Treatment of mood disorders during pregnancy and postpartum

Tre a t m e n t o f M o o dD i s o rd e r s D u r i n gP re g n a n c y a n dP o s t p a r t u m Lee S. Cohen, Betty Wang, MD,Ruta Nonacs, MD, PhD, Adele C. Viguera, MD,Elizabeth L. Lemon, MA, Marlene P. Freeman, MD  Mood disorders  Pregnancy  Postpartum Although pregnancy was once believed to be a time of emotional well-being forwomen,studies now suggest that pregnancy does not protect women from theemergence or persistence of mood disorders.Mood and anxiety disorders areprevalent in women during the childbearing yand, for many women, thesemood disorders are chronic or recurrent. Maintenance antidepressant therapy isoften indicated during the reproductive years and women face difficult treatmentdecisions regarding psychotropic medications and pregnancy. Treatment ofpsychiatric disorders during pregnancy involves a thoughtful weighing of the risksand benefits of proposed interventions (eg, pharmacological treatment) and thedocumentedand theoretical risks associated with untreated psychiatric disor-ders such as depression. Collaborative decision making that incorporates patienttreatment preferences is optimal for women trying to conceive or who arepregnant.
With increasing evidence of high rates of relapse following discontinuation of psychotropic medications (eg, antidepressants,mood antipsy-and benzodiazepines) and other data that describe new-onset psychiatricillness during pregnancy,the value of psychiatric consultation during pregnancyand after delivery is intuitive. The risks of untreated mood disorders during pregnancyto the mother and the baby (eg, preterm delivery, poor nutrition, inadequate weightgain, poor prenatal care, inability to care for oneself, substance use, termination ofthe pregnancy, and postpartum depressionalso deserve attention. Depression Perinatal and Reproductive Psychiatry, Department of Psychiatry, Massachusetts GeneralHospital, Harvard Medical School, 185 Cambridge Street, Boston, MA 02114, USA* Corresponding author.
E-mail address: Psychiatr Clin N Am 33 (2010) 273–293doi:10.1016/j.psc.2010.02.001 0193-953X/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.
during pregnancy is a strong predictor of postpartum depression, a condition that canhave dire consequences for the mother, the baby, and the entire family. Therefore, itcould be argued that nothing is more critical than sustaining maternal emotionalwell-being during pregnancy.
Because of the substantial unknowns of long-term effects of medication exposure during pregnancy and those of untreated mood disorders, women with similar illnesshistories often make different decisions about their care in collaboration with theirphysicians during pregnancy. Because rapid discontinuation of medication seemsto increase the risk of relapse of mood episodes,women should be educatedabout the risks and benefits of medications during pregnancy so that medicationsare not abruptly stopped (out of fear of exposing the fetus to medication). Furthermore,medications with benign reproductive safety profiles across classes of moleculesshould be used as first-line agents in women of reproductive age being treated forpsychiatric illness.
Acute major depressive episodes are often untreated or undertreated during preg- Screening for, and successful treatment of, depression during pregnancycan minimize maternal suffering, as well as the potential negative consequences ofuntreated maternal depression on infant development and family functioning.
This article reviews the diagnosis and treatment guidelines of mood disorders during pregnancy and post partum, as well as the use of psychotropic medicationsduring this time.
PERINATAL PSYCHIATRY: FROM SCREENING TO TREATMENT Clinicians who manage the care of female psychiatric patients before, during, andafter pregnancy may be called to evaluate women who experience a broad spectrumof difficulties. Symptoms may be mild, although the consultant is typically requestedwhen symptoms become severe. It is not uncommon for women to present weeks oreven months after the onset of psychiatric symptoms. Many women and their healthcare providers mistakenly believe that even serious mood symptoms are normal post-partum reactions, and many women may be afraid or embarrassed to disclose thatthey are suffering from depression. Psychiatric disorders may emerge anew duringpregnancy, although more often clinical presentations represent persistence or exac-erbation of an existing illness. Physicians, therefore, should screen more aggressivelyfor psychiatric disorders either before conception or during pregnancy, integratingquestions about psychiatric symptoms and treatment into the obstetric history. Iden-tification of at-risk women allows the most thoughtful, acute treatment before, during,and after pregnancy.
One recent report has described the finding that even among women with identified psychiatric illness during pregnancy, definitive treatment is frequently lacking orThe extent to which women suffering from postpartum psychiatricillness are under treated as a group is also well described. One of the reasons forfailure to treat women with psychiatric disorders during pregnancy is the concernregarding potential risks associated with fetal exposure to psychotropics. Many clini-cians can conceptualize the need to weigh relative risks of fetal exposure on the onehand versus the risk of withholding treatment on the other. However, given the inabilityto quantify these risks absolutely, clinicians often defer treatment entirely and conse-quently put patients at risk for the sequelae of untreated maternal psychiatric illness.
Clinicians should realize that the process of managing psychiatric illness during preg-nancy and the puerperium is not a process like threading a needle; it is not clear-cutand much treatment described in the literature is not evidence based. Despite the growing number of reviews on the subject, management of antenatal depression is stilllargely guided by experience, with few definitive data and no controlled treatmentstudies to inform treatment. The best treatment algorithms depend on the severityof the disorder, on a patient’s psychiatric history, her current symptoms, and her atti-tude toward the use of psychiatric medications during pregnancy, and, ultimately, thepatient’s wishes. However, thoughtful collaborative decisions can still be made withthese patients as clinicians review the best available evidence with them and as clini-cian and patient realize that no decision is risk free and no decision is perfect.
Thoughtful treatment decisions can be made nonetheless, taking into accountavailable information regarding relative risks of treatment and the patient’s wishes.
PHARMACOLOGICAL TREATMENT OF DEPRESSION DURING PREGNANCYClinical Guidelines Making the diagnosis of depression during pregnancy can be difficult becausedisturbances in sleep and appetite, symptoms of fatigue, and changes in libidocan be normal during pregnancy. Clinical symptoms that may support the diagnosisof major depressive disorder (MDD) include anhedonia, feelings of guilt and hope-lessness, poor self-esteem, and thoughts of suicide. In addition, symptoms thatinterfere with function signal a psychiatric condition that warrants treatment.
Suicidal ideation is not uncommonhowever, risk of frank self-injurious orsuicidal behaviors seems to be low in women who develop depression duringpregnancy.
Multiple reviews have been published in the last decaderegarding the risks associated with fetal exposure to antidepressants. Although data accumulated inthe last 30 years have suggested that some antidepressants have favorable risk/benefit profiles during pregnancy,information regarding the full spectrum andrelative severity of risks of prenatal exposure to psychotropic medications is stillincomplete. Moreover, the risks of medication use must be balanced against the risksassociated with untreated psychiatric disorders that may adversely affect the motherand the fetus.
As with other medications, 4 types of risk are typically cited with respect to potential use of antidepressants during pregnancy: (1) risk of pregnancy loss or miscarriage, (2)risk of organ malformation or teratogenesis, (3) risk of neonatal toxicity or withdrawalsyndromes during the acute neonatal period, and (4) risk of long-term neurobehavioralsequelae.To guide physicians about the reproductive safety of various prescriptionmedications, the US Food and Drug Administration (FDA) has established a systemthat classifies medications into 5 risk categories (A, B, C, D, and X) based on dataderived from human and animal studies. Medications in category A are designatedas safe for use during pregnancy, whereas category X drugs are contraindicated, asthey are known to have risks to the fetus that outweigh any benefit to the patient.
Most psychotropic medications are classified as category C agents, for which humanstudies are lacking and for which risk cannot be ruled out. No psychotropic drugs areclassified as safe for use during pregnancy (ie, category A).
This system of classification has noteworthy limitations. First, categorization is often ambiguous and may lead to unwarranted conclusions. For example, certain tricyclicantidepressants (TCAs) have been labeled as category D agents, indicating positiveevidence of risk, although the pooled available data do not support this assertionand suggest that these drugs are safe for use during pregnancy.Second, thecategorization is usually assigned when only a small amount of animal data is avail-able, and when human data are sparse or absent. Third, when larger and more rigorous studies become available on the reproductive safety profile of a medication,the category is rarely altered. Fourth, the categorization system fails to take intoaccount the risks of the untreated maternal psychiatric disorder for the woman andher fetus. Therefore, the physician must also rely on other sources of informationwhen counseling patients about the potential use of psychotropics during pregnancy.
Randomized, placebo-controlled studies that examine the effects of medication useon pregnant populations are lacking. Therefore, many of the data related to the profileof reproductive safety for a medication are derived from retrospective studies andcase reports. More recently, studies that have evaluated the reproductive safety ofantidepressants have used a more rigorous prospective design,or have reliedon programs.Given the lack of clarity of the FDA risk categories, this agency hasrecently proposed a modification of the classification system that incorporatesa more individualized and sophisticated approach to the use of medications inpregnancy.
As a general guiding principle, treatment of depression during pregnancy is determined by the severity of the underlying disorder, history of treatmentresponses, and individual patient preferences. For women who present with thenew onset of depressive symptoms during pregnancy, or mild to moderate majordepression, nonpharmacological treatment strategies should be explored first,consistent with recent recommendations by representatives of the AmericanPsychiatric Association and the American College of Obstetrics and Women with mild to moderate depressive symptoms may benefit from nonphar-macological treatments that include supportive psychotherapy, cognitive behav-ioral therapy (CBT), or interpersonal therapy (IPT).These interventions maybe beneficial for reducing the severity of depressive symptoms and may eitherlimit or obviate medications. Given the importance of interpersonal relationshipsin couples who are expecting a child and the significant role transitions thattake place during pregnancy and after delivery, IPT may be ideally suited forthe treatment of depressed pregnant women.In general, pharmacological treat-ment is pursued when nonpharmacological strategies have failed or when it isthought that the risks associated with psychiatric illness during pregnancyoutweigh the risks of fetal exposure to a particular medication.
In patients with less severe major depression, discontinuation of ongoing pharma- cological therapy during pregnancy should be considered. Although data on the use ofIPT or CBT to facilitate antidepressant discontinuation before conception are not avail-able, it makes sense to pursue such treatment of women on maintenance antidepres-sant therapy who are planning to become pregnant. These treatment modalities mayreduce the risk of recurrent depressive symptoms during pregnancy; however, thishas not been studied systematically. Close monitoring of affective status during preg-nancy is essential throughout pregnancy for women with a history of a mood disorder,regardless of whether medication is continued or discontinued. Psychiatrically illwomen are at high risk for relapse during pregnancy, and early detection and treat-ment of recurrent illness may significantly reduce morbidity associated with affectivedisorder.
Many women who discontinue antidepressants during pregnancy experience recur- rent depressive symptoms.In 1 recent study, women who discontinued theirmedications were 5 times more likely to relapse (with a rate of relapse of 68%)compared with women who maintained their antidepressants across pregnancy.
Thus, women with recurrent or refractory depressive illness may decide (in collabora-tion with their clinician) that the safest option is to continue pharmacologic treatment during pregnancy to minimize the risk for recurrent illness. In this setting, the clinicianshould attempt to select medications during pregnancy that have a well-characterizedreproductive safety profile that may necessitate switching psychotropics (to one witha better reproductive safety profile). In an ideal world, modification of the treatmentplan would occur before pregnancy, and allow time for confirming euthymia ona new medication. For example, one might switch from duloxetine, a medication forwhich there are sparse data on reproductive safety, to an agent such as fluoxetineor citalopram. In other situations, one may decide to use a medication for which infor-mation regarding reproductive safety is sparse (eg, a woman with refractory depres-sion who has responded only to 1 particular antidepressant for which specific dataon reproductive safety are limited [eg, venlafaxine]). The patient may choose tocontinue this medication during pregnancy rather than risk potential relapse associ-ated with antidepressant discontinuation or switch to another antidepressant forwhich she has no history of response.
Even if a woman continues an antidepressant during pregnancy, relapse may occur. Cohen and colleaguesreported that 26% of women who continue antide-pressants had a relapse of MDD during pregnancy. Therefore, careful monitoring isrequired even if maintenance medications are continued. Only a small amount ofinformation is available on the pharmacokinetic profile of selective serotonin reup-take inhibitors (SSRIs) and newer antidepressants across withsome but not all women having lower plasma concentrations of medication inlate pregnancy. Therefore, some women may require higher doses of medicationas pregnancy progresses to maintain therapeutic benefits; this supports a needfor frequent assessment.
In situations in which pharmacological treatment is more clearly indicated, the clinicianshould select medications with the safest reproductive profile. Fluoxetine and citalo-pram, with extensive data that support their reproductive safety, can be considered asfirst-line choices. Among the SSRIs, paroxetine is the most controversial, givenreports regarding cardiovascular malformations with first-trimester exposure.
However, more comprehensive studies and pooled teratovigilance data did notsupport this risk. Nevertheless, many women and their obstetrical health careproviders may remain anxious about use of paroxetine in pregnancy. The TCAs andbupropion have also been well characterized and can be considered reasonable treat-ment options during pregnancy. Among the TCAs, desipramine and nortriptyline arefrequently cited as preferred because they are less anticholinergic and less likely toexacerbate orthostatic hypotension during pregnancy. The amount of literature onthe reproductive safety of the newer SSRIs is increasing, and these agents may beuseful in certain settings, particularly if a woman has had a good response to 1 ofthem yet has poorer responses to better-characterized Whenprescribing medications during pregnancy, an attempt should be made to simplifythe medication regimen. For instance, a more sedating antidepressant may beselected for a woman who presents with depression and sleep disturbance insteadof selecting a more activating antidepressant in combination with trazodone ora benzodiazepine.
Cumulative reports that describe the reproductive safety of SSRIs have been recently These reports provide some reassurance that as a group ofmedicines, SSRIs are not major teratogens. Initially, reports suggestedthat first-trimester exposure to paroxetine was associated with an increased risk ofcardiac defects (including atrial and ventricular septal defects). Although these findings prompted the FDA to change the labeling of paroxetine from category C to D,2 independent, peer-reviewed, comprehensive meta-analyses of studies assessingparoxetine exposure during the first failed to prove the increasedteratogenicity of paroxetine. Therefore, although it is widely believed that paroxetinemay confer an increased risk of congenital malformations with first-trimester expo-sure, the most comprehensive studies to date have not supported this; paroxetineshould still be considered a treatment option for women who, before pregnancy,have had a positive response to the agent.
The data about the risk of major malformations after first-trimester use of SSRIs remain inconsistent. A large body of literature has failed to show a risk of major mal-formations with first-trimester exposure, but 1 study suggested that SSRI use duringthe first trimester of pregnancy was associated with increased risk of omphalocele,craniosynostosis, and anencephaly.Another study suggested that first-trimesterSSRI use was not associated with significantly increased rates of craniosynostosis,omphalocele, or cardiac defects, but did note an increase in malformations withparticular SSRIs. In this analysis, sertraline was associated with omphalocele andseptal defects, whereas paroxetine exposure was associated with right ventricularoutflow tract obstruction Bupropion may be an attractive option for women who have not responded well to fluoxetine or TCAs. Data thus far have not indicated an increased risk of malformationsassociated with bupropion use during Bupropion deserves specialconsideration if a woman is attempting to abstain from smoking during pregnancy,as it is also approved by the FDA for smoking cessation, and tobacco use during preg-nancy is associated with a spectrum of risks. Bupropion may be an attractive optionfor women with attention deficit disorder who are receiving stimulants, as reproductivesafety data regarding this class of medicines are more sparse than those forbupropion, an antidepressant that has been used with benefit in some patients withattention-deficit/hyperactivity disorder.
Limited data are available on the use of the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxineduring pregnancy. Nonetheless, given the frequencyof use of these medicines and the frequency of unplanned pregnancy,thedata supporting safety of venlafaxine are increasingly reassuring. There is littleinformation available on the use of duloxetine in pregnancy. Mirtazapine is a novelpiperazinoazepine antidepressant; although the data regarding the use of thismedication during pregnancy are sparse, in 1 small study it did not seem toincrease the rate of major Although small studies of medicationexposures may provide reassuring preliminary information, large definitive trialsare necessary to assess risks that might be rare (and observable only withadequate sample sizes).
Although selection of the safest antidepressant based on teratogenic potential is critical if pharmacotherapy is to be pursued during pregnancy, other clinical consider-ations such as dosage of medication used across pregnancy also warrant comment.
Clinicians must use an adequate dosage of medication to obtain and sustain euthy-mia. Frequently the dosage of a medication is reduced during pregnancy in an attemptto limit risk to the fetus. However, this type of modification in treatment may insteadplace the woman at greater risk for recurrent illness. During pregnancy, changes inplasma volume and increases in hepatic metabolism and renal clearance may signif-icantly affect drug Several investigators have described a reduction (up to65%) in serum levels of TCAs during Subtherapeutic levels may beassociated with depressive ; therefore, an increase in daily TCA or SSRIdosage may be required to obtain sustain affective Perinatal Outcomes Following Antidepressant Exposure Despite the growing literature that supports the relative safety of fetal exposure toSSRIs with respect to teratogenic risk, multiple reportshave described adverseperinatal outcomes (including decreased gestational age, low birth weight, and poorneonatal adaptation) following in utero exposure to these medicines. Nonetheless,other studieshave failed to note these associations. Particular concern hasbeen raised regarding the potential effects of late-pregnancy exposure to SNRI; 1recent noted jitteriness, tachypnea, and tremulousness. These effects havebeen described as transient (limited to several days following delivery). In general,most reports characterize a neonatal syndrome following maternal antidepressantuse as mild and not requiring clinical intervention.
Conflicting reports have also raised a question about whether SSRI use in later pregnancy is associated with a serious but rare developmental lung condition, persis-tent pulmonary hypertension of the newborn (PPHN). Chambers and colleaguesraised this concern when they noted an association between PPHN and SSRI use ina nested case-controlled study. They reported the risk of PPHN with exposure toSSRIs after 20 weeks at about 1%. However, more recent studies have shown a loweror perhaps absent association. Ka¨ll en and Otterbladalso found an association between late SSRI use in pregnancy and PPHN, albeit a substantially smaller riskthan that found by Chambers and colleagues.The most recent study, however,failed to show any association between SSRI use during pregnancy and PPHN.PPHN is correlated with multiple established risk factors, including cesarean section,race, body mass index (calculated as weight in kilograms divided by the square ofheight in meters), and other factors not associated with SSRI use.
Another concern about antidepressant use in late pregnancy is neonatal withdrawal or adaptation syndrome. Further investigation is warranted to clarify the associationbetween SSRI use and neonatal risks, as symptoms reported to be associated withlate-pregnancy antidepressant use have also been reported among neonates ofmothers with untreated depression and anxiety. Most reports that have attemptedto delineate the potential effects of peripartum exposure to SSRIs have been limitedby small sample size, nonsystematic assessment of infant outcome, and frequentuse of nonblinded raters.
With multiple studies supporting the finding of transient jitteriness, tremulousness, and tachypnea associated with peripartum use of some physicians (aswell as labeling across the SSRIs mandated by the FDA) have suggested the discon-tinuation of antidepressants just before delivery to minimize the risk of neonataltoxicity. Another potential rationale for antidepressant discontinuation before deliveryis derived from the assumption that this would attenuate the risk of PPHN that hasbeen associated with late-trimester exposure to SSRIs.The recommendation isnot data driven and such a practice may carry significant risk as it withdraws treatmentfrom a patient precisely as she is about to enter the postpartum period, a time ofheightened risk for affective illness. In consideration of the well-characterized risksto mother, baby, and family associated with untreated maternal mood disorder, treat-ment goals should include having a woman enter the postpartum period in a depres-sion euthymic state. The strategy of medication discontinuation before delivery,however, may increase the risk of recurrent depression on the cusp of the puerperalperiod and may be associated with significant morbidity, and recovery from recru-descing illness may also take considerable time.
Although a limited amount of data are available regarding the long-term effects of fetal exposure to antidepressants as a class, fluoxetine and TCAs are the best-characterized agents in this regard. In children exposed to fluoxetine, TCAs or nomedication, no differences have been detected in behavioral or cognitive development(in terms of IQ, language, temperament, behavior, reactivity, mood, distractibility, andactivity level) among groups when followed through early childhood. Although thegreatest emphasis of research regarding antidepressant use and pregnancy hasaddressed the effect of antidepressant drugs on risk for congenital malformation,more research is needed to assess the long-term effects of prenatal antidepressantexposure. Therefore, although these and other dataavailable are reassuring, theyare still limited and further, more definitive, investigation into the long-term neurobeha-vioral effects of prenatal exposure to antidepressants is warranted.
Consideration of the use of electroconvulsive therapy (ECT) during pregnancy typicallygenerates anxiety among clinicians and patients. However, its safety record has beenwell documented in the last 50 years,particularly when instituted in collaborationwith a multidisciplinary treatment team, including an anesthesiologist, psychiatrist,and obstetrician.Requests for psychiatric consultation for pregnant patientswho require ECT tend to be emergent and dramatic. For example, expeditious treat-ment is imperative in instances of mania during pregnancy or psychotic depressionwith suicidal thoughts and disorganized thinking. Such clinical situations are associ-ated with a danger from impulsivity or self-harm. A limited course of treatment maybe sufficient followed by institution of treatment with 1 or a combination of agents(such as antidepressants, neuroleptics, benzodiazepines, or mood stabilizers).
ECT during pregnancy tends to be underused because of concerns that treatment will harm the fetus. Despite 1 report of placental abruption associated with the use ofECT during considerable experience supports its safe use in severely illgravid women. Reviews of ECT during pregnancy note the efficacy and safety of thisprocedure.In a review of the 339 cases of ECT during pregnancy published inthe past 65 years, only 11 of the 25 fetal or neonatal complications, including 2 deaths,were likely caused by ECT. Given its relative safety, ECT may also be considered analternative to conventional pharmacotherapy for women who wish to avoid extendedexposure to psychotropics during pregnancy or for women who fail to respond tostandard antidepressants.
Although the effect of pregnancy on the natural course of bipolar disorder (BPD) is notwell described, studies suggest that any protective effects of pregnancy on risk forrecurrence of mania or depression in women with BPD are limitedand the risk forrelapse and chronicity following discontinuation of mood stabilizers is high.Given these data, clinicians and women with BPD who are either pregnant or whowish to conceive find themselves between a ‘‘teratologic rock and a clinical hardplace.’’ Historically, women with BPD have been counseled to defer pregnancy (given an apparent need for pharmacological therapy with mood stabilizers) or to terminatepregnancies following prenatal exposure to drugs (such as lithium or valproic acid).
However, more recent and comprehensive data suggest that women can select treat-ment strategies that allow for pregnancy with the mother and baby’s safety in mind.
The risk of lithium exposure during pregnancy has been reassessed and is consideredsafer than it was decades ago. Concerns regarding fetal exposure to lithium, forexample, have typically been based on early reports of higher rates of cardiovascular malformations (eg, Ebstein anomaly) following prenatal exposure to this drug.More recent data suggest the risk of cardiovascular malformations following prenatalexposure to lithium is smaller than previous estimates (1/2000 vs Prenatalscreening with high-resolution ultrasound and fetal echocardiography is recommen-ded at or about 16 to 18 weeks of gestation to screen for cardiac anomalies. Nonethe-less, the woman with BPD is faced with a decision regarding use of lithium duringpregnancy; it is appropriate to counsel such a patient about the small risk of organdysgenesis associated with prenatal exposure to this medicine.
Lamotrigine is another mood stabilizer that is an option for pregnant women with BPD who show a clear need for prophylaxis with mood stabilizer. Although previousreports failed to show an increased risk of malformations associated with lamotriginedata from the North American Anti-Epileptic Drug registry indicate anincreased risk of oral cleft in infants exposed to lamotrigine during the first trimester;the prevalence was approximately 9 per 1000 births.
Compared with lithium and lamotrigine, prenatal exposure to some anticonvulsants is associated with a far greater risk for organ malformation. An association betweenprenatal exposure to mood stabilizers, including valproic acid and carbamazepine,and neural tube defects (3%–8%) and spina bifida (1%) also has beenobserved.Fetal exposure to anticonvulsants has been associated not onlywith high rates of neural tube defects, such as spina bifida, but also with multipleanomalies (including midface hypoplasia [also known as the anticonvulsant face],congenital heart disease, cleft lip or palate, growth retardation, and microcephaly).
Factors that may increase the risk for teratogenesis include high maternal serum anti-convulsant levels and exposure to more than 1 anticonvulsant. This finding of dose-dependent risk for teratogenesis is at variance with that for some other psychotropics(eg, antidepressants). Thus, when using anticonvulsants during pregnancy, the lowesteffective dose should be used, anticonvulsant levels should be monitored closely, andthe dosage adjusted appropriately. Ideally, women of reproductive age should avoidtreatment with valproate, and it should not be considered a first-line therapy in womenwith reproductive potential.
Information about the reproductive safety of newer anticonvulsants sometimes used to treat BPD (including gabapentin, oxcarbazepine, and topiramate) remainsOther efforts are under way to accumulate data from prospective registriesregarding teratogenic risks across a broad range of anticonvulsants. The North Amer-ican Antiepileptic Drug Pregnancy Registry was established as a way of collectingsuch information rapidly and efficiently ().
Prenatal screening following anticonvulsant exposure for congenital malformations (including cardiac anomalies) with fetal ultrasound at 18 to 22 weeks of gestation isrecommended. The possibility of fetal neural tube defects should be evaluated withmaternal serum a fetoprotein and ultrasonography. In addition, 4 mg a day of folicacid before conception and in the first trimester for women receiving anticonvulsantsis frequently recommended. However, supplemental use of folic acid to attenuate therisk of neural tube defects in the setting of anticonvulsant exposure has not beensystematically evaluated.
Although use of mood stabilizers (including lithium and some anticonvulsants) has become the mainstay of treatment of the management of acute mania andthe maintenance phase of BPD, most patients with BPD are not treated withmonotherapy. Rather, use of adjunctive conventional and newer antipsychoticshas become common clinical practice for many patients with BPD. Moreover,with increasing data supporting the use of atypical antipsychotics as monotherapyin the treatment of BPD, patients and clinicians will seek information regarding the reproductive safety of these newer agents. To date, some data exist that supportthe reproductive safety of typical antipsychotics; these data have been reviewedextensively However, despite their expanding use in psychiatry, avail-able reproductive safety data regarding the atypical antipsychotics are limited, butincreasing. The National Pregnancy Registry for Atypical Antipsychotics (was established to systemati-cally collect data on the maternal and fetal outcome of women who continue atyp-ical antipsychotic medication during pregnancy. Some patients who benefit fromtreatment with antipsychotics may decide with their clinician to discontinue anatypical antipsychotic or switch to a typical antipsychotic with a better-character-ized safety profile. Atypical antipsychotics are best avoided if possible, althoughthey are not absolutely contraindicated during pregnancy. Atypical antipsychoticsshould be reserved for use in more challenging clinical situations in which treat-ment with more conventional agents has not been helpful. Given the limiteddata supporting the use of typical antipsychotics as monotherapy for BPD, thatcourse of therapy should not be pursued.
Patients with a history of a single episode of mania and prompt full recovery, fol- lowed by sustained well-being, may tolerate discontinuation of a mood stabilizerbefore an attempt to Even among women with a history of prolongedwell-being and sustained euthymia, discontinuation of prophylaxis for mania may beassociated with subsequent relapse. In 1 study, the risk of recurrence of a moodepisode during pregnancy in women who discontinued their mood stabilizer duringpregnancy was For women with BPD and a history of multiple and frequent recurrences of mania or bipolar depression, several options can be considered. Some patients may choose todiscontinue a mood stabilizer before conception, as outlined earlier. An alternativestrategy for this high-risk group is to continue treatment until pregnancy is verifiedand then taper off the mood stabilizer. Because the uteroplacental circulation is notestablished until approximately 2 weeks following conception, the risk of fetal expo-sure is minimal. Home pregnancy tests are reliable and can document pregnancyas early as 10 days following conception, and with a home ovulation predictor kit,a patient may be able to time her treatment discontinuation accurately. This strategyminimizes fetal exposure to drugs and extends the protective treatment up to the timeof conception, which may be particularly prudent for older patients because the timerequired for them to conceive may be longer than for younger patients. However,a potential problem with this strategy is that it may lead to abrupt discontinuation oftreatment, thereby potentially placing the patient at increased risk for relapse. Withclose clinical follow-up, however, patients can be monitored for early signs of relapse,and medications may be reintroduced as needed. Another problem with the strategyof discontinuation of mood stabilizers emerges when the patient is being treated withvalproic acid. The teratogenic effect of valproic acid occurs early in gestation(between weeks 4 and 5), often before the patient even knows she is pregnant. Insuch a scenario, any potential teratogenic insult from valproic acid may alreadyhave occurred by the time the patient discovers the pregnancy.
For women who tolerate discontinuation of maintenance treatment, the decision of when to resume treatment is a matter for clinical judgment. Some patients and clini-cians prefer to await the initial appearance of symptoms before restarting medication;others prefer to limit their risk of a major recurrence by restarting treatment after thefirst trimester of pregnancy. Preliminary data suggest that pregnant women withBPD who remain well throughout pregnancy may have a lower risk for postpartumrelapse than those who become ill during pregnancy.
For women with particularly severe forms of BPD, such as with multiple severe episodes, and especially with psychosis and prominent thoughts of suicide, mainte-nance treatment with a mood stabilizer before and during pregnancy may be thesafest option. If the patient decides to attempt conception, accepting the small abso-lute increase in teratogenic risk with first-trimester exposure to lithium or lamotriginewith or without antipsychotic, for example, may be justified because such patientsare at highest risk for clinical deterioration if pharmacological treatment is withdrawn.
Many patients who are treated with sodium valproate or other newer anticonvulsants,such as gabapentin, for which there are particularly sparse reproductive safety data,may never have received a lithium trial before pregnancy. For such patients, a lithiumtrial before pregnancy may be a particularly reasonable option.
Even if all psychotropics have been safely discontinued, pregnancy in a woman with BPD should be considered as a high-risk pregnancy, because the risk of major psychi-atric illness during pregnancy is increased in the absence of treatment with a mood-stabilizing medication and it is even higher in the postpartum period. Extreme vigilanceis required for early detection of an impending relapse of illness, and rapid interventioncan significantly reduce morbidity and improve overall prognosis. Therefore, closemonitoring with assessment of mood, sleep, and other symptoms are urgedthroughout pregnancy and the immediate postpartum period.
POSTPARTUM MOOD AND ANXIETY DISORDERS: DIAGNOSIS AND TREATMENT The postpartum period has typically been considered a time of risk for the develop-ment of affective Although several studies have suggested that rates ofdepression during the postpartum period are equal to those in nonpuerperal controls,other research has identified subgroups of women at particular risk for postpartumworsening of mood.At highest risk are women with a history of postpartumpsychosis; up to 70% of women who have had 1 episode of puerperal psychosisexperience another episode following a subsequent pregnancy.Similarly,women with a history of postpartum depression are at significant risk, with rates ofpostpartum recurrence as high as Women with BPD also seem to be partic-ularly vulnerable during the postpartum period, with rates of postpartum relapseranging from 30% to 50%.The extent to which a history of MDD influencesthe risk for postpartum illness is less clear. However, in all women (with or withouta history of MDD) the emergence of depressive symptoms during pregnancy signifi-cantly increases the likelihood of postpartum During the postpartum period, about 85% of women experience some mood distur- bance. For most women the symptoms are mild; however, 10% to 15% of womenexperience clinically significant symptoms. Postpartum depressive disorders typicallyare divided into 3 categories: (1) postpartum blues, (2) nonpsychotic major depres-sion, and (3) puerperal psychosis. Because there may be some overlap across these3 diagnostic subtypes, it is not clear if they actually represent 3 distinct disorders. Itmay be more useful to conceptualize these subtypes as existing along a continuum,on which postpartum blues is the mildest and postpartum psychosis the most severeform of puerperal psychiatric illness.
Postpartum blues does not indicate psychopathology; it is common and occurs in approximately 50% to 85% of women following Symptoms of reactivityof mood, tearfulness, and irritability are, by definition, time limited and typically remitby the 10th postpartum day. As postpartum blues is associated with no significantimpairment of function and is time limited, no specific treatment is indicated. Symp-toms that persist beyond 2 weeks require further evaluation and may suggest an evolving depressive disorder. In women with a history of recurrent mood disorder, theblues may herald the onset of postpartum MDD.
Several studies describe a prevalence of postpartum MDD of between 10% and The signs and symptoms of postpartum depression usually appear inthe first 2 to 3 months following delivery and are indistinguishable from the character-istics of MDD that occur at other times in a woman’s life. The presenting symptomsof postpartum depression include depressed mood, irritability, and loss of interestin usual activities. Insomnia, fatigue, and loss of appetite are frequently described.
Postpartum depressive symptoms also commingle with anxiety and obsessionalsymptoms, and women may present with generalized anxiety, panic disorder, or hypo-chondriasis.Although it may sometimes be difficult to diagnose depression inthe acute puerperium given the normal occurrence of symptoms suggestive ofdepression (eg, sleep and appetite disturbance, low libido), it is an error to dismissneurovegetative symptoms (such as severe decreased energy, profound anhedonia,and guilty ruminations), as normal features of the puerperium. In its most severeform, postpartum depression may result in profound dysfunction. Risk factors forpostpartum depression include antenatal depression, antenatal anxiety, and a historyof depression.
A wealth of literature on this topic indicates that postpartum depression, especially when left untreated, may have a significant effect on the child’s well-being and devel-opment.In addition, the syndrome demands aggressive treatment to avoid thesequelae of an untreated mood disorder, such as chronic depression and recurrentdisease. Treatment should be guided by the type and severity of the symptoms andby the degree of functional impairment. However, before initiating psychiatric treat-ment, medical causes for mood disturbances (eg, thyroid dysfunction and anemia)must be excluded. Initial evaluation should include a thorough history, physicalexamination, and routine laboratory tests.
Although postpartum depression is common, few studies have systematically assessed the efficacy of nonpharmacological and pharmacological therapies in thetreatment of this disorder. Nonpharmacological therapies are useful in the treatmentof postpartum depression, and several preliminary studies have yielded encouragingresults. Appleby and colleagueshave shown in a randomized study that short-termCBT was as effective as treatment with fluoxetine in women with postpartum depres-sion. IPT has also been shown to be effective for the treatment of women with mild tomoderate postpartum depression.
These nonpharmacological interventions may be particularly attractive to those patients who are reluctant to use psychotropics (eg, women who are breastfeeding)or for patients with milder forms of depressive illness. Further investigation is requiredto determine the efficacy of these treatments in women who suffer from more severeforms of postpartum mood disturbances. Women with more severe postpartumdepression may choose to receive pharmacological treatment, either in addition toor instead of nonpharmacological therapies.
To date, only a few studies have systematically assessed the pharmacological treat- ment of postpartum depression. Conventional antidepressants (eg, fluoxetine, sertra-line, and venlafaxine) have shown efficacy in the treatment of postpartumIn all of these studies, standard antidepressant doses wereeffective and well tolerated. The choice of an antidepressant should be guided bythe patient’s prior response to antidepressants and the side-effect profile of a givenmedication. SSRIs are ideal first-line agents because some are anxiolytic, nonsedat-ing, and well tolerated; bupropion is also another good option, particularly for anergicpatients. TCAs are used frequently and, because they tend to be more sedating, may be more appropriate for women who have prominent sleep disturbances. Given theprevalence of anxiety in women with postpartum depression, adjunctive use ofa benzodiazepine (eg, clonazepam or lorazepam) may be helpful.
Some investigators have also explored the role of hormonal manipulation in women who suffer from postpartum depression. The postpartum period is associated withrapid shifts in the reproductive hormonal environment, most notably a dramaticdecrease in estrogen and progesterone levels, and postpartum mood disturbancehas not infrequently been attributed to a deficiency (or change in the levels) in thesegonadal steroids. However, clear evidence supporting this hypothesis regarding thecause of postpartum mood disorder is sparse. Although early reports suggestedthat progesterone may be no systematically derived data exist to supportits use in this setting. Two studies have described the benefit of exogenous estrogentherapy, either alone or in conjunction with an antidepressant in women with post-partum depression.Although these studies suggest a role for estrogen in thetreatment of women with postpartum depression, these treatments remain under-studied. Estrogen delivered during the acute postpartum period is not without riskand has been associated with changes in breast-milk production and more significantthromboembolic events. Antidepressants are safe, well tolerated, and highly effective;they remain the first choice for women with moderate to severe postpartum depres-sion in particular.
In cases of severe postpartum depression, inpatient hospitalization may be required, particularly for patients who are at risk for suicide. In Great Britain, innovativetreatment programs involving joint hospitalization of the mother and the baby havebeen successful; however, mother-infant units are less common in the United States.
Women with severe postpartum illness should be considered candidates for ECT. Theoption should be considered early in treatment because it is safe and highly effective.
In choosing any treatment strategy, it is important to consider the effect of prolongedhospitalization or incomplete response to treatment by the mother on infant develop-ment and attachment.
Although symptoms of postpartum panic attacks and obsessive compulsive disorder (OCD) symptoms are frequently included in the description of postpartummood disturbance, several studies support the likelihood that postpartum anxietydisorders are discrete diagnostic Several investigators have describedpostpartum worsening of panic disorder in women with pregravid histories of thisanxiety disorder but with an absence of comorbid depressive illness. PostpartumOCD has also been described in the absence of comorbid postpartum MDD. Symp-toms often include intrusive obsessional thoughts to harm the newborn in the absenceof psychosis. Treatment with antiobsessional agents, such as fluoxetine or clomipr-amine, has been Postpartum psychosis is a psychiatric emergency. The clinical picture is most frequently consistent with mania or a mixed state consistent with an episode ofand may include symptoms of restlessness, agitation, sleep disturbance, para-noia, delusions, disorganized thinking, impulsivity, and behaviors that place motherand infant at risk. The typical onset is within the first 2 weeks after delivery, and symp-toms may appear as early as the first 72 hours post partum. Although investigatorshave debated whether postpartum psychosis is a discrete diagnostic entity or a mani-festation of BPD, treatment should follow the same algorithm to treat acute manicpsychosis, including hospitalization and potential use of mood stabilizers, antipsy-chotics, benzodiazepines, and ECT.
Although it is difficult to reliably predict which women will experience a postpartum mood disturbance, it is possible to identify certain subgroups of women (ie, women with a history of mood disorder) who are more vulnerable to postpartum affectiveillness. Several investigators have explored the potential efficacy of prophylacticinterventions in these women at risk.
Several studies report that women with a history of BPD or puerperal psychosis benefit from prophylactic treatment with lithium, instituted either before delivery (at36 weeks’ gestation) or no later than the first 48 hours following delivery.Prophylactic lithium seems to significantly reduce relapse rates and diminish theseverity and duration of puerperal illness.
For women with a history of postpartum depression, Wisner and have described a beneficial effect of a prophylactic antidepressant (either a TCA or anSSRI) administered after delivery. However, a subsequent randomized, placebo-controlled study from the same group did not report a positive effect in women treatedprophylactically with nortriptyline.These investigators have suggested that nortrip-tyline may be less effective than SSRIs for the treatment of postpartum depression. Theefficacy of prophylactic treatment with SSRIs in this population is under investigation.
Postpartum depressive illness may be conceptualized along a continuum, in whichsome women are at lower risk for puerperal illness and others are at higher risk.
Although a less aggressive, wait-and-see approach is appropriate for women withno history of postpartum psychiatric illness, women with BPD or a history of post-partum psychiatric illness deserve not only close monitoring but also specific prophy-lactic measures.
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