistics holds information on therapeutic drug sales, the personal identifier, specification of the medication, and drug classification code (the anatomical therapeutic chemical (ATC) classification system, World Health Organization).19 On redemption (that is, the filling of a prescription), information from each prescription, including date of redemption, is stored with the purpose of financial compensation. All drugs included in this study are sold by certified pharmacies according to prescriptions written by a doctor, and every pharmacy in Denmark reports to the register.
 
The fertility database17 includes demographic information on every person in the fertile age group in Denmark and their children. We calculated the combined income of the mother and father during the year of their child's birth based on information in the database. If information on income for both parents was missing we used data from the previous calendar year.
 
The national hospital register18 20 holds information on all admissions and outpatient hospital contacts in the country. Each patient has a date of admittance and ICD-10 (international classification of disease, 10th revision) coded diagnoses from the study period. We included information from 1 January 1996 to 31 December 2005. Malformations were coded according to the Eurocat categorisation,21 and congenital heart defects were further categorised in developmentally based subgroups as suggested by Louik et al.13 As information on malformations in stillborn children is incompletely registered we included only liveborn children in the analyses. We considered only malformations detected at birth or within the first year after birth. We also performed additional analyses with truncation after two years to investigate for potential differences in time of diagnosis.
 
The exposure window was defined as 28 days before to 112 days after the beginning of gestation. Exposure was defined as two or more redemptions of an SSRI in this time period (ATC codes N06AB). Women with only a single redemption in the exposure window were included in later analyses. We excluded women with any redemption of insulin or antihypertensive medications in a period of three months before the estimated beginning of gestation and those with any redemption during the exposure window to other psychotropic medications, such as antiepileptic medication, antipsychotics, and anxiolytics. Antidepressants other than SSRIs, such as tricyclic antidepressants and venlafaxine, were excluded from the main analyses but included in later sensitivity analyses.
 
We thus constructed a cohort consisting of all liveborn children in Denmark between 1 January 1996 and 31 December 2003 based on information from the medical birth registry (n=553 689). From these we excluded 1213 children because of coding errors, 22 045 because of emigration, 8388 because of exposure to other psychoactive or antidiabetic drugs as described above, and 21 653 multiple births and 3509 stillbirths. The final study population comprised 496 881 singleton liveborn children.
 
Statistical analyses were performed with Stata (version 9, StataCorp, Texas, USA). We conducted multiple logistical regressions on dichotomous outcomes adjusted for maternal age (<20, 20-24, 25-29, 30-34, ≥35), calendar time (1996-8, 1999-2001, 2002-3), marital status (unmarried, married, divorced, widow), income (three categories), and smoking (no/yes). Less than 1% had missing values in these variables except for smoking (17% missing), and we performed sensitivity analyses without the smoking variable. Significance was defined as a two sided P value <5% and adjusted odds ratios are provided with 95% confidence intervals. Odds ratios were used to estimate relative prevalence rate ratios. We used causal diagrams (directed acyclic graphs) to guide the selections of potential confounders to be controlled.22 No adjustments were made for multiple comparisons.
 
Results
 
The final study population comprised 496 881 liveborn singletons. For these children, 1370 mothers had two or more redemptions for individual SSRIs in the exposure window. These pregnancies were regarded as exposed. In keeping with a previous study,8 women taking an SSRI were more likely to be older, living alone, unmarried, and smokers (data not shown).
 
The combined prevalence of major malformations (odds ratio 1.21, 95% confidence interval 0.91 to 1.62) or non-cardiac malformations (1.12, 0.79 to 1.59) was not significantly higher among exposed children, but SSRI use was associated with an increased prevalence of septal heart defects (1.99, 1.13 to 3.53) (table 1Go).
 
No specific SSRI was significantly associated with major malformations overall or non-cardiac malformations (table 2). There was an increased prevalence of septal heart defects for children of women who used sertraline (3.25, 1.21 to 8.75) and citalopram (2.52, 1.04 to 6.10), but not fluoxetine (1.34, 0.33 to 5.41).Among the 299 exposed to paroxetine we found one septal heart malformation (crude odds ratio 0.76). Redemption of more than one type of SSRI in the exposure window was associated with heart malformations (3.42, 1.40 to 8.34), particularly septal heart defects (4.70, 1.74 to 12.7) (table 2).
 
In women with no recorded use of antidepressants, 1.2% redeemed a prescription for psychotropic medication, compared with 16% of women who had been prescribed an SSRI. The estimates remained virtually unchanged, however, when these women were included in the analyses—for example, SSRI use was still associated with septal heart defects (2.00, 1.41 to 2.85).
 
We found 84 women with two or more redemptions for tricyclic antidepressants and 91 for venlafaxine in the exposure window. The numbers were too small to allow for informative adjusted analyses—for instance, we found three major malformations among the children exposed to tricyclic antidepressants (crudeodds ratio 1.14, 0.23 to 3.45) and one among those exposed to venlafaxine (0.35).
 
In subanalyses, we included women with one or more redemptions for antidepressants. We found that 3010 women redeemed one or more SSRI, 265 for tricyclic antidepressants, and 150 for venlafaxine. None of the antidepressants were associated with the combined prevalence of major malformations with the less strict exposure definition (see table A on bmj.com). Septal heart defects were associated with any SSRI use (1.83, 1.22 to 2.75), in particular citalopram (2.16, 1.12 to 4.17) and sertraline (2.01, 0.83 to 4.86), albeit the estimates of sertraline did not reach significance (see table B on bmj.com). In eight women prescribed fluvoxamine there were no reported malformations. Again, the numbers were too small to allow investigation of associations between tricyclic antidepressants or venlafaxine and specific malformations (table A on bmj.com).
 
Analyses excluding information on smoking had comparable results—forexample, septal heart malformations were associated with sertraline (3.18, 1.18 to 8.56) and more than one SSRI (4.45, 1.65 to 12.0), but the confidence interval for citalopram included zero (2.36, 0.98 to 5.71).
 
Follow-up of the children for two years after birth with regards to congenital malformation resulted in similar results to the one year follow-up—for example, an odds ratio of 1.70 (1.13 to 2.55) for SSRI and septal heart malformations. As expected, the absolute differences in prevalence of birth defects were limited. We found septal heart defects in 12 (0.9%) children of women with one or more redemption of SSRI, four (2.1%) children of women who redeemed more than one type of SSRI (2.1%), and 2315 (0.5%) children of unexposed women. The prevalence of septal heart defects among the children exposed to a specific SSRI was 0.6% for fluoxetine, 1.1% for citalopram, and 1.5% for sertraline (table 2). Thus, the prevalence of septal heart defects was 0.4 percentage points higher for children of women with one or more redemption of SSRI compared with children of unexposed women, corresponding to a number needed to treat to harm (NNH) of 246. The corresponding number for children of women who redeemed more than one type of SSRI was 62.
 
Discussion
 
In this population based cohort study we found that septal heart defects were more prevalent in children of women who redeemed a prescription for a selective serotonin reuptake inhibitor (SSRI) in the first trimester of pregnancy. Sertraline and citalopram, but not paroxetine or fluoxetine, were associated with septal heart defects, though the largest association was found forredemption of more than one type of SSRI. The suggested associations, if causal, represent limited differences in prevalence. We found no associations between SSRIs and non-cardiac malformations.
 
Comparison with other studies
 
The four most commonly used SSRIs (fluoxetine, citalopram, sertraline, and paroxetine) were associated with septal heart defects. The various patterns in existing studies, however, are still confusing. A large US case-control study found that sertraline was associated with septal heart defects,13 and the agreement with data from a different population with a different study design is reassuring for the validity of our results. A study from Finland found no overall association with major malformation (as in our study) but presented no data on septal heart defects.6 One population based study reported an increased prevalence of heart defects after use of citalopram in the first trimester.23 We found no associations between paroxetine and heart defects as shown inprevious studies9 12 14 but the previous finding was based on only one child with septal heart defect and we were unable to take dose into account.12 As in most previous studies, none of our results for fluoxetine showed an odds ratio above two and none were significant.13 One recent study, however, found that fluoxetine was associated with cardiovascular anomalies, with an adjusted odds ratio of 4.47 (1.31 to 15.27).24 In that study over 30% of the women exposed to fluoxetine also used benzodiazepine,24 and the combination of an SSRI and benzodiazepine has been associated with heart defects in a different study.23 We excluded from our study women with redemptions of other psychotropic medications.
 
Use of more than one type of SSRI
 
We found the highest prevalence of septal heart defects among children of women who redeemed prescriptions for more than one type of SSRI in the exposure window. Redemptions for more than one SSRI might represent a change in type of SSRI or simultaneous use of different SSRIs. Both scenarios might result in more pronounced effects on the serotonin transporter, as change in type of SSRI might also result in a period of overlap. Our result could show an additive effect of the different types of SSRI, although confounding by the indication cannot be ruled out.
 
Clinical implications
 
Treatment of depression during pregnancy balances the risk of the medicine with that of the depression, and we investigated only a part of the information needed to make evidence based decisions. The reported odds ratios represent small absolute differences in prevalence, and even if SSRI use is causallyrelated to septal heart defects, these heart defects might not necessarily require treatment and some might resolve spontaneously. Some children with septal heart defects, however, need to undergo an operation, but we were unable to estimate the proportion because, for example, the operation might be performed years after the end of our follow-up period.
 
Strengths and limitations of study
 
The information on drugs was recorded by skilled pharmacists when the prescriptions were redeemed. We used these redemptions as proxy measures for exposure, which eliminates recall bias and increases the precision of the information on type of antidepressant. Interview during pregnancy might result in confusion of related names, such as sertraline and Seroxat (paroxetine), and increased focus on one drug could result in bias. This precision is essential for the differentiation between specific types of SSRI and would have been difficult if we had relied on women's reports. Our results, however, depend on a correlation between redemptions of prescriptions and drug use. Non-compliance might be a problem for this type of exposure definition and could mask true associations if some of the "exposed" were in fact unexposed. We considered two or more redemptions as an indication of more certain exposurethan one prescription only. The main analyses with this more strict exposure definition resulted in slightly stronger estimates with the same pattern related to septal heart defects, which is as expected if the drug had the side effects under study. Use of antidepressant drugs without prescription is unlikely and, if present, would result in underestimation of a true association.
 
Our choice of the exposure window allowed sufficient time for two or more redemptions and was identical to the exposure window in the study by Louik et al.13 Additionally, our study was designed to investigate the potential association with various malformations with different windows of susceptibility, and as a result the exposure window was wider than needed for most malformations. With an exposure window wider than the susceptible period forconditions such as heart defect, the women defined as exposed might actually have been unexposed in the critical periods, which could result in an underestimation of true associations for various malformations. It does not explain the reported associations with septal heart defects.
 
The disentanglement of the effects of treatment from the effect of the disease is a profound problem in pharmacoepidemiological studies. We had no information on the severity of the depression, and potential confounding by indication is impossible to rule out in a non-randomised design. We were unable to carry out comparisons with children of untreated depressed women or of women with a prescription for an SSRI that was not redeemed. Variation in the disease severity, however, is unlikely to explain our observed differences between the specific types of SSRI as we believe that the disease characteristics of women who use different SSRIs are likely to be comparable in the study period. The warning on paroxetine from the US Food and DrugAdministration was published after the exposure period of this study.15 After this warning the pattern of SSRIs used during pregnancy is likely to have changed.
 
We adjusted for potential confounding factors, including maternal age and smoking, but all potential confounders were considered in crude categories. Residual confounding or unmeasured confounding might still be present, but the association between the confounder and heart malformation needs to be strong and specific for individual SSRIs to explain our findings; we don't know of any such factors.
 
We used nationwide registries with almost complete follow-up of liveborn infants. Induced or spontaneous abortions might have introduced selection bias if the drug reduces the survival of a fetus or if exposed women undergo more intensive screening. For instance, more intense surveillance among drug users could result in more prenatal diagnoses and subsequent induced abortions. This could obscure a true teratogenic effect in studies of livebornchildren and bias our results towards no effect. Late abortion (after 12 weeks of pregnancy) because of septal heart defects, however, would not be granted in Denmark. The information on malformations from the hospital registry is subject to some misclassification. The sensitivity of detection of malformation is expected to be higher for severe and visible malformations. If the misclassification was unrelated to exposure it would in most cases lead to bias towards no association. If children of women with depression or with a specific pharmacological treatment for a depression were likely to be examined more thoroughly than other children, however, we might have overestimated specificassociations. The similar overall prevalence of malformations by the different exposures indicates no such detection problem.
 
We used data from a period with an almost fourfold increase in the proportion of pregnant women who were prescribed an SSRI. A parallel change in the detection of septal heart defects could lead to bias if calendar time was not considered—for example, an increased or improved use of ultrasonography before or after birth could lead to a false association between SSRIs and heartdefects. The estimates changed only slightly, however, when we adjusted for calendar time in the multivariate analyses. Additionally, we found only a small increase in the prevalence of septal heart defects in the period that did not parallel the much larger increase in the use of SSRIs (see figure on bmj.com).
 
The study was designed to investigate the potential association between SSRIs and several malformations with no adjustment for multi-hypotheses testing, and the findings could potentially have occurred by chance. Our results, however, are in accordance with those of previous studies that used different methods in other populations. In this light we find that random error isunlikely to be the only explanation of the results.
 
Conclusion and policy implications
 
SSRIs, particularly citalopram or sertraline, were associated with an increased prevalence of congenital septal heart defects. The largest prevalence was found after redemptions of more than one type of SSRI in the exposure window, and simultaneous use of different SSRIs or change in type of SSRI during early pregnancy might be problematic. Our results suggest a class effect of the SSRI on heart defects, and the equivocal results from existing studies could represent differences in doses or study population. The associations, if causal, represent limited risks of an exposed child having congenital heart defects. Future studies need much larger sample sizes, preferably with sufficient power to further investigate potential associations with more severe malformations.
 
What is already known on this topic
Use of an SSRI during pregnancy is common and increasing
The teratogenic effects of specific SSRIs are unconfirmed
What this study adds
 
Sertraline and citalopram were associated with an increased prevalence of septal heart defects
 
Use of more than one type of SSRI during the first trimester was associated with a fourfold increase in prevalence of septal heart defects
 
 
 
 
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