Clinical Implications
• There are risks to the developing child from the use of antidepressants during pregnancy and, in turn, risks to both mother and child of untreated depression during pregnancy.
• The discontinuation of antidepressants for pregnancy is associated with a high relapse rate of depression.
• Nonpharmacological interventions that prevent or prophylax against relapse of mood disorders during pregnancy are needed.
• Though more research needs to be done, potential alternative interventions that could be used to treat or potentially prevent relapse of depression during pregnancy include psychotherapy, exercise, light box therapy (LBT), repetitive transcranial magnetic stimulation (rTMS), electroconvulsive therapy (ECT), alternative “holistic” interventions, and nutritional and herbal supplements.
Introduction
The choice of whether to prescribe a medication during pregnancy is a difficult one that must take into account the potential risks and benefits of both treatment and nontreatment to the unborn infant and the mother. When the mother is diagnosed with a potentially life threatening illness, the choice of whether to prescribe a medication often becomes obvious. However, when the mother faces an illness that is not viewed as immediately life threatening, such as a mood disorder, the decision to prescribe becomes more complicated. One such area of controversy is the use of antidepressants during pregnancy.Reference Payne and Meltzer-Brody1 Perinatal depression has an estimated prevalence rate of at least 10%Reference O'Hara and Swain2–Reference Yonkers, Ramin and Rush5 in the general population, and this rate approaches 25% or higherReference Payne, Roy and Murphy-Eberenz6 in women with a history of major depressive disorder (MDD) or bipolar disorder. Rates of antidepressant medication during pregnancy and lactation have continued to rise in North America over the past decade,Reference Payne and Meltzer-Brody1, Reference Mills7, Reference Cooper, Willy, Pont and Ray8 and antidepressant use during pregnancy is now estimated to be at least 7%Reference Cooper, Willy, Pont and Ray8–Reference Mitchell, Gilboa and Werler10 of all pregnancies.
The choice of whether to use an antidepressant medication during pregnancy often generates strong opinions and confusion, leaving women with mood disorders and their physicians unsure of how to proceed. There are several issues that complicate the interpretation of what little data exist. For example, there are two people involved, including both the mother and the developing child, and at times they have competing interests. There are also few studies that have attempted to separate out the effects of exposure to depression from the effects of exposure to medication. Most studies are complicated by the frequent use of multiple medications and the lack of long-term follow-up studies. In addition, though there are documented risks of exposure to psychiatric medications, such as antidepressants, in utero, the majority of exposed infants do not develop an associated adverse outcome, and it remains unclear what influences these differences. For example, particular environmental exposures or genetic risk factors could, in theory, influence outcomes in infants exposed to medications in utero. Finally, some of the controversy surrounding the use of psychiatric medications during pregnancy is a direct result of the continued lack of understanding of the risks associated with untreated psychiatric illness and the common belief that antidepressants and other psychiatric medications are “luxury” medications that should be stopped in the setting of pregnancy. Women with mood disorders who want to have a child are therefore “stuck between a rock and a hard place”: If they stop their medications for pregnancy, they run the risk of relapse and exposing their developing child to depression, and if they do not stop their medications, they expose their developing child to the medication. There is a clear need for interventions that would allow women to discontinue their antidepressant medications for pregnancy but prevent relapse of their mood disorder. Techniques that prolong time to relapse or even prophylax against relapse altogether would help ensure that many women would be able to discontinue their medications for pregnancy and still remain well. The goals of this review are to discuss the current literature summarizing the risks associated with the use of antidepressants during pregnancy, to review the current literature summarizing the risks associated with untreated depression during pregnancy, and to discuss potential alternatives to antidepressant use during pregnancy.
The Risks Associated with Antidepressant Use During Pregnancy
A complete and thorough discussion of the literature investigating the risks associated with the use of antidepressants during pregnancy is beyond the scope of this review. The interested reader should review the 2010 report issued by the American Psychiatric Association and the American College of Obstetricians and Gynecologists.Reference Yonkers, Wisner and Steward11 The available literature is at times conflicting and is complicated by the frequent use of multiple medications, the difficulty of controlling for maternal psychiatric illness and comorbid health behaviors (such as smoking, lack of exercise), and the difficulty of controlling for length of exposure and dosage. We have briefly reviewed the primary conclusions of the available literature below:
The impact of antidepressant use on birth outcomes
A number of studies have demonstrated a slightly increased risk for miscarriage with the use of antidepressants early in pregnancy. In a meta-analysis, this risk has been estimated at 12.4% in women who took antidepressants versus 8.7% for women who did not.Reference Hemels, Einarson, Koren, Lanctot and Einarson12 Antidepressant use has also been associated with reductions in birth weight and preterm birth.Reference Yonkers, Wisner and Steward11
The impact of antidepressant use on major organ malformations
The available literature has not consistently identified specific organ malformations associated with the use of antidepressants during pregnancy. Paroxetine use during the first trimester has been associated with a higher risk of cardiac malformations by some studiesReference Källén and Otterblad Olausson13–Reference Cole, Modell and Haight15 but not others.Reference Louik, Lin, Werler, Hernandez-Diaz and Mitchell16, Reference Alwan, Reefhuis, Rasmussen, Olney and Friedman17 One study found that the combination of a benzodiazepine with a SSRI, but not a SSRI alone, increased the incidence of congenital heart defects. The overall consensus in the field is that the risk of major organ malformations, if it exists, is small in the setting of antidepressant monotherapy.Reference Yonkers, Wisner and Steward11
Antidepressant use and persistent pulmonary hypertension
Persistent pulmonary hypertension (PPH) is a failure of the pulmonary vascular resistance to decrease at birth and, if severe, is fatal. Known risk factors for PPH include obesity, maternal smoking, diabetes, C-section, meconium aspiration, and sepsis, among others. There have been 6 studies to date examining the association between selective serotonin reptake inhibitor (SSRI) antidepressant use late in pregnancy and PPH: 3 have been positiveReference Chambers, Hernandez-Diaz and Van Marter18–Reference Kieler, Artama and Engeland20 and 3 have been negative.Reference Andrade, McPhillips and Loren21–Reference Wilson, Zelig and Harvey23 Complicating the interpretation of these studies is the fact that several known risk factors are more common in the psychiatric population, and not all of these factors were controlled for in all studies. The risk of PPH is extremely rare, thus the absolute risk to exposed babies is very low, with greater than 99% of exposed infants not developing this syndrome.
The use of SSRIs during the third trimester and poor neonatal adaptation (PNA)
A constellation of symptoms that has been collectively termed poor neonatal adaptation (PNA) has been detected in approximately 30% of infants exposed to SSRIs during the third trimester.Reference Oberlander, Misri and Fitzgerald24, Reference Levinson-Castiel, Merlob, Linder, Sirota and Klinger25 PNA is defined loosely as a cluster of symptoms including tachypnea, hypoglycemia, temperature instability, irritability, a weak or absent cry, and seizures.Reference Yonkers, Wisner and Steward11, Reference Chambers, Johnson, Dick, Felix and Jones26 This syndrome has also been identified in infants exposed to tricyclic antidepressantsReference Ter Horst, Jansman and van Lingen27 and other centrally acting classes of medications including anti-epileptic drugs and antihistamines,Reference Koch, Jäger-Roman and Lösche28 and is therefore not specific to SSRIs. Symptoms are usually transient, and the underlying mechanism is unclear. PNA has been regarded as reflecting a toxicity reaction and/or a withdrawal syndrome, among others.Reference Yonkers, Wisner and Steward11 Whether or not the presence of PNA portends more persistent effects on infant or child developmental outcomes is currently unknown.
The Risks Associated with a Major Depressive Episode (MDE) During Pregnancy
Discontinuation of antidepressants for pregnancy is associated with a high relapse rate of MDD
Terminating antidepressant treatment in pregnant women with a history of MDD has been shown to lead to relapse in 60–70% of women.Reference Cohen, Altshuler and Harlow29, Reference Cohen, Nonacs and Bailey30 Relapse then exposes the developing infant to the effects of untreated depression, which leads to adverse consequences for the patient, infant, and family.Reference Yonkers, Wisner and Steward11, Reference Murray, Sinclair and Cooper31, Reference Marmorstein, Malone and Lacono32 Women with MDD are therefore left with a difficult choice of whether to expose their babies to the risks of untreated depression or to the risks of antidepressant use during pregnancy.
Exposure to a MDE in utero is associated with poor outcomes for the exposed infant
There is evidence that exposure to a MDE in utero is associated with poor outcomes for the infant as well.Reference Yonkers, Wisner and Steward11 It remains unclear whether these undesirable outcomes are associated with the underlying biological consequences of the MDE itself (such as elevated cortisol levels) or whether they are a result of behavioral changes in the mother when she is depressed. Antenatal depression has been associated with low maternal weight gainReference Yonkers, Wisner and Steward11; increased rates of preterm birthReference Yonkers, Wisner and Steward11, Reference Li, Liu and Odouli33; low birth weightReference Yonkers, Wisner and Steward11; increased rates of cigarette, alcohol, and other substance useReference Zuckerman, Amaro, Bauchner and Cabral34; increased ambivalence about the pregnancy; and overall worse health status.Reference Orr, Blazer, James and Reiter35 Children exposed to perinatal (either during pregnancy or postpartum) maternal depression also have higher cortisol levels than infants of mothers who were not depressed,Reference Ashman, Dawson, Panagiotides, Yamada and Wilkinson36–Reference Halligan, Herbert, Goodyer and Murray39 and this continues through adolescence.Reference Halligan, Herbert, Goodyer and Murray39 Importantly, maternal treatment of depression during pregnancy appears to help normalize infant cortisol levels.Reference Brennan, Pargas and Walker40 While the long-term effects of elevated cortisol levels remain unclear, these findings may partially explain the mechanism for an increased vulnerability to psychiatric conditions in children of mothers with antenatal depression.Reference O'Connor, Ben-Shlomo and Heron41 In summary, exposure to maternal depression in utero should be considered an exposure for the developing infant that, just as with an exposure to a medication, may result in undesired outcomes and risks.
Untreated depression during pregnancy is associated with postpartum depression
Untreated depression during pregnancy is one of the strongest risk factors for the development of postpartum depression (PPD). PPD has potentially devastating consequences, including suicide and infanticide. While the risk for suicide deaths and attempts is lower during and after pregnancy than in the general population of women, suicides account for up to 20% of all postpartum deaths and represent one of the leading causes of peripartum mortality.Reference Lindahl, Pearson and Colpe42 PPD has been associated with significantly increased rates of infantile colic and impaired maternal–infant bonding.Reference Akman, Kuscu and Ozdemir43 PPD also interferes with parenting behavior, including less adequate infant safety and healthy child development practices,Reference Flynn, Davis, Marcus, Cunningham and Blow44 such as the increased use of harsh discipline.Reference McLearn, Minkovitz, Strobino, Marks and Hou45 Likely due to changes in parenting behavior, exposure to postpartum depression is also associated with slower language development, more behavioral problems, and lower IQ in the child.Reference Grace, Evindar and Stewart46 Depression either during or after pregnancy is therefore a risk exposure for the child, and given the high relapse rate of depression during pregnancy when antidepressants are stopped (up to 70%), the lack of antidepressant use during pregnancy in a woman with a mood disorder cannot be considered a more benign intervention.
Clinical Management of Women with Mood Disorders During Pregnancy
Only 20–30% of pregnant women report that antidepressants are an acceptable treatment option for depression during pregnancy.Reference Kim, Sockol and Barber47 In this study, the majority of pregnant women stated that if depressed, they would opt for either talk therapy or no treatment at all.Reference Kim, Sockol and Barber47 Ideally, conversations about treatment should begin prior to pregnancy onset, and both the patient and her clinician should have a good understanding and plan of what the preferred treatment should be and what would happen if the patient relapsed with her mood disorder while pregnant.
For women who are clinically well prior to attempting pregnancy, the decision of whether or not to continue antidepressants during pregnancy is a difficult one. On one hand, continued antidepressant use exposes their child to the medication. On the other, discontinuation has a good chance of exposing the child to the illness itself, which, as discussed, is a significant risk factor for poor outcomes. Interventions that could be used to prevent relapse of depression after discontinuation of antidepressants during pregnancy would represent a large step forward in the management of mood disorders during pregnancy. Unfortunately there are few studies that have specifically looked at interventions that prevent relapse during pregnancy; however there are a number of alternative interventions that could potentially be used in this manner, though data on prevention of relapse are generally lacking. These include psychotherapy, exercise, light box therapy (LBT), repetitive transcranial magnetic stimulation (rTMS), electroconvulsive therapy (ECT), alternative or “holistic” interventions and nutritional and herbal supplements (Table 1). We briefly review each below:
Alternative Treatments for Depression in Pregnancy
IPT: Interpersonal Therapy; MDD: Major Depression; LBT: Light Box Therapy; SAD: Seasonal Affective Disorder; DHA: docosahexaenoic acid EPA: eicosapentaenoic acid; BDI: Beck Depression Inventory; EPDS: Edinburgh Postnatal Depression Scale; HAM-D: Hamilton Depression Rating Scale
Psychotherapy
There are many studies of various types of psychotherapy, including group psychotherapy, and other psychosocial interventions for the treatment of antenatal and/or postpartum depression. Reviews of these studies have generally concluded that well-designed randomized trials are needed in order to determine if any of these therapies is effective in this particular population.Reference Dennis48–Reference Dimidjian and Goodman50 The most rigorously studied intervention is interpersonal therapy (IPT). O'Hara etal. Reference O'Hara, Stuart and Gorman51 reported a randomized (but not blinded) study of IPT versus wait list control in 120 postpartum women who met Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria for a MDE and found improved outcomes in the IPT intervention. One version of IPT, partner assisted IPT, was specifically developed for perinatal depression and demonstrated promising results in a preliminary proof of concept trial in women who were depressed either during or after pregnancy.Reference Brandon, Ceccotti and Hynan52 A number of studies have examined the efficacy of cognitive behavior therapy (CBT), but overall have not used strong designs.Reference Dimidjian and Goodman50 Other work has also provided support for the use of supportive or nondirective counseling.Reference Dimidjian and Goodman50 In terms of prevention of depression in groups of women at high risk for perinatal depression, again the most promising appears to be IPT.Reference Zlotnick, Miller and Pearlstein53 The literature in this area is limited, however, as it is mixed with various definitions of “at risk” status, small sample sizes, fewer treatments than usual (for example with CBT), and the use of clinicians who are not experts in the intervention under study.Reference Dimidjian and Goodman50 One promising prevention strategy that has not been studied in the population is the use of mindfulness-based cognitive therapy, which has been shown to significantly reduce rates of depressive relapse in adults with recurrent major depression.Reference Dimidjian and Goodman50, Reference Teasdale, Segal and Williams54, Reference Ma and Teasdale55 Further work in this area is needed.
Exercise
Exercise has been shown to reduce the risk for MDD. Population-based studies strongly support the role of regular physical activity as an intervention that protects against the onset of MDD.56 For example, Blumenthal etal. Reference Blumenthal, Babyak and Moore57 studied 156 adults with MDD who were randomly assigned to aerobic exercise, sertraline, or both, and found that exercise was equally as effective as antidepressant medication in reducing depressive symptoms. An extension of this study found that the exercise group had significantly lower relapse rates than subjects in the medication group.Reference Babyak, Blumenthal and Herman58 The same group went on to complete a placebo-controlled trial of 202 adults diagnosed with MDD and assigned to one of the following conditions: (1) group exercise, (2) home exercise, (3) medication, or (4) placebo.Reference Blumenthal, Babyak and Doraiswamy59 Although there was a high placebo response, the exercise groups improved as much as the medication group, indicating that efficacy of exercise might be equivalent to medication in the treatment of MDD.Reference Blumenthal, Babyak and Doraiswamy59 Finally, a recent study found that aerobic exercise during pregnancy reduced depressive symptoms in women with no psychiatric history.Reference Robledo-Colonia, Sandoval-Restrepo, Mosquera-Valderrama, Escobar-Hurtado and Ramírez-Vélez60 This suggests that exercise may decrease the risk of relapse of depression in women with MDD who want to stop their antidepressants for pregnancy. Once again, more work needs to be done to test this hypothesis. Commitment to exercise is difficult for many people, and doing so while pregnant may be even more difficult. However, for the motivated patient who wants to stay off medication while pregnant, exercise may represent a viable alternative.
Light box therapy
LBT has been established as an appropriate therapy for seasonal affective disorder (SAD), in which a person experiences repeated bouts of major depression usually during the fall and winter when there is less daylight.Reference Lam and Levitt61, 62 The observation that exposure to light alters circadian rhythms and suppresses melatonin secretion is thought to be the biological basis of its positive effects.Reference Lewy, Wehr, Goodwin, Newsome and Markey63, Reference Wirz-Justice, Terman and Oren64 Light therapy in general is well-tolerated and safe, and therefore has a very favorable risk-to-benefit ratioReference Levitt, Joffe and Moul65, Reference Terman and Terman66 as well as ophthalmologic safety.Reference Gallin, Terman and Reme67 A number of studies have demonstrated the efficacy of LBT in nonseasonal MDD (for example, Kripke etal.,Reference Kripke, Mullaney, Klauber, Risch and Gillin68 Kripke,Reference Kripke69 and Yamada etal. Reference Yamada, Martin-Iverson, Daimon, Tsujimoto and Takahashi70). One meta-analysis found that there was a significant reduction in depression severity with LBT with an effect size equivalent to those in antidepressant trials.Reference Golden, Gaynes and Ekstrom71 A systematic review of LBT in nonseasonal depression found that most studies in this area poorly controlled the issue of placebo and were limited by small sample sizes.Reference Even, Schroder, Friedman and Rouillon72 Despite these limitations, the reviewers concluded that, “Overall, bright light therapy is an excellent candidate for inclusion into the therapeutic inventory available for the treatment of nonseasonal depression …” (p. 20) and concluded that more research should be done in this area.Reference Even, Schroder, Friedman and Rouillon72
LBT has also been demonstrated to be effective in depressed pregnant women. Oren etal. Reference Oren, Wisner and Spinelli73 conducted an open label trial of bright light therapy in an A-B-A design in 16 pregnant patients with MDD who were depressed. They found that mean depression ratings improved by 49%.Reference Oren, Wisner and Spinelli73 There have been two randomized trials of LBT in antepartum depression. Epperson etal. Reference Epperson, Terman and Terman74 found that women randomized to LBT (10,000 lux) had a 60% improvement in depression ratings compared to 41% in the placebo group (500 lux). The difference was not statistically different in this small sample (n = 10).Reference Epperson, Terman and Terman74 A larger randomized trial of LBT (10,000 lux) in comparison to sham LBT (70 lux red light) in 27 depressed pregnant women found that LBT was superior, with 81% of the LBT sample responding versus 45% of the placebo group.Reference Wirz-Justice, Bader and Frisch75 No studies have examined the role of LBT in the maintenance of remission in patients, either pregnant or nonpregnant, with mood disorders.
Repetitive transcranial magnetic stimulation
Repetitive transcranial magnetic stimulation (rTMS) delivers a focused magnetic pulse to specific areas of the cerebral cortex.Reference Gershon, Dannon and Grunhaus76 It is currently approved by the U.S. Food and Drug Administration for treatment in adults with MDD who have failed at least one antidepressant trial in the current depressive episode.
A few case reports and open label studies have provided insight into the utility of rTMS in treating depression in pregnant women.Reference Nahas, Bohning and Molloy77–Reference Kim, Epperson and Paré81 In one open label study, Kim etal. Reference Kim, Epperson and Paré81 administered 20 daily sessions of rTMS, each lasting for 10 minutes and targeted to the right dorsolateral prefrontal cortex, in 10 pregnant women with MDD who were clinically depressed. In this study, 70% of the patients responded to treatment, and 30% met criteria for remission. One limitation of the study is that some subjects were on antidepressants during the trial. However, there was no difference in response between groups based on medication status. In addition, no adverse pregnancy or fetal outcomes were reported.Reference Kim, Epperson and Paré81
The benefits of using rTMS to treat major depression during pregnancy include a minimal side effect profile, good tolerability, and decreased fetal exposure to medications. In general, side effects from rTMS are only mild to moderate in intensity.Reference Janicak, O'Reardon and Sampson82 Similarly, when rTMS was used to treat depression in pregnancy, fetal heart rate was not affected by the treatment, and there were no adverse outcomes of the fetus, including changes in intrauterine growth or gestational period.Reference Kim, Epperson and Paré81 rTMS is also well-tolerated during pregnancy, and the majority of subjects who were enrolled completed their trials.Reference Zhang and Hu79, Reference Kim, Epperson and Paré81 Finally, another benefit of rTMS in treating depression during pregnancy is that it eliminates fetal exposure to medication side effects and toxicity.
There are also some potential risks and limitations to the use of rTMS to treat a major depressive episode during pregnancy. One risk is that, because this treatment is still very new, no long-term data are available on the effects of TMS on children born to women exposed to this intervention. A second risk is that it is unknown if pregnancy, specifically changes in circulating reproductive hormones, alters the efficacy of the treatment. A third risk is that, although the side effect profile is, in theory, relatively mild, headache and the theoretical risk of seizures may be a deterrent for some patients. Finally, recent studies have implemented anywhere from 10 consecutive days of treatments to 4–6 weeks of treatment every 2–3 days.Reference Kennedy, Milev and Giacobbe83 The frequency of treatments may also be a limitation for some people that cannot attend appointments as regularly as recommended for successful treatment. It remains to be tested whether the use of rTMS as a prevention or maintenance strategy is effective, and whether the frequency of treatments can be reduced in that setting.
Maintenance electroconvulsive therapy (ECT)
The practice of ECT is well established as an effective and safe treatment for acute episodes of severe MDD and bipolar depression.84, Reference Heijnen, Birkenhager and Wierdsma85 The use of ECT as a maintenance therapy in patients who have failed multiple medication trials but have responded to ECT has also been demonstrated, though specific guidelines for when it should be instituted are currently lacking.Reference Rabheru and Persad86, Reference Rabheru87 ECT has been used successfully during pregnancy, and in some cases is used preferentially, particularly when the mother has had successful ECT in the past.Reference O'Reardon, Cristancho and von Andreae88 There are currently no case reports or trials of the use of maintenance ECT in a woman who was previously well on antidepressants and who wished to prevent relapse during pregnancy. While the use of maintenance ECT as a preventative strategy during pregnancy is certainly feasible, there are a number of disadvantages, including the use of anesthesia and the unestablished frequency of treatments. Many practitioners would likely feel that the use of ECT in any but severe cases is unwarranted.
Alternative “holistic” interventions
Two recent Cochrane reviews concluded that the evidence for alternative “holistic” treatments such as massage therapy, acupuncture, and hypnosis for treating or preventing antenatal depression is currently inconclusive, and that the available randomized trials have been small and few and have lacked rigorous design methods.Reference Dennis and Allen89, Reference Sado, Ota, Stickley and Mori90 Both reviews noted that the lack of rigorous research in this area was surprising, given the need for nonpharmacological treatments and prevention strategies for antenatal depression.Reference Dennis and Allen89, Reference Sado, Ota, Stickley and Mori90 These types of interventions are often attractive to women with mood disorders who are contemplating pregnancy, as they can be done conveniently and intermittently and do not require a daily or necessarily frequent commitment. However, given the lack of evidence supporting their use, they can really only be recommended as adjunctive treatments at this time.
There is one randomized trial of acupuncture in 150 pregnant women who met criteria for MDD in which women were randomized to acupuncture, control acupuncture, or massage therapy for 8 weeks.Reference Manber, Schnyer and Lyell91 Those who received acupuncture specific for depression experienced a greater reduction of depressive symptoms compared to control groups and had a significantly different (positive) response rate.Reference Manber, Schnyer and Lyell91 However, a more recent study of electroacupuncture for postpartum depression did not find significant differences between the active acupuncture group and the sham group, though the study was complicated by a small sample size.Reference Chung, Yeung and Zhang92 There have been no studies examining the use of acupuncture as a prevention or maintenance treatment during pregnancy.
Nutritional and herbal supplements
Nutritional and herbal supplements that have been explored as potentially useful agents in the treatment of perinatal depression include omega-3 polyunsaturated fatty acids, S-adenosylmethionine (SAM-e), 25-hydroxyvitamin D (vitamin D), folate, and St. John's wort. Although most have been found to have some utility in treating major depression in nonpregnant patients, overall there have been mixed results in efficacy in treating peripartum depression. An excellent review of this area by Freeman.Reference Freeman93
Meta-analyses of randomized controlled trials of omega-3 polyunsaturated fatty acids in mood disorders indicate a statistically significant antidepressant effect, but there is overall a lack of consistency in study results and large heterogeneity in study designs.Reference Parker, Gibson and Brotchie94, Reference Lin, Mischoulon and Freeman95 Trials investigating the role of omega-3 fatty acids in perinatal depression have also demonstrated mixed efficacy, but some have shown decreases in depression rating scales.Reference Su, Huang and Chiu96, Reference Hösli, Zanetti-Daellenbach, Holzgreve and Lapaire97 Better trials with optimal doses and larger sample sizes are warranted.
Initial studies indicate that treatment/supplementation with SAM-e may alleviate depressive symptoms, and the Agency for Healthcare Research and Quality has indicated that further studies regarding its role as an antidepressant are warranted. However, its role in treating perinatal depression remains unclear, largely because it has not been studied in detail, though there is evidence suggesting a beneficial role in relieving “psychological distress” during the peripartum period.Reference Cerutti, Sichel, Perin, Grussu and Zulian98
Numerous studies have shown an improvement in depression when patients are supplemented with high-dose vitamin D,Reference Lansdowne and Provost99, Reference Jorde, Sneve, Figenschau, Svartberg and Waterloo100 but results are still mixed since other studies have not shown any improvement.Reference Kjærgaard, Waterloo and Wang101, Reference Sanders, Stuart and Williamson102 In peripartum depression, low levels of vitamin D have been associated with depression, but more studies are needed to determine the role of supplementation in treating depressive symptoms in this population.Reference Cassidy-Bushrow, Peters, Johnson, Li and Rao103
A role for the use of folate as an augmentation agent in conjunction with antidepressants has been established in nonpregnant patients,Reference Coppen and Baily104 but no significant changes in depression rating scales during the peripartum period were observed in a recent study, although some benefit was demonstrated in the postpartum period.Reference Lewis, Araya, Leary, Smith and Ness105
St. John's wort, an over-the-counter supplement, has also shown mixed efficacy in the treatment of major depression.106, Reference Lecrubier, Clerc, Didi and Kieser107 Studies in the treatment of peripartum depression with St. John's wort have demonstrated some improvement, but both safety and efficacy trials are still needed.Reference Howland108
Overall, nutritional supplements show a significant amount of promise in both their efficacy as alternatives to “typical” antidepressants, as well as supplementation/augmentation with antidepressant therapy. However, further studies are warranted to investigate their safety and efficacy profiles before they can be considered mainstream treatment of peripartum depression.
Conclusions
The management of mood disorders during pregnancy is complex. Treatment decisions are usually made based on the individual's history and the patient's preferences. Antidepressant use during pregnancy is an exposure for the unborn child, and it currently remains unclear what long-term repercussions there might be from this exposure, though available data are reassuring. There are increased risks of antidepressant use during pregnancy, including miscarriage, preterm birth, low birth weight, and possibly a very small increased risk for persistent pulmonary hypertension. The most common risk is the development of PNA syndrome in the newborn postpartum, though the significance of this syndrome remains unclear. On the other hand, there are risks for both the mother and child of untreated depression during pregnancy. Available data indicate that untreated depression during pregnancy is also associated with low birth weight and preterm birth. Mothers who are depressed during pregnancy are more likely to smoke and have other unhealthy habits. Antepartum depression increases the risk of postpartum depression, which has been demonstrated repeatedly to have significant effects on the exposed child's language development, IQ, and behavior. There is a real need for research into nonpharmacological strategies for the prevention of relapse of mood disorders in pregnant women who go off medications during pregnancy. We have reviewed a number of potential candidate interventions, including psychotherapies, holistic treatments, exercise, LBT, rTMS, ECT, and nutritional supplements. Currently there is a lack of evidence supporting the use of such strategies in the prevention of relapse during pregnancy, though most of these strategies have support for their use in the treatment of a major depressive episode. Carefully conducted research using one or more of these strategies in women who want to discontinue antidepressants for pregnancy is sorely needed.
Disclosures
Jennifer Payne has the following disclosure information: Pfizer, consultant, consulting fees; Astra Zeneca, consultant, consulting fees. Erica Richards does not have anything to disclose.
