Prozac hit the market in 1988, the first selective serotonin reuptake inhibitor (SSRI) antidepressant approved by the FDA for the treatment of depression. Because it was safer and more tolerable than the antidepressants that preceded it, Prozac was soon the most commonly prescribed antidepressant in the United States.
In the late 1980s and early 90s, if a woman taking Prozac was planning a pregnancy or if she inadvertently conceived, she had an important decision to make. Would she continue to take the antidepressant during pregnancy, or would she stop it? At that point in time, we had little information regarding the course of psychiatric illness during pregnancy, and we had even fewer data regarding the reproductive safety of Prozac.
Nearly 25 years later, we stand in a very different place. Now we have far more information to guide us. We know that pregnancy is not protective against new onset or recurrent mood episodes and that women who stop their antidepressants during pregnancy are at high risk of depressive relapse. We also have accumulated data to indicate that untreated depression in the mother carries significant independent risks for the woman and her pregnancy.
Over the last two decades, numerous reports derived from the analyses of available data sources have addressed the reproductive safety of antidepressants; but ironically, it seems that having more data has actually made the decision-making process regarding the use of antidepressants during pregnancy even more complicated. Research regarding the reproductive safety of the SSRIs has yielded conflicting and often inconsistent results. While some studies suggest that SSRIs increase the risk of certain types of malformations – for example, cardiac septal defects – most studies do not demonstrate a link between SSRIs and congenital malformations. While some studies report serious adverse effects related to exposure to SSRIs late in pregnancy, such as pulmonary hypertension of the newborn (PPHN), most studies describe a more benign and self-limited pattern of symptoms, labeled as “poor neonatal adaptation”. Often the information yielded by these studies is so nuanced and complex that it is extremely difficult for patients and their doctors to fully understand the clinical implications, leaving them confused about their treatment options.
One guiding principle in the assessment of drug safety in pregnancy is that medications that cause birth defects (teratogens) do so consistently across studies that are adequately large, and the type of birth defects should also be consistent across studies. We do have known teratogens among some medications used to treat psychiatric disorder, most notably valproic acid (Depakote), a mood stabilizer, known to substantially increase the risk of neural tube defects. There are a relatively large number of studies of SSRIs in pregnancy; however, what we have seen is inconsistent findings of small risks of different problems varying across these studies. Interpretation of disparate findings is made even more complicated because across available studies, the contribution of underlying psychiatric disorder to the outcome is so often incompletely taken into account.
While we cannot say that SSRIs or any medications are risk-free during pregnancy, we can say that studies over decades have failed to demonstrate a consistent risk of teratogenicity. In fact, we have more data for SSRIs in pregnancy than for most medications that are commonly used in pregnancy,
Over the past few weeks we have received many calls and emails from patients and clinicians regarding a review article published in the journal Human Reproduction entitled “The risks of selective serotonin reuptake inhibitor use in infertile women: a review of the impact on fertility, pregnancy, neonatal health and beyond.” What has concerned, and confused, readers of this article is its stance that SSRIs should be avoided during pregnancy. Even more alarming than the review itself are the reiterations of the article in the lay press, many carrying alarmist messages: “Study suggests too much risk associated with SSRI usage and pregnancy.”
In the abstract of this article, Domar and colleagues stated that they “conducted a review of all published studies that evaluate females with depressive symptoms who are taking antidepressant medications and who are experiencing infertility.” That being said, the exclusion from discussion or review of many reputable reports and the consequent omission of references from peer-reviewed journals of articles which failed to demonstrate clinically significant effects on pregnancy outcomes is particularly striking. Furthermore, the authors’ failure to discuss many of the limitations inherent in the research studies included in the review is noteworthy and disconcerting.
For example, in the section on long-term neurobehavioral outcomes associated with fetal exposure to antidepressants, the authors cite three articles demonstrating the adverse a effects of antidepressant exposure on development. However, they fail to include the seminal research of Nulman and colleagues who prospectively followed over 200 children exposed to antidepressants in utero and found no differences in IQ, cognitive development, temperament, behavior, reactivity, mood, distractibility, or activity level between exposed and non-exposed children.
One of the most glaring omissions of this review is the long list of studies which indicate that depression, when left untreated, carries certain risks. While we must advise our patients regarding the risks of exposure to medications, we cannot ignore the impact of untreated depression in the mother. Untreated depression is associated with poor prenatal care, increased risk of self-harm and behaviors which may negatively affect outcomes, including smoking and the use of alcohol and illicit drugs. There have also been reports which indicate that depressive symptoms and/or anxiety may increase the risk of various outcomes including preterm birth and low birthweight. Rather than reviewing those reports, the authors simply declare that evidence supporting the independent association of depression with these outcomes is weak.
Domar and colleagues point out that there are alternatives to the use of antidepressants during pregnancy. Cognitive-behavioral therapy (CBT) has been shown to be effective for the treatment of major depression. They also cite various complementary and alternative treatments which might be effective for treating depression during pregnancy, including physical exercise, yoga, acupuncture, omega-3 fatty acids, and myo-inositol.
While there is strong evidence to support the use of CBT in cases of mild to moderate depression, we are concerned that some readers may be led to believe that these other alternative treatments are more attractive and/or safer than using antidepressants. However, the efficacy of these alternative interventions has not been well-established in pregnant or non-pregnant samples of women. Yoga is currently under study for the treatment of depression in pregnancy but at this time has not been shown to be efficacious for major depression. Exercise alone has not been established as an effective treatment for depression, in gravid or non-gravid women, although it is a reasonable part of a treatment plan considering it does have mood elevating properties and confers other benefits.
To date, the studies of omega-3 fatty acids indicate that omega-3 fatty acids seem to augment the response to an antidepressant; the efficacy of omega-3 fatty acids as monotherapy has not been established. Inositol remains largely unstudied, and its safety in pregnancy is not established.
The use of alternative treatments with unproven efficacy when effective treatments are available and when the clinical situation demands definitive treatment places the woman – and her pregnancy – at risk.
Unfortunately, the article by Domar and colleagues fails to emphasize that treatment chosen is dependent upon the severity of the depression. For some women, depression may be a mild and circumscribed illness, amenable to treatment with a variety of interventions and may not require long-term treatment with an antidepressant. We suspect that this may be the case for many women experiencing infertility, the population specifically addressed in this article.
However, for many women, particularly those taking antidepressants on a long-term basis, depression is a severe, recurrent illness that impacts all areas of life and health. Antidepressants, particularly SSRIs, are first-line treatments for moderate to severe depression. In our clinic, most of the women come to the prospect of planning to conceive or an actual pregnancy with knowledge of the disorder for which they are treated. Often they have tried many different types of interventions, including medication and psychotherapy. And for so many of these women, the road to euthymia has been an arduous and painful one.
In our clinical experience, women who can safety stop antidepressants during pregnancy usually do. Many women attempt to discontinue antidepressants and relapse, often becoming acutely ill, and some ultimately require more medication than they were initially taking in order to restore emotional well-being. Women in this situation often struggle with the treatment decisions they are forced to make, decisions that are all the more difficult due to stigma against psychiatric illness and psychiatric medications and the confusion surrounding psychiatric illness and treatment among health care providers and the lay public. Quite simply, women do not decide in a cavalier fashion to use medications during pregnancy. To suggest otherwise is at best glib, and at worst disrespectful and cruel.
It is in such a climate that thoughtfully written and carefully researched review articles and consensus guidelines are important, if not essential, to the clinical decision-making process. A review article takes all of the available data, evaluates it, and presents a well-balanced summary of the information. However, an article that fails to effectively synthesize the available data makes thoughtful decision-making around a critical issue, such as use of psychiatric medications during pregnancy, that much more challenging for the women and their clinicians who wrestle with wishes for a healthy pregnancy and the need for treatment of underlying psychiatric disorder
An article that is not balanced, that discredits the use of psychotropic medication regardless of illness severity, unfortunately serves to create an environment in which women feel judged and guilty for pursuing treatment for illnesses that are associated with substantial morbidity and even mortality. As clinicians and researchers, it should be our goal to provide women in this difficult situation with clinically relevant and carefully researched information regarding their illness and treatment options and help them to make informed, well-considered decisions regarding their care.
Marlene Freeman, MD
Lee Cohen, MD
Domar AD, Moragianni VA, Ryley DA, Urato AC . The risks of selective serotonin reuptake inhibitor use in infertile women: a review of the impact on fertility, pregnancy, neonatal health and beyond. Hum Reprod. 2012 Oct 31.
Thank you so much for this article. As someone who discontinued SSRI (paxil) throughout both of my pregnancies and then “becoming acutely ill, … ultimately require more medication than they were initially taking in order to restore emotional well-being,” I understand the complexities of the decision.
I do wish that there is more dialogue btwn mental health practitioners and OB/Gyns on this issue, and that OBGyns would put as much research into the decision facing pregnant women in treatment as the women themselves do.
Thank you again for your insightful thoughtful comments. I share your wisdom daily with my clients.
Wishing you all warm holiday wishes.
Pec Indman EdD, MFT
This is a terrific article. Thank you for the excellent rebuttal data!
I think it is important to refer to SSRI medications as both antidepressant and antianxiety treatment. As a provider, I find myself saying ‘antidepressant’. When I am done with my monolog trying to make a patient feel comfortable with a medication I often hear, “but I have anxiety.” I realize that they probably didn’t hear anything I said after I referred to the medication as only an antidepressant.
Thank you for this post. As a pregnant woman currently taking an SSRI, I was alarmed when I read the article you mention. I found the section on long-term neurobehavioral abnormalities particularly troubling. Shortly after made a follow-up appointment at MGH to discuss my treatment plan as my pregnancy progresses. I was also concerned that my care providers would read the article and recommend that I discontinue my SSRI.
Yet, as a social scientist, I recognized some limitations of the review study, and am so glad to see that you have noted these limitations, and done so in such a timely fashion. Certainly, more research is needed, and SSRIs may indeed have negative effects that we are as yet unaware of, but the literature is far from conclusive. In my opinion, SSRIs remain a reasonable treatment for pregnant women who do not have an adequate response to non-pharmaceutical treatments.
This is a tremendous resource for patients and clinicians alike.
Republished with permission from The Brigham Women’s Mental Health Division
A recent review article (Domar et al. 2012) about the risks of selective serotonin reuptake inhibitor (SSRI) antidepressants during pregnancy and infertility treatment has generated considerable media attention, including prominent coverage in the Boston Globe, Harvard Gazette, and HMS News. In essence, it concludes that there is no credible evidence for efficacy of SSRIs in treating mild to moderate depression, and that SSRIs cause significant harm to offspring after exposure during pregnancy. This has caused consternation and confusion among many patients and health care providers. For this reason, we would like to clarify the evidence base related to the article’s key points, as a guide for clinicians whose patients have questions.
• Decisions about treatment with antidepressants during pregnancy are made on an individual basis. The authors assert at the outset that it is a “standard recommendation” that “the benefit of antidepressant use outweighs the risk of depression during the gestational and post-partum period”. This is not the case. The standard recommendation, repeated in the conclusions of numerous studies of antidepressant use during pregnancy, is to carefully weigh the risks of prescribing medication against the risks of withholding medication in each individual case. This is well expressed in the words of a Food and Drug Administration (FDA) advisory regarding antidepressant use during pregnancy: “Women who are pregnant or thinking about becoming pregnant should not stop any antidepressant without first consulting their physician…The decision to continue medication or not should be made only after there has been careful consideration of the potential benefits and risks of the medication for each individual pregnant patient.”
• Untreated maternal depression during pregnancy is not risk free. The authors state that “There is an assumption in the psychiatric community that the risks to a fetus are greater if the mother has untreated symptoms of depression”. This is not an assumption; it is a finding from numerous studies. For example, untreated maternal depression during pregnancy is associated with reduced prenatal care (Marcus 2009), preterm birth (Li et al. 2009; Bansil et al. 2010), reduced birth weight (Henrichs et al. 2010), altered behavior at birth (Zuckerman et al. 1990), increased risk of infection (Rahman et al. 2004; Traviss et al. 2012), and more difficult temperaments (Huot et al. 2004). There is increasing evidence that some of these effects are due to epigenetic influences on fetal development that are mediated by elevated cortisol levels (Glover et al. 2009; Oberlander et al. 2008).
• Antidepressants, when appropriately indicated, ARE effective in the treatment of depression. The authors state that “The best available evidence suggests that antidepressants do not provide clinically meaningful benefit for most women with depression.” While they raise the important point that publication bias has marred appraisal of the efficacy of many medications, including antidepressants, recent research using methodology to correct for publication bias (Duval and Tweedie 2000) continues to substantiate the efficacy of antidepressants.
• Both depression and SSRI may have direct and indirect, positive and negative effects on fertility. Regarding the impact of antidepressants on fertility, the authors correctly state that systematic data are sparse. A meta-analysis of 14 studies of women using assisted reproductive technologies found that depressive symptoms had no significant effect on the likelihood of becoming pregnant (Bolvin et al. 2011), although depression can contribute to a decision to stop infertility treatment earlier (Verhaak et al. 2010). Retrospective data comparing women undergoing in vitro fertilization found no significant difference in pregnancy rates or live birth rates with or without SSRI use. By contrast, some study findings suggest the possibility that SSRIs can reduce fertility in men (Safarinejad 2008; Tanrikut and Schlegel 2007; Tanrikut et al. 2010).
• Obstetric and neonatal risks of SSRIs. The authors report a number of obstetric and neonatal risks of SSRI use during pregnancy as definitive findings. Here are some clarifications:
o Miscarriage: The authors are correct that this is a consistent finding in prospective, controlled studies. However, the authors fail to highlight the magnitude of the effect or explore its context to rates of miscarriage (spontaneous abortion) in the general population. In a prospective study (Einarson et al ,2009) the rates of spontaneous abortion in the group exposed to antidepressants were found to be (13%) as compared to (8%) in the non-exposed group. Similar rates were found in a meta-analysis ( Hemels et al, 2005). In weighing these findings, it is important to keep in mind that the rate of spontaneous abortions in the general population is believed to be between 12-15% (Robinson et al, 2012). In a review of literature of antidepressants in pregnancy (Lorenzo et al, 2011), the degree of risk was qualified as “a small increased risk for spontaneous abortions” in women who are exposed to antidepressants.
o Birth defects: The authors report a “consistent ‘signal’ implicating SSRI use during pregnancy to various congenital anomalies”. In fact, prospective, controlled studies (collectively including more than 20,000 exposures to antidepressants) and meta-analyses do not show an association between antenatal SSRI exposure and any congenital anomaly. Large, retrospective database studies have had highly inconsistent findings, ranging from no association to association with a variety of different anomalies, with no specific pattern. These studies are unable to disentangle the effects of key compounds, and most have not corrected for doing multiple statistical tests. The only exception is that first trimester paroxetine exposure has been associated with an increased risk of cardiac anomalies in several retrospective (although no prospective) studies. Although this association remains controversial, a resultant FDA advisory appropriately focuses on individual risk/benefit analyses: “Physicians who are caring for women receiving paroxetine should alert them to the potential risk to the fetus if they plan to become pregnant or are currently in their 1st trimester of pregnancy. Discontinuing paroxetine should be considered for these patients. In individual cases the benefits of continuing paroxetine may outweigh the potential risk to the fetus.”
o Preterm birth: SSRI reduce gestational age by less than a week similarly to untreated antenatal depression. The authors are correct that studies have found an association between antenatal SSRI use and preterm birth. What they failed to report is that the most careful head-to-head study found no significant difference between the effects of untreated antenatal depression and the effects of SSRI antidepressants on preterm birth (Wisner et al. 2009). They also failed to report the magnitude of the effect: both depression and antidepressants reduce gestational age by less than a week (Einarson et al. 2011; Marroun et al. 2012, Yonkers et al. 2012).
o Neonatal side effects: side effects are found in 7-8% of neonates and are typically mild and transient. The authors correctly report that “up to 30%” of SSRI-exposed newborns develop neonatal side effects, however, they fail to note that only one study (the one they cite) found that 30% of babies had side effects; other studies have typically found about 7 – 8% of babies are affected. In addition, they described these effects as “persistent” despite consistent findings that it is rare for these effects to last more than 1 – 2 days.
o Persistent pulmonary hypertension (PPHN): The authors correctly state that antenatal SSRI use is associated with an increased risk of PPHN in several, but not all studies. However, they fail to report the magnitude of this effect. The estimated prevalence of PPNH in the general population is 1.9/1000; the combined reported cases after SSRI exposure show a prevalence of 2.0/1000 (Occhiogrosso et al. 2012).
o Pre-eclampsia: The authors report studies suggesting an association between SSRI use and increased risk of hypertension during pregnancy in this section, although those findings are preliminary and did not include findings of increased risk of pre-eclampsia. They failed to report studies showing increased risk of pre-eclampsia from untreated depressive symptoms.
o Long-term neurobehavioral effects: The authors do not cite the most methodologically sound prospective, controlled studies, which showed no significant neurodevelopmental differences between exposed and control children (Nulman 2012). They fail to report the considerable methodologic limitations of some of the studies whose conclusions they cite.
The Brigham Women’s Mental Health Service remains committed to helping women achieve and maintain optimal health for themselves and their babies during pregnancy and the postpartum period. Our individual thorough evaluations help to identify factors that render women vulnerable to perinatal depression, and factors that promote resilience. Our treatment plans are multifaceted, encompassing evidence-based psychotherapies, nutritional modifications, aerobic exercise and phototherapy when indicated. We conduct careful risk/benefit analyses about the use of antidepressant medication, and use prescribing practice which reduce risks. The sooner a woman comes to see us, the more we can help her reduce the risks of both untreated symptoms and medications. The optimal time to refer is preconception. Preconception consultation for women with pre-existing psychiatric disorders, or risk factors such as premenstrual dysphoria or family history, can help women and their obstetric providers form a proactive treatment plan that will promote a healthy pregnancy.
If you have additional questions about the Domar et al article, about other studies regarding perinatal depressive symptoms and antidepressant use, or about our clinical services, please feel free to contact us.
Laura Miller MD
Director, Women’s Mental Health Division
Lindsay Merrill MD
Women’s Mental Health Fellow
Orit Avni-Barron MD
Director, Women’s Mental Health at Fish Center for Women’s Health
Geena Athappilly MD
Women’s Mental Health Psychiatrist
BWHC Department of Psychiatry
Bansil P, Kuklina EV, Meikle SF et al: Maternal and fetal outcomes among women with depression. J Womens Health (Larchmt) 19(2):329-34, 2010
Bolvin J, Griffiths E, Venetis CA: Emotional distress in infertile women and failure of assisted reproductive technologies: meta-analysis of prospective psychosocial studies. Brit Med J 34(7795):2011
Domar AD, Moragianni VA, Ryley DA et al: The risks of selective serotonin reuptake inhibitor use in infertile women: a review of the impact on fertility, pregnancy, neonatal health and beyond. Hum Reprod Oct 31, 2012 Epub
Duval S, Tweedie R: Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta-analyses. Biometrics 56(2):455-63, 2000
Einarson A, Choi J, Koren G et al: Outcomes of infants exposed to multiple antidepressants during pregnancy: results of a cohort study. J Popul Ther Clin Pharmacol 18(2):e390-6, 2011
El Marroun H, Jaddoe VW, Hudziak JJ et al: Maternal use of selective serotonin reuptake inhibitors, fetal growth, and risk of adverse birth outcomes. Arch Gen Psychiatry 69(7):706-14, 2012
Glover V, Bergman K, Sarkar P et al: Association between maternal and amniotic fluid cortisol is moderated by maternal anxiety. Psychoneuroendocrinology 34(3):430-5, 2009
Henrichs J, Schenk JJ, Roza SJ et al: Maternal psychological distress and fetal growth trajectories: The Generation R Study. Psychol Med 40(4):633-43, 2010
Huot RL, Brennan PA, Stowe ZN et al: Negative affect in offspring of depressed mothers is predicted by infant cortisol levels at 6 months and maternal depression during pregnancy, but not postpartum. Ann NY Acad Sci 1032:234-6, 2004
Li D, Liu L, Odouli R: Presence of depressive symptoms during early pregnancy and the risk of preterm delivery: a prospective cohort study. Hum Reprod 24(1):146-53, 2009
Marcus SM: Depression during pregnancy: rates, risks and consequences – Motherisk Update 2008. Can J Clin Pharmacol 16(1):15-22, 2009
Nulman I, Citron S, Todorow M et al: Neurodevelopment of children exposed to antidepressant and antipsychotic medications during pregnancy. In: Preece PM, Riley EP, editors. Clinical in Developmental Medicine No. 188. Alcohol, Drugs and Medication in Pregnancy: the Long-term Outcome for the Child. London, United Kingdom. Mac Keith Press. Chapter 5, 2011
Oberlander TF, Weinberg J, Papsdorf M et al: Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress response. Epigenetics 3(2):97-106, 2008
Occhiogrosso M, Omran SS, Altemus M: Persistent pulmonary hypertension of the newborn and selective serotonin reuptake inhibitors: Lessons from clinical and translational studies. Am J Psychiatry 169(2):134-40, 2012
Rahman A, Iqbal Z, Bunn J et al: Impact of maternal depression on infant nutritional status and illness: a cohort study. Arch Gen Psychiatry 61(9):946-52, 2004
Safarinejad MR: Sperm DNA damage and semen quality impairment after treatment with selective serotonin reuptake inhibitors detected using semen analysis and sperm chromatin structure assay. J Urol 180(5):2124-8, 2008
Tanrikut C, Feldman AS, Altemus M et al: Adverse effects of paroxetine on sperm. Fertil Steril 94(3):1021-6, 2010
Tanrikut C, Schlegel PN: Antidepressant-associated changes in semen parameters. Urol 69(1):185 e5-7, 2007
Traviss GD, West RM, House AO: Maternal mental health and its association with infant growth at 6 months in ethnic groups: results from the Born-in-Bradford birth cohort study. PLoS One 7(2): Feb 10 2012 Epub
Verhaak CM, Lintsen AM, Evers AW et al: Who is at risk of emotional problems and how do you know? Screening of women going for IVF treatment. Hum Reprod 25(5):1234-40, 2010
Wisner KL, Sit DK, Hanusa BH et al: Major depression and antidepressant treatment: impact on pregnancy and neonatal outcomes. Am J Psychiatry 166(5):557-66, 2009
Yonkers KA, Norwitz ER, Smith MV et al: Depression and serotonin reuptake inhibitor treatment as risk factors for preterm birth. Epidemiology 23(5):677-85, 2012
Zuckerman B, Bauchner H, Parker S et al: Maternal depressive symptoms during pregnancy and newborn irritability. J Dev Behav Pediatr 11(4):190-4, 1990