Using Antidepressants During Pregnancy: An Update
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Psychiatrists, primary care physicians, neurologists, obstetricians, nurse practitioners, nurse midwives, psychiatric nurses, and other mental health care professionals. Continuing medical education credit is available for most specialties. To determine whether this article meets the CE requirements for your specialty, please contact your state licensing board.
Elizabeth King is a research assistant; Dr Stowe is associate professor of psychiatry and behavioral sciences and director of the Emory Women's Mental Health Program; and Dr Newport is assistant professor of psychiatry and behavioral sciences and associate director of the Emory Women's Mental Health Program in Atlanta.
Elizabeth Z. King has no conflicts of interest with the subject matter of this article. Dr Stowe has served on speaker's bureaus for GlaxoSmithKline, Pfizer, and Wyeth; he has served on the advisory boards for Bristol-Myers Squibb and GlaxoSmithKline. He has received research grant support from GlaxoSmithKline, Pfizer, Wyeth, and the National Institutes of Health. Dr Newport has served on speaker's bureaus for AstraZeneca, Eli Lilly, Glaxo- SmithKline, and Pfizer; and has received research grant support from Eli Lilly, GlaxoSmithKline, Wyeth, the National Alliance for Research on Schizophrenia and Depression, and the National Institutes of Health.
This research is supported by a National Institutes of Health Specialized Center of Research P50 MH 68036 (ZNS) and a Mentored Patient-Oriented Career Development Award K23 MH 63507 (DJN).
Despite, or perhaps because of, heightened attention to the use of antidepressants during pregnancy over the past decade, the management of prenatal maternal depression has become increasingly controversial. The myriad complexities of prenatal psychiatric care include the following:
Nevertheless, careful synthesis of the extant data can inform the development of evidence-based guidelines for the use of antidepressants during pregnancy.
One clinical option is to avoid antidepressant therapy during pregnancy altogether. Treatment discontinuation, however, is not done without consequences. Indeed, the conventional package label warning that use in pregnancy is not recommended unless the potential benefits justify the potential risks to the fetus is impossible to follow unless the risks of both antidepressant therapy and treatment discontinuation are understood.
The risks of treatment discontinuation are determined by (1) the likelihood of relapse in the absence of antidepressant therapy; (2) the availability and efficacy of nonpharmacologic therapies; and (3) the impact of untreated maternal prenatal depression on the well-being of offspring.
Although pregnancy has traditionally been viewed as a period of emotional well-being, as many as 70% of women present with depressive symptoms during pregnancy and up to 16% fulfill criteria for major depression.1-5 Furthermore, 11.5% of those evaluated for postpartum depression report onset during pregnancy.6 A recent study, demonstrating a hazard ratio of 5.0 (95% confidence interval, 2.8-9.1) for depressive relapse during pregnancy when antidepressant treatment is discontinued, should dispel any notion that pregnancy confers any protection from depression.7
Psychotherapy represents the principal alternative to antidepressant treatment during pregnancy, although other modalities, including brain stimulation therapies (transcranial magnetic stimulation and electroconvulsive therapy), hormonal therapies, herbal therapies, and light therapy, have been suggested. A recent meta-analysis of the relative efficacy of antidepressants and psychosocial treatments during pregnancy and the postpartum period suggests that antidepressants might be critical to maximizing therapeutic benefit.8 Specifically, the authors report effect sizes for reducing perinatal depressive symptoms of 3.048 for antidepressant monotherapy and 3.871 for antidepressants coadministered with cognitive behavioral therapy (CBT). More modest effect sizes were observed when psychosocial therapies were used alone: 2.045 for group therapy (CBT, educational and transactional analysis), 1.260 for interpersonal therapy, 0.642 for CBT, 0.526 for psychodynamic therapy, 0.418 for supportive counseling, and 0.100 for psychoeducation. These data, suggesting that antidepressant treatment might be preferable or even necessary for moderate to severe depression, coupled with the potential barriers to psychotherapy (eg, compliance, cost, availability), indicate that antidepressants remain pivotal treatment alternatives for many depressed pregnant women.
If fetal well-being is the preeminent objective, antidepressant therapy might still be unwarranted. Treatment that causes even minimal risk should be avoided if the illness poses little threat to the unborn child. For example, many pregnant women refuse treatment for mild self-limited conditions, eg, tension headaches and upper respiratory tract infections, that do not appear to affect fetal viability, the course of pregnancy, or obstetric outcome. Unfortunately, however, there is growing evidence that maternal depression during pregnancy carries numerous risks to the fetus.
The adverse impact of prenatal depression can be observed in maternal health behaviors during pregnancy, acute neonatal outcome, and longer-term neurodevelopmental effects in the child. Depressed pregnant women are more likely to neglect prenatal care, receive inadequate nutrition, engage in suicidal behavior, and use tobacco, alcohol, and cocaine.9,10 Maternal depression is associated with up to 3-fold higher rates of preterm delivery,11,12 4-fold higher rates of low birth weight,11 and a doubling of operative delivery and neonatal ICU admission rates.13
Emerging evidence indicates that fetal exposure to maternal depression can adversely affect cognitive development14 and lead to emotional and behavioral problems that remain evident in older children.15-19 Prenatal depression has also been linked to alterations in stress-respondent CNS activity.20 Recent investigations by our group have demonstrated alterations in hypothalamic-pituitary-adrenal axis reactivity as evidenced by increased salivary cortisol in the infants of women with prenatal depression (P. A. Brennan, PhD, Z. N. Stowe, MD, unpublished data, April 2006). These clinical studies are complemented by an extensive array of animal research in both rodents and nonhuman primates that indicates that prenatal stress has persistent, adverse effects on the growth, learning, and function of various biobehavioral systems in the offspring.21
Reproductive safety data have accumulated so rapidly over the past decade that antidepressants are now among the best-studied classes of medications in pregnancy; nevertheless, there remain critical gaps in our knowledge regarding their safety in pregnancy. The volume of published reproductive safety data for any given antidepressant is largely dictated by the length of time it has been on the market. Consequently, newer agents remain relatively devoid of prenatal safety data.
One critical limitation permeating the current literature is the consistent failure to validate fetal exposure. For example, previous investigations assume that maternal antidepressant compliance is 100%. No existing studies have confirmed fetal antidepressant exposure using laboratory assay of maternal/umbilical cord antidepressant concentration, documentation of prescription refill compliance, or other potential measures of compliance. Similarly, existing studies have relied on maternal self-report rather than objective laboratory documentation of substance use during pregnancy. As such, the proportion of women using illicit substances is likely underreported because of concerns about stigma and social services referral.
Taking these limitations into account, the theoretical risks of prenatal antidepressant exposure include:
Collectively comprising nearly 20,000 first-trimester infant exposures (Table 1), the prospective data arederived from an amalgam of pregnancy registries, poison control centers, managed health care databases, case series, and controlled observational studies. The overall major malformation rate associated with first trimester antidepressant exposure (2.66%) is actually lower than the 3% to 4% rate commonly reported in the general population.22-24 Despite this reassuring finding, safety data remain limited for several newer compounds and older, seldomused agents.
A recent preliminary analysis of a managed care database, demonstrating a statistically higher odds ratio for major malformations (particularly cardiovascular malformations) after first-trimester paroxetine exposure in comparison to exposure to other antidepressants,25 led the FDA to reclassify paroxetine's pregnancy category.26 Although the FDA deemed the data sufficiently compelling to alter the pregnancy classification, definitive conclusions are precluded by numerous limitations in this preliminary data set (ie, there is no nonexposed control group, the paroxetine malformation rates reported in this study approximate population norms, and the significant finding in 1 arm of the study is eliminated when those with exposure to other known teratogens are excluded).
Certainly, a conservative approach is warranted when dealing with medication use in pregnancy. Nevertheless, it is reassuring that more extensive data are available for antidepressants as a class than for many other medications commonly prescribed to pregnant women, with an overall malformation rate comparable to or below population-based averages.
Data regarding the impact of prenatal antidepressant exposure on the vulnerability to miscarriage, preterm delivery, and low birth weight are decidedly mixed. Some have reported an association with such outcomes27-30 whereas others have not.31-34 This scenario is further complicated by yet other studies reporting an association of prenatal maternal stress and/or depression with prematurity and low birth weight.11,12 Thus, no definitive conclusions can be drawn as to whether antidepressant use during gestation conveys an adverse impact on fetal growth or the timing of parturition.
A syndrome of neonatal symptoms associated with fetal exposure to antidepressants, specifically serotonergic antidepressants, proximate to delivery has drawn increasing attention and has been extensively reviewed.35 Controlled prospective studies suggest that there may be an association between antidepressant exposure and poor neonatal adaptation (Table 2); however, closer scrutiny of these reports reveals a cadre of methodologic shortcomings. Little effort has been made to mask those evaluating the neonates as to fetal antidepressant exposure; there has been no effort to control for the severity of maternal mental illness; and key confounding exposures such as gestational age at delivery, maternal smoking, and/or maternal use of other medications have either been ignored altogether or controlled for in the crudest fashion (as dichotomous variables derived from unconfirmed maternal self-report).
A putative mechanism for antidepressant-associated neonatal respiratory difficulty has been suggested by a recent retrospective case-control study.36 The study reported an overrepresentation of selective serotonin reuptake inhibitor (SSRI) exposure after gestational week 20 among neonates with persistent pulmonary hypertension (PPHN) than those without PPHN (adjusted odds ratio, 6.1 [2.2 - 16.8]). However, the fact that only 3.7% of the neonates with PPHN were exposed to an SSRI in late pregnancy, coupled with the recognition that PPHN is itself a relatively rare condition affecting approximately 0.19% of newborns,37 raises questions as to whether this statistically significant finding is as clinically meaningful as the authors contend.
Another recent case-control study, comparing the exposure of neonates who required observation with healthy neonates,38 further highlights the importance of controlling for confounding factors. In this study--in which all neonates (N = 46) were exposed to antidepressants and born to mothers fulfilling diagnostic criteria for major depression--the mothers of those who required observation had significantly higher scores on Hamilton Depression (21.7 vs 16.2) and Hamilton Anxiety (21.1 vs 13.6) rating scales, were significantly more likely to have a comorbid anxiety disorder (92.8% vs 53.1%), and were on average exposed to higher doses of clonazepam (0.43 mg/d vs 0.14 mg/d).
To date, only 4 studies have systematically assessed child development after prenatal antidepressant exposure. The first 2 reports, from the same group, assessed children aged 15 to 86 months, collectively comparing 126 children exposed prenatally to a tricyclic antidepressant and 90 children exposed to fluoxetine with 120 children of women with no history of depression. Using age-adjusted rating instruments, the investigators found no differences with respect to global cognition, psychomotor development, or language development.21,39
The third study, assessing children aged 6 to 40 months, compared 13 children of women who were depressed but did not take antidepressant medication during gestation with 31 children prenatally exposed to an SSRI.40 This group also found no differences in global cognition; however, lower psychomotor scores were reported for the children exposed to SSRIs.
Unfortunately, the limitations of these 3 studies render their implications speculative at best. First, children were not age-matched in any of these studies. Although the authors reported age-adjusted index scores, the predictive validity of these indices across child developmental stages has not been established.41 Consequently, differences in the ages of the children among the study groups might confound the results. Second, the last study mentioned above is further confounded by the fact that 29% of the participants were enrolled after delivery. This inclusion of a retrospective (postnatally enrolled) sampling could result in an overrepresentation of children with developmental delay.
The most recent investigation, by Oberlander and colleagues,42 evaluated children at fixed time points (aged 2 and 8 months) thereby eliminating the age adjustment confounder. This study reported no difference between 46 infants exposed to SSRIs and 23 children of healthy volunteers with respect to either cognitive or motor development.
Finally, the interpretation of neonatal adaptation and neurodevelopmental outcome studies is potentially dictated, at least in part, by the sensitivity of the outcome measures employed. Recent studies are to be applauded for an increasing reliance on standardized rating instruments of infant well-being and development; however, such instruments were not specifically designed to elucidate the potential effects of fetal exposure to antidepressants or maternal depression. As a result, the sensitivity of the measures used in these studies remains open to debate. A gross measure may lack the sensitivity to identify an adverse effect and might therefore lead to an erroneous conclusion that none has occurred. Conversely, an exquisitely sensitive measure might identify an effect that is statistically significant but of little or no functional consequence and could therefore lead to an erroneous conclusion that harm has occurred.
There are many shortcomings in the evidence regarding depression during pregnancy, its effects, and its treatment. The ethical implications of conducting research during pregnancy mandate the use of observational studies rather than randomized, placebocontrolled clinical trials. Conducting observational studies, however, requires considerable forethought so that confounding variables can be appropriately controlled. Too often, outcomes are attributed to antidepressant exposure in the absence of proper controls for illness effects, and vice versa.
Despite these limitations, 2 facts have clearly emerged: (1) discontinuing treatment during pregnancy dramatically increases the likelihood of recurrent depression; and (2) moderate to severe depression during pregnancy carries considerable risk for infant well-being. Consequently, there is no risk-free alternative when advising women with histories of depression regarding treatment during pregnancy. In each clinical encounter, the likelihood and risks of untreated prenatal depression must be weighed against the risks of fetal exposure to antidepressant medication.
One common clinical scenario is that of a woman who is currently being administered antidepressant therapy and planning to conceive. Preconception planning affords an opportunity for patient education and planning of clinical decision making before fetal exposure has occurred. During this visit, the clinician should assess the current mood state, the frequency and severity of past depressive episodes, and the presence of comorbid psychiatric and/or medical disorders. A comprehensive obstetric history should include the occurrence of prior depressive episodes during pregnancy and the postpartum period, any history of medical complications during previous pregnancies, plans for breast-feeding and, finally, prior treatment history with a detailed assessment of response to psychotherapy and specific antidepressant agents.
Patients with mild, infrequent episodes of depression might prefer to avoid antidepressant therapy in favor of psychotherapy. When antidepressant therapy is warranted, the preferred agent is one with an extensive reproductive safety database that has Finally, the interpretation of neonatal adaptation and neurodevelopmental outcome studies is potentially dictated, at least in part, by the sensitivity of the outcome measures employed. Recent studies are to be applauded for an increasing reliance on standardized rating instruments of infant well-being and development; however, such instruments were not specifically designed to elucidate the potential effects of fetal exposure to antidepressants or maternal depression. As a result, the sensitivity of the measures used in these studies remains open to debate. A gross measure may lack the sensitivity to identify an adverse effect and might therefore lead to an erroneous conclusion that none has occurred. Conversely, an exquisitely sensitive measure might identify an effect that is statistically significant but of little or no functional consequence and could therefore lead to an erroneous conclusion that harm has occurred.
Clinicians must also consider the patient's age with respect to treatment planning. Delaying conception to implement therapeutic trials of alternative therapies could inadvertently increase risk secondary to advanced maternal age. This is avoidable by treating women of reproductive capacity from the very outset as if they are, or might soon become, pregnant. In all cases, the clinician should educate women about healthy behaviors--prenatal vitamins; reduction in maternal obesity; avoidance of tobacco, alcohol, and caffeine; and proper hydration and exercise.
Half of all pregnancies in the United States are unplanned.43 Typically, patients are 6 or more weeks into an unplanned pregnancy before realizing that they are pregnant. In this scenario, it is often wise to advise a patient to continue her present treatment. Because prenatal exposure to an antidepressant has already occurred, the goal at this juncture is to protect the fetus from other potentially harmful exposures.
Abruptly stopping treatment is unwise, since it carries an extremely high risk for relapse with its attendant potential for harm. Gradually tapering medication entails an additional 3 to 4 weeks of fetal antidepressant exposure (including time for residual medication to clear), by which time organogenesis would be nearing completion. As a result, the fetus is afforded little protection from the effects of antidepressant exposure and is left vulnerable to maternal depression.
Finally, switching antidepressants to an agent with more extensive reproductive safety data is also inadvisable at this juncture. Switching after conception exposes the fetus to yet another medication and inadvertently increases the likelihood of fetal exposure to maternal depression, since there is no certainty that the second antidepressant will work effectively.
To avoid the reputed transient effects of serotonergic antidepressants on the neonate, discontinuing antidepressant treatment a few weeks before to delivery has been suggested.44 Although this approach might improve neonatal adaptation in the hours and days immediately following delivery, it is not without its shortcomings. In particular, it eliminates treatment just when the new mother will be most vulnerable to depressive illness, ie, as she approaches the postpartum period. The well-documented effects of maternal postpartum depression on infant development must, therefore, be weighed against the transient effects of antidepressant exposure at delivery that in all existing studies have been self-limited and have required no clinical intervention.
Some women who are vulnerable to postpartum depression are fortunate enough to experience relative euthymia during gestation. Conventional wisdom has been to initiate prophylactic antidepressant therapy for such women 4 to 6 weeks before anticipated delivery. Increasing concerns regarding neonatal adaptation in newborns exposed to antidepressants suggest that waiting to initiate antidepressant therapy immediately after delivery might be preferable. Two small placebo-controlled studies in women with a history of postpartum depression have produced discordant results using this approach to postpartum prophylaxis.45,46
There is a propensity in the medical literature and the news media to emphasize adverse outcomes, whereas negative study results seldom garner much attention. This is true for both medication and illness exposures. The quest to conduct the perfect study is akin to the search for the Holy Grail. Consequently, clinicians must practice within their comfort zone and have ready access to incomplete yet reliable information.
Thoughtful consideration of potential pregnancy in the treatment planning for women of reproductive capacity serves to reduce the consternation precipitated by a positive pregnancy test. By inquiring routinely about birth control at all visits when treating women during the reproductive years, clinicians can provide a conduit for discussion and treatment planning that aims to reduce risk for mother and child.
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