The Management of Major Depression During Pregnancy
Jennifer L. Payne, M.D.
Dr. Payne is Associate Professor of Psychiatry and Director, Women's Mood Disorders Center, Johns Hopkins School of Medicine, Baltimore, MD.
Within the past 12 months, Dr. Payne has been a consultant to AstraZeneca and Pfizer.
Off-label uses of medications will be discussed throughout this Cyberounds.
Release Date: 07/01/2012
Termination Date: 07/01/2015
Estimated time to complete: 1 hour(s).
Albert Einstein College of Medicine designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Albert Einstein College of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
Learning ObjectivesUpon completion of this Cyberounds®, you should be able to:
The treatment of major depressive disorder (MDD) during pregnancy is complicated by the fact that few studies have been conducted on whether clinical care should differ during pregnancy or what the long-term effects may be on the developing fetus. There is a long and appropriate tradition of minimizing the use of medications during pregnancy; however, unlike many medications used for conditions such as asthma and hypertension, psychiatric medications are often considered “luxury” medications and are discontinued, at times without consulting the treating psychiatrist.
Abrupt discontinuation of psychiatric medication can result not only in withdrawal symptoms but relapse of the illness. Further, multiple studies have demonstrated that exposure to psychiatric illness in utereo results in poorer outcomes for both mother and child. This Cyberounds® will discuss the clinical approach to treating major depression during pregnancy and breastfeeding.
How Common Are Mood Disorders During Pregnancy?
Pregnancy was, at one time, considered to be protective against relapse in mood disorders.(1)(2) Further research has shown, however, that pregnancy is not protective but is rather risk-neutral for the development of mood episodes. For example, a recent study conducted as part of the 2002 National Epidemiologic Survey on Alcohol and Related Conditions interviewed 14,549 women with a known past-year pregnancy status and compared rates of major psychiatric illness during pregnancy, postpartum and in the non-pregnant female population.(3) No increase in risk for major depression was found during pregnancy as compared to the non-pregnant population.(3)
Many women experience relapse during pregnancy — both on and off medication.
In the bipolar population, Viguera and colleagues retrospectively compared the risks of recurrence in pregnant and non-pregnant women when tapered off lithium.(4) They found no difference in the risks of recurrence between pregnant and non-pregnant women over the same time period, with rates of 52% in pregnant women and 58% in non-pregnant women, thus demonstrating that pregnancy does not appear to increase the risk of relapse.
Even if pregnancy is risk neutral for recurrence of mood disorders, it is not risk free. Many women experience relapse during pregnancy — both on and off medication. In one study, approximately 50% of women with either major depression or bipolar disorder reported significant mood symptoms during, after or both during and after pregnancy.(5)
In contrast, the risk for relapse during pregnancy increases in both patients with major depression and bipolar disorder in the setting of discontinuation of medications. For example, Cohen and colleagues demonstrated a 68% relapse rate in women with major depression who discontinue their medications during the first trimester.(6) In women with bipolar disorder, Viguera reported that in pregnant women who discontinued mood stabilizer there was a recurrence risk of 81-85.5%, while women who continued mood stabilizer treatment had a much lower risk (29-37%).(4)(7) The recurrence risk in a recent study comparing discontinuation of any mood stabilizer to lamotrigine was 100% in the group of women who discontinued medications.(8) The finding that at least 80% of women with bipolar disorder and 60% of women with major depression will relapse when taken off medication suggests that treatment during pregnancy for many patients is necessary in order to prevent recurrence.
Mood Disorder as an Exposure for the Baby
There is evidence in the literature that exposure to mood disorders in utero increases the risk of poor outcomes for the baby. Depression during pregnancy has been associated with low maternal weight gain, increased rates of preterm birth,(9)(10) low birth weight, increased rates of cigarette, alcohol and other substance use,(11) increased ambivalence about the pregnancy and overall worse health status.(12)
Untreated depression during pregnancy is also one of the strongest risk factors for the development of postpartum depression.
Additionally, prenatal exposure to maternal stress has been shown to have consequences for the development of infant temperament.(13) Children exposed to perinatal (either during pregnancy or postpartum) maternal depression have higher cortisol levels than infants of mothers who were not depressed(14)(15)(16)(17) and this finding continues through adolescence.(17) Importantly, treatment of depression during pregnancy appears to help normalize infant cortisol levels.(18) These findings may partially explain the mechanism for an increased vulnerability to psychopathology in children exposed to depression in utero.(19)
Untreated depression during pregnancy is also one of the strongest risk factors for the development of postpartum depression. One should note that postpartum depression has potentially devastating consequences including suicide and infanticide. While the risk for completed suicides and suicide 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.(20)
Postpartum depression is also associated with worse parenting behavior, including decreased rates of infant safety and healthy child development practices,(21) as well as increased use of harsh discipline practices.(22) Impaired bonding during this critical time has been linked to attachment insecurity in the child. Likely due to changes in parenting behavior, exposure to postpartum depression is associated with slower language development, more behavioral problems and lower IQ in the child.(23)
Clinical Care of Women with Mood Disorders During Pregnancy
The patient’s past psychiatric history, severity of symptoms and medication response history all play a significant role in designing a course of clinical care during pregnancy. For example, while fluoxetine and sertraline are considered appropriate antidepressant choices during pregnancy, if a woman has a history of not responding to either of these medications they cannot be part of the treatment plan. Severity of illness is important to take into account: a case in which the symptoms of depression were mild, responded well to medication and did not recur could be considered for discontinuation of the medication prior to pregnancy. In contrast, a case in which depression was severe, dangerous and required hospitalization several times would not be a candidate for medication discontinuation. Similarly, a woman’s reproductive age should play a role in deciding when and if to attempt to change medications prior to pregnancy: an older woman may not have the reproductive time to experiment with a different medication prior to pregnancy.
At the same time, the patient and her partner’s wishes regarding medication use during pregnancy should be taken into account when designing a treatment plan. If one or the other is strongly against medication use during pregnancy, it is best for the treatment provider to make sure they understand the risks of no treatment to both the mother and the baby, the rates of relapse, and to outline a course of close follow-up during and after pregnancy rather than insist on the use of medication during pregnancy. A partnership with good communication with the patient and her partner is important to maintain, so that if there is a relapse of illness the patient will remain safe and is more likely to seek care and treatment.
While each case should be considered individually there are some “rules of thumb” that can be used to design a treatment strategy:
Use medications that we know something about: older is usually better.
Common side effect for many psychiatric medications is sedation — baby should be monitored for excessive sleepiness.
General Recommendations for Breastfeeding
The benefits of breastfeeding for the baby are well documented. Currently, the American Academy of Pediatrics advocates breastfeeding through the first six months of life. Most psychotropic medications pass readily into breast milk. As noted above, it often does not make sense to switch a medication, to which the infant was exposed in utero, so the mother can more safely breastfeed. Exceptions to this include: 1) the mother’s psychiatric illness has relapsed and the current medication regimen is not working; 2) the mother is on a medication that has a risk of severe side effects with continued exposure for the infant (for example, clozaril); 3) the infant appears to be having side effects or medical complications related to the medication exposure during breastfeeding.
If the medication regimen needs to be changed during breastfeeding, the patient, her family and her doctors should consider whether continued breastfeeding is worth the risks of increasing exposures to medications for the infant. Examples of when the risk may be greater than the benefit of continued breastfeeding include: 1) exposure to a new class of medications (for example, going from an exposure to an antidepressant in utero to a mood stabilizer with breastfeeding); 2) exposure to several new medications while breastfeeding; 3) the addition of a medication that may require blood draws for monitoring in the infant. Again, there are no definite rules — each patient and their infant will have unique circumstances and feelings that will need to be considered.
As noted, it is important to involve the pediatrician in the decision-making process and to ask him or her to help monitor the baby for potential side effects. If the baby is being exposed to a medication that can be monitored via blood levels, then a plan should be worked out for ordering appropriate blood work and checking blood levels in the baby. A common side effect for many psychiatric medications is sedation and the baby should be monitored for excessive sleepiness and decreased feeding, particularly during the feeding after the mother takes the medication. Many babies are fussy, colicky or have feeding difficulties without exposure to medications during breastfeeding, so it can be difficult to distinguish what is secondary to medication side effects and what is simply a fussy baby. When in doubt the wisest choice is to do what makes the mother the most comfortable.
General recommendations for minimizing exposure to medications during breastfeeding include: 1) If possible take medication in one dose, at the same time; 2) Take the medication after the baby has been fed and just before the longest time the baby sleeps; 3) “Pump and dump” for the next feeding and use either stored breast milk or formula for that feeding; 4) Resume breastfeeding for the next meal. While there is little research in this area, common sense dictates that these rules may not always need to be followed strictly for medications that do not, to date, appear to have a high risk of side effects in infants (for example, SSRI antidepressants) and should be more strongly recommended when medications have a higher risk of toxicity for the young infant (for example, lithium). It is good practice to discuss these guidelines with the mother, as many women find it comforting that they can actively do something to minimize exposure for their child.
Take the medication after the baby has been fed.
Choosing Medications During Pregnancy
Prescription drug use during pregnancy is common. Between 1996 and 2000, 64% of all women who delivered a child had a drug other than a vitamin or mineral supplement prescribed in the 270 days before delivery, 97% of which were not FDA Pregnancy Category A (i.e., “safest”).(25) The choice of whether or not to prescribe a medication during pregnancy is challenging and prescribing should take into account not only the potential risks and benefits for the unborn infant but also for the mother.
There are a number of reasons why the use of psychiatric medications during pregnancy is controversial. First, psychiatric medications are often considered “luxury” medications, i.e., ones that can and should be stopped during pregnancy, in the same category as ibuprofen or sleep aids. This belief stems from both a common misperception of psychiatric illnesses as different from, and not as serious as, medical illnesses, as well as from the fact that psychiatric diagnoses are made on the basis of clinical history and not via a lab test or physical findings.
Since 1979, the Federal Drug Administration (FDA) has required that pharmaceutical product information include information about safety during pregnancy.(26) Products are classified under one of five letter categories, largely based, until recently, upon animal studies. The categories are, however, confusing and imply an increasing level of risk from category A to category X, which is not, in fact, the case. For example, oral contraceptives are in category X simply because there is no reason to use them in pregnancy, not because there is evidence of birth defects if they are used during pregnancy.
The level of investigation used to categorize individual medications varies from medication to medication, as does the level of risk actually imposed by a particular drug. Medications may be placed in the same category and have vastly different levels of risk and/or different levels of evidence supporting their categorization. The FDA Pregnancy Categories can therefore provide a “quick and dirty” assessment but may not provide information that is useful in planning clinical care.
Antidepressants and Pregnancy and Lactation
Overall there does not appear to be an increased risk of major malformations with exposure to antidepressants in utero, though for many agents there are few or no data available. The one exception is paroxetine which has been associated with a small increased risk of cardiac defects (2 out of 1000) with first trimester exposure and should, therefore, be used only if there are no other choices for that particular patient.(27)(28)
In general, many practitioners will prescribe SSRI medications during pregnancy for major depression since they are well tolerated. Of the SSRI medications, both fluoxetine and sertraline have more data regarding safety than the newer SSRIs such as escitalopram. The older tricyclic antidepressants should also be considered for use during pregnancy, though their common side effects, particularly constipation and orthostatic hypotension, may be exacerbated by pregnancy.(10)
Most antidepressants appear to be relatively safe during breastfeeding.
Despite limited data on the use of serotonin-norepinephrine reuptake inhibitors (SNRIs), bupropion, mitazapine and monoamine oxidase inhibitors, any of these agents may be appropriate in a particular patient. Einarson et al. reported there was no increased risk of major malformations in infants exposed to venlafaxine in utero in a multicenter prospective study of pregnant women taking venlafaxine.(29) Similarly, Cole et al. reported that there did not seem to be an increased risk of malformations for infants exposed to bupropion in utero(30) and one study indicated that it could be helpful for pregnant women who are trying to quit smoking.(31) Finally, Djulus et al. conducted a prospective study investigating the teratogenic effects of mirtazepine and found no increase in major fetal malformations in a group of 104 pregnant women.(32)
Most antidepressants appear to be relatively safe during breastfeeding. SSRIs are generally well tolerated. Fluoxetine has the longest history of use during lactation, but also has a long half-life, which can in theory lead to higher levels, even toxicity, in the young infant.(33) Similarly, citalopram has a high milk/plasma concentration and therefore a higher risk of toxicity.(33) Therefore, these agents should be used with caution and only if used successfully during pregnancy or previously in a particular patient.(33) Tricyclic antidepressants also have a well established history of use during lactation. Serum levels should be followed and the baby monitored for side effects including sedation and constipation. Again, similar to the literature on exposure during pregnancy, there are little data on SNRIs, bupropion, mitazapine and monoamine oxidase inhibitors. The available data are generally reassuring despite one case report of a seizure in an infant exposed to buproprion.(34)
Potential Risks to the Fetus Associated with Antidepressant Use During Pregnancy
Persistent Pulmonary Hypertension (PPHN)
To date, there have been six studies on the association between SSRIs and PPHN in the newborn with conflicting results. The first was published in 2006(39) and is the basis for the FDA Alert issued in July 2006 regarding the possible association of PPHN with SSRI antidepressants. This case-control study compared 377 women who had infants diagnosed with PPHN to 836 matched control women with infants not diagnosed with PPHN. Fourteen of the infants with PPHN had been exposed to a SSRI after the 20th week of gestation; in contrast, six infants of those who did not have PPHN were exposed to SSRI medications.(39) This generated an adjusted (for maternal diabetes, race, body-mass index) odds ratio of 6.1.
A second study, conducted through the Swedish Medical Birth Register for the years 1997-2005, examined the medical records of 831,324 women who had given birth during this period.(40) Antidepressant use was identified at the first antenatal care visit (usually first trimester) and through prescriptions written by the antenatal health service. This method did not include prescriptions written by other physicians such as psychiatrists, and thus information on antidepressant use late in pregnancy was incomplete. Of 506 infants with PPHN, 11 had been exposed early in pregnancy to an SSRI, which generated a relative risk estimate of 2.01 (CI 1.00-3.60). When only those cases with a known exposure late in pregnancy and born at or after 37 weeks were included, the relative risk rose to 3.70 (CI 1.01-9.48).(40)
A third study used data from the HMO Research Network Center for Education and Research on Therapeutics from 1996-2000.(41) Infants exposed to SSRIs (n=1104) during the third trimester were compared to a matched sample of 1104 infants not exposed to SSRIs. Five infants, two from the exposed group and three from the non-exposed group, were identified with PPHN. There was no difference in prevalence rates between the two groups.(25)
Wichman et al.(41) conducted a retrospective review of the medical records of all pregnant women presenting to the Rochester, MN Mayo Clinic site from 1993-2005. They identified ~25,000 deliveries and found that 808 women had been treated with SSRIs at some point in their pregnancy. Of the 16 infants who developed persistent pulmonary hypertension, none had an exposure to SSRIs. Wilson et al.(42) performed a case-controlled study with a 1:6 ratio of infants delivered at Madigan Army Medical Center with persistent pulmonary hypertension from 2003-2009. Twenty cases were identified, none of whom had been exposed to SSRIs. Finally, in the largest study to date, Kieler et al.(43) examined prospectively-collected data from the national health registers in Denmark, Finland, Iceland, Norway and Sweden from 1996-2007. The researchers found 1935 cases of persistent pulmonary hypertension in the non-exposed group (out of 1.5 million infants), 32 cases out of 17,053 infants exposed to SSRIs early in pregnancy (odds ratio of 1.4) and 33 cases out of 11,014 infants exposed to SSRIs late in pregnancy (odds ratio of 2.1).
PPHN is an extremely rare condition.
One issue that complicates interpretation of these studies is that several factors associated with the development of PPHN in the general population, including maternal smoking, maternal diabetes and high pre-pregnancy BMI, are also associated with MDD and psychiatric disorders in general. Future prospective studies that control for such factors are needed in order to fully elucidate the association between SSRIs and the development of PPHN in the newborn.
It is also important to keep the potential elevated risk in perspective by considering the absolute risk. PPHN is an extremely rare condition, occurring in 1-2 infants out of 1000 in the general population.(36)(37) If one assumes that SSRIs increase the odds of the development of PPHN by six times the rate in the general population, only 6-12 (0.6-1.2%) infants exposed to SSRIs will develop PPHN out of 1000 exposed. Thus, approximately 99% of women who take SSRIs during pregnancy will give birth to a healthy infant who does not develop PPHN. In contrast, the risks associated with untreated depression during pregnancy are much higher and more common.
Poor Neonatal Adaptation Syndrome.
Regardless, the FDA instituted a class labeling change in 2004 for both SSRI and SNRI antidepressants, warning that third trimester exposure to these antidepressants may be associated with signs and symptoms consistent with the syndrome. According to the label change, “reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying.”
As a consequence of the FDA action, many practitioners have recommended tapering antidepressants prior to labor and delivery even though it remains unclear if tapering decreases the risk for the syndrome and increases the risk for postpartum depression. It should be noted that most cases of the neonatal syndrome appear to be very mild, self-limited and do not appear to be associated with lasting repercussions.(45)
Other confounding factors and unanswered questions further complicate the decision to continue or taper antidepressants including: 1) what effect breastfeeding may have on the risk for the neonatal syndrome? 2) what is the contribution of maternal psychiatric illness? and 3) what is the use of multiple psychotropic agents during pregnancy?(45) Available data suggest that approximately one-third of exposed infants will have at least mild symptoms consistent with the syndrome and that this risk increases when multiple agents, particularly benzodiazepines, are used.(46) Larger more rigorous studies of the syndrome, as well as strategies to minimize its rate, are needed because, at this time, there is not enough evidence from a safety perspective to recommend tapering of antidepressants in the third trimester, particularly in cases of moderate to severe maternal mental illness.
Psychotherapy and Pregnancy
Psychotherapy for patients with psychiatric illness who are also pregnant is an important part of any treatment plan. Supportive therapy that addresses such issues as coping skills, stress reduction, conflicts regarding becoming a parent and improving relationship skills can all be an important part of providing good care to the pregnant psychiatric patient. From a practical perspective, pregnancy is probably not the time to treat deep-seated psychological issues, as the treatment provider’s goal should be to minimize stress and the triggering of anxiety or depressive symptoms.
Depression, anxiety and other psychiatric disorders respond to various forms of psychotherapy during pregnancy in the same way that they respond at other times of a woman’s life, though little work in this area has been completed. A Cochrane review of psychotherapeutic interventions for the treatment of depression during pregnancy found only one randomized controlled trial in interpersonal therapy, which did reduce depressive symptoms in pregnant women but concluded that there was not enough rigorous work in this area.(47) There has been one trial of interpersonal therapy in pregnant women(48) but in general there is currently a lack of large randomized controlled trials of cognitive behavioral therapy and interpersonal therapy for the treatment of MDD during pregnancy.(47) Despite this lack of data these approaches should be considered either as adjunctive care to medication use or instead of medication use for pregnant women with MDD who wish to discontinue medications during pregnancy. Future work should better define the use of these modalities in pregnant women with MDD.
Give the fact that Ms. Candice has a history of recurrent depression and that her last episode of depression was severe, Ms. Candice is at high risk of recurrence if her antidepressant medication is discontinued. However, though there is currently no evidence that escitalopram is associated with teratogenic changes in an exposed infant, it is a newer antidepressant and less information is therefore available. Since Ms. Candice has not been treated with other antidepressants in the past (and therefore has not failed other medications), one option would be to change her antidepressant to a medication with which we have a longer experience such as sertraline or fluoxetine.
If Ms. Candice remains stable, ideally for at least three months, she could then proceed with pregnancy. The treatment provider should explain the risks and benefits of treatment during pregnancy, as well as the risks of no treatment. The provider should discuss the option of switching medications, as well as the potential risks associated with switching including relapse and delay of pregnancy. Ultimately the decisions whether or not to switch and whether to use medication during pregnancy should be made by Ms. Candice and her husband, as they will need to be satisfied that they made the correct decision for their family.
In this version, the clinical history is the same but the patient has become pregnant prior to planning medication changes. Should the treatment provider suggest a change in medication to an older and more established antidepressant? The short answer is “no” because the goal is to limit the number of exposures for the baby. Since the baby has already been exposed to the escitalopram it does not make sense to expose the baby to another, different antidepressant unless Ms. Candice were to relapse while taking the escitalopram. The treatment provider should review the risks and benefits of taking medication versus the risks of untreated mood disorder during pregnancy and provide reassurance to the patient. The treatment provider should also discuss the treatment plan with the family and other treatment providers involved with the case.
Since there is no clear history of major depressive episodes and the fluoxetine was originally prescribed for premenstrual symptoms, it is appropriate in this case to suggest tapering off the fluoxetine. Before attempting to get pregnant, the patient should wait for at least three months after ending fluoxetine to make sure that she is psychiatrically stable.
Many women with MDD will need medication management during pregnancy due to the severity of their illness, the high rate of relapse in women who stop their medications, and the poor outcomes associated with untreated MDD during pregnancy to both the mother and the child. A thoughtful approach, weighing both the risks and the benefits of medication use, as well as the potential risks of untreated illness, should be undertaken, ideally prior to pregnancy.
The goal of psychiatric management during pregnancy should be to limit the number of exposures to the baby, including exposure to psychiatric illness. As a class, antidepressant medications are generally not associated with major organ malformations, with the exception of paroxetine, and older medications that we know more about from the literature are preferred to newer ones. SSRIs have been associated with two potential syndromes: persistent pulmonary hypertension and poor neonatal adaption syndrome.
While studies are conflicting regarding persistent pulmonary hypertension, the relative risk is less than 1% of those exposed. Approximately 30% of infants exposed to SSRI medications during the third trimester will develop poor neonatal adaptation syndrome, most with mild symptoms. The long-term sequelae of this syndrome remains unclear and much work needs to be done to better define this syndrome and the clinical practices that can be used to minimize its occurrence.
Overall, the literature to date is relatively reassuring regarding the use of antidepressants for significant psychiatric illness during pregnancy, though every case should be considered individually and the risks and benefits fully explored with each patient.
Future directions of research should include: examination of whether tapering SSRIs during the third trimester minimizes the risk of poor neonatal adaptation syndrome; exploration of clinical interventions, including specific psychotherapies that decrease the rate of relapse in women who discontinue their medications for pregnancy; and a fuller understanding of the association between psychiatric illness during pregnancy and poor outcomes for the child.