Every day, we see women in our clinic who are deciding whether to continue a selective serotonin reuptake inhibitor (SSRI) for management of depression or anxiety during pregnancy. As a class, SSRI use during pregnancy is generally not associated with a significant overall risk for major congenital malformations. While we often do think about SSRIs as a class, each medication within this class is indeed different and has its own safety data in regards to its use in pregnancy.
Recently, a number of women have presented to our clinic with the question of whether to continue fluvoxamine (Luvox) during pregnancy. Fluvoxamine is a SSRI, yet it is not typically used as a first-line medication for depression or anxiety disorders. Fluvoxamine was initially approved by the FDA to treat obsessive-compulsive disorder (OCD) and is thought by many to be particularly efficacious in treating OCD. For that reason, we often see women on fluvoxamine who have true OCD or have obsessive-like features to their anxiety. Many of these women have symptoms that have not responded to the other, more widely used SSRIs, like fluoxetine (Prozac) and sertraline (Zoloft).
Since fluvoxamine is not as widely used as the other SSRIs, the safety data around its use in pregnancy is limited. In fact, a meta-analysis that examined individual SSRI use during pregnancy and the risk of subsequent congenital malformations did not even include fluvoxamine in its analysis.1 A closer look at some recent studies may guide us in understanding more about the safety of fluvoxamine in pregnancy.
In a 2009 prospective cohort study in Canada at the Motherisk Program, the rates of congenital malformations were compared between 928 infants exposed to antidepressants in the first trimester of pregnancy and 1243 unexposed infants.2 Only 52 of the 928 infants exposed to antidepressants were exposed to fluvoxamine – that is 0.06% of all cases in this study. The authors report that subsequent analyses of each, individual antidepressant did not reveal an increased risk for congenital malformations with exposure to any individual antidepressant; however, the small size of the study greatly limits such analyses. Importantly, when the investigators examined antidepressants as an entire class (which included all SSRIs as well as bupropion, venlafaxine and other antidepressants), those infants exposed to antidepressants in the first trimester were not at increased risk of congenital malformations compared to the unexposed group (risk ratio 0.96, 95% CI 0.55 to 1.67).
Larger studies are required for us to better understand the risks of specific SSRIs like fluvoxamine. In a 2011 retrospective cohort study of national population-based registers in Finland from the years 1996 to 2006, 6,976 infants were exposed to an SSRI during the first-trimester.3 The rates of major congenital malformations in these SSRI-exposed infants were compared to over 600,000 infants who were unexposed to SSRIs. Of those 6,976 infants exposed to SSRIs in the first trimester, only 240 of those were exposed to fluvoxamine. In other words, fluvoxamine accounted for only 0.03% of the SSRI-exposed cases. There was no increased risk of major congenital malformations in infants exposed to fluvoxamine compared to the unexposed infants (crude odds ratio 0.81, 95% CI 0.38-1.73), even when controlling for other factors like maternal age at end of pregnancy, smoking status, maternal diabetes (adjusted odds ratio 0.71, 95% CI 0.31-1.51).
In an even larger 2015 study, investigators reviewed nationwide health registers in Scandinavia between 1996 and 2010.4 Ultimately, they reviewed the cases of 2.3 million infants, 36,772 of whom had been exposed to an SSRI or venlafaxine in early pregnancy. Of those infants exposed to SSRIs or venlafaxine in early pregnancy, 255 of those infants (0.01%) were exposed to fluvoxamine specifically. There was no increased risk of major congenital malformations in those infants exposed to fluvoxamine during pregnancy compared to the unexposed groups when controlled for maternal age, (crude odds ratio 1.13, 95% CI 0.58 to 2.19), even when controlling for other factors, such as maternal age, smoking status, and diabetes (adjusted odds ratio 0.77, 95% CI 0.38 to 1.56).
|Study||Number of infants exposed to fluvoxamine||Number of major congenital malformations in exposed infants||Types of Malformations|
|Einarson et al., 2009||52||Number not provided||Atrial septal defect; umbilical hernia|
|Malm et al., 2011||240||7||Ventricular septal defect; non-specified cardiovascular anomaly; neural tube defects; non-specified digestive system and musculoskeletal system anomalies|
|Furu et al., 2015||255||9||Not listed for fluvoxamine|
|Total||547||At least 16|
A summary of the data from these studies is above. While these studies are indeed reassuring in regards to the risk of congenital malformations with exposure to fluvoxamine during pregnancy, they highlight how infrequently fluvoxamine is used in pregnancy compared to the other SSRIs and, subsequently, how relatively few exposures we have for fluvoxamine in pregnancy compared to other medications in its class. It is estimated that at least 400 to 600 exposures would be required to detect a 2-fold increase in more common malformations. The total of exposures in these studies is 547 infants, well within this threshold range. It is important to note that we do not know the exact number of major congenital malformations in the Einarson study. However, even without that study, we have a total number of 495 cases in the remaining studies, and in those two samples, there were 16 cases of congenital malformations, making the overall risk of malformations 3.2%. This rate is consistent with the 3-4% risk of congenital malformations seen in the general population. Again, these data are indeed reassuring, but more investigation into the use of fluvoxamine in pregnancy is warranted.
So what are women who are taking fluvoxamine and planning for pregnancy to do? As always, there is no single answer to this question. Every recommendation must be made on an individualized basis. For women who are planning pregnancy in the next one to two years and who have not received a trial of one of the better-studied SSRIs, we may recommend that she discontinue fluvoxamine and try a better-studied SSRI. We may recommend she put off her plans to conceive until she is stabilized on a better-studied agent. However, as most women find themselves on fluvoxamine after failing the more widely studied SSRIs, many women are less likely to be interested in this option, particularly if fluvoxamine has brought them the greatest improvement in their symptoms compared to other SSRIs. Moreover, some women are unable to put off their plans for pregnancy and take the time to try a new medication prior to conception. In these cases, we may recommend continuation of fluvoxamine during pregnancy based on the reassuring safety data on SSRIs as a whole and the woman’s own history of significant improvement with fluvoxamine. Adequate control over a women’s depressive and anxiety symptoms during pregnancy is essential for the health of mother and baby, as we know that untreated maternal anxiety and depression in pregnancy can lead to poor outcomes like preterm delivery and low infant birthweight. The limited safety data on fluvoxamine in pregnancy must be weighed against the mother’s own history of symptoms and her own response to fluvoxamine.
Kathryn Zagrabbe, MD
- Myles N, Newall H, Ward H, Large M. Systematic meta-analysis of individual selective serotonin reuptake inhibitor medications and congenital malformations. Aust N Z J Psychiatry. 2013;47(11):1002-12.
- Einarson A, Choi J, Einarson TR, Koren G. Incidence of major malformations in infants following antidepressant exposure in pregnancy: results of a large prospective cohort study. Can J Psychiatry. 2009;54(4):242–6.
- Malm H, Artama M, Gissler M, Ritvanen A. Selective serotonin reuptake inhibitors and risk for major congenital anomalies. Obst Gynecol. 2011;118(1):111–20.
- Furu K, Kieler He, Haglund B et al. Selective serotonin reuptake inhibitors and venlafaxine in early pregnancy and the risk of birth defects: population based cohort study and sibling design. BMJ. 2015;350:h1798.