Depression and Pregnancy

The treatment of major depressive disorder (MDD) during pregnancy is not straightforward. It’s complicated by the fact that not many studies have looked at whether treatment should differ during pregnancy, or what the long-term effects may be on the developing fetus. There is a long (and perhaps appropriate) tradition of minimizing the use of medications during pregnancy. Unlike many medications used for conditions such as asthma and blood pressure, psychiatric medications are often considered “luxury” medications and are discontinued, at times without consulting the treating psychiatrist.

Treating major depression during pregnancy can make a difference to the health of both the mother and the child. Finding the best way to do it is not always simple.

But is it a good idea to discontinue medications during pregnancy? It’s a complicated question, and the answer may surprise you. Here is a case study that illustrates the dilemma; we’ll introduce other patients into the discussion later on.

There are some serious drawbacks of stopping antidepressants during pregnancy: Abrupt discontinuation of psychiatric medication can result not only in withdrawal symptoms but relapse of the illness. On the other hand, multiple studies have demonstrated that when a fetus is exposed in utereo to psychiatric illnesses such as depression, this can result in poorer outcomes for both mother and child, and these can be long term.

As a result, treating major depression during pregnancy can make a difference to the health of both the mother and the child. Finding the best way to do it is not always simple, which is why it’s essential to work with your mental health care provider to figure out the best route to take.

Pregnancy was, at one time, considered to be protective against relapse in mood disorders, but now we know that it doesn’t seem to have much effect either way. For example, a recent study compared rates of major psychiatric illness during pregnancy, postpartum, and in non-pregnant women. No increase in risk for major depression was found during pregnancy as compared to the non-pregnant population.

When medications are discontinued, the risk for relapse during pregnancy increases in patients with major depression or bipolar disorder.

In contrast, when medications are discontinued, the risk for relapse during pregnancy increases in patients with major depression or bipolar disorder. Some studies have found a 68% relapse rate for women who stop medications in their first trimester. In women with bipolar disorder, the risk is even higher when mood stabilizers are discontinued (81-85.5%), compared to women who continued their medications (29-37%). 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 really is crucial in order to prevent recurrence.

One reason it’s so important to treat mood disorders in utero is that these disorders can increase the risk of poor outcomes for the baby. Depression during pregnancy has been associated with low maternal weight gain, increased rates of preterm birth, low birth weight, increased rates of cigarette, alcohol and other substance use, increased ambivalence about the pregnancy, and overall worse health status.

Additionally, prenatal exposure to maternal stress has been shown to have consequences for the development of infant temperament. For example, children exposed to perinatal (that is, during pregnancy or postpartum) maternal depression have higher levels of the stress hormone cortisol than infants of mothers who were not depressed and this link continues through adolescence. Importantly, treatment of depression during pregnancy appears to help normalize infant cortisol levels. These findings may partially explain the mechanism for an increased likelihood for psychological problems in children exposed to depression in utero.

Postpartum depression is also associated with worse parenting behavior, including decreased rates of infant safety and healthy child development practices, as well as increased use of harsh discipline practices.

Postpartum depression is also associated with worse parenting behavior, including decreased rates of infant safety and healthy child development practices, as well as increased use of harsh discipline practices. It may also lead to problems with mother-infant bonding during this critical time, and has been linked to the development of an insecure (unhealthy) attachment between the mother and child. Exposure to postpartum depression is associated with slower language development, more behavioral problems and lower IQ in the child, which is likely the result of changes in parenting behavior in the mother. All this is to say that while there may be risks associated with medications during pregnancy, there are also risks associated with not treating depression, which can affect both mother and child.

There are many issues to take into account and to discuss with your doctor when deciding on the best treatment plan. Your psychiatric history, the severity of your symptoms and your response to medications in the past all play a significant role in designing a course of clinical care during pregnancy. For example, while fluoxetine (Prozac) and sertraline (Zoloft) are considered appropriate antidepressant choices during pregnancy. If you have a history of not responding to either of these medications, they cannot be part of the treatment plan. Severity of illness is also important to take into account:

If symptoms of depression are mild, and they responded well to medication and did not recur, discontinuation of the medication prior to pregnancy can be considered. In contrast, if your depression is severe, dangerous and required hospitalization several times, discontinuation of medication would not be suggested. Similarly, a woman’s reproductive age should play a role in deciding when and if to attempt to change medications prior to pregnancy: For example, an older woman may not have the reproductive time to experiment with a different medication prior to pregnancy.

Your psychiatric history, the severity of your symptoms and your response to medications in the past all play a significant role in designing a course of clinical care during pregnancy.

At the same time, your wishes, along with your partner’s, 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 important for your treatment provider to make sure he or she understands the risks of no treatment to both you and the baby, the possibility 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. Good communication with your doctor should be ongoing, so that if there is a relapse of illness you will remain safe and be sure to seek care and treatment.

While each case should be considered individually, there are some “rules of thumb” that you and your doctor follow to design the best treatment strategy:

1. All medication changes should be done prior to pregnancy if possible. This minimizes the number of exposures to the baby and promotes mood stability for the mother.
2. Ideally, the mother-to-be should be stable psychiatrically for at least three months before attempting pregnancy. This is not always practical but should provide some evidence and reassurance that the mood of the mother-to-be is stable before entering pregnancy.
3. Use medications that we know something about: older is usually better. The longer a medication has been available in the marketplace, the more likely there will be evidence of any links with major developmental problems in the fetus.
4. Use medications that have been tried in larger, non-psychiatric populations. Anti-seizure medications, which are sometimes used to treat bipolar disorder, have been tested in the larger population of women with seizure disorders. While many anti-seizure medications do have negative effects on fetal development, some (e.g., gabapentin and lamotrigine) have psychiatric indications and have been shown to be safer during pregnancy.

Make sure both your Ob-Gyn and your pediatrician are in communication with each other will minimize differences of opinion and maximize treatment outcomes for you and your baby.e

5. Minimize the number of medication exposures for the baby. Try to minimize the number of medications used but keep this in mind: Exposure to psychiatric illness is also a type of exposure. Changing medications for breastfeeding increases the number of exposures. One common scenario is for a woman on a newer antidepressant who becomes pregnant to receive the recommendation to switch antidepressants to an older medication that has more evidence for safety during pregnancy. While this might have made sense prior to pregnancy, this plan would actually increase the exposures for the baby significantly. Because the baby has already been exposed to the newer antidepressant, switching to a second medication would be another exposure. In addition, the likelihood that the patient would relapse while switching is high, thus exposure to the mood disorder would be considered a third exposure for the child.
6. Consider breastfeeding when planning for pregnancy. Consider whether the medication should be used during breastfeeding and what the plan would be for monitoring the medication during breastfeeding.
7. If a baby was exposed to a medication during pregnancy, it may not make sense to discontinue the medication prior to breastfeeding (or alternatively not breastfeed). Although the baby experienced a larger concentration of the drug in utero compared to the concentration in breast milk, there are certain medications for which it might be more difficult to justify the continued exposure during breastfeeding. Overall, breastfeeding is quite beneficial, so discouraging a mother from breastfeeding an infant already exposed to a medication in utero rarely makes sense. There are obvious exceptions: when the mother does not feel comfortable breastfeeding while taking a medication or if the baby appears to be having side effects (for example, sedation) from the medication.
8. Use a team approach. This rule applies to two groups, both family and doctors involved in the patient’s care. Becoming educated regarding the risk-benefits of treatment versus no treatment, as well as signs and symptoms of relapse, is essential to good care for both mother and child. Make sure both your Ob-Gyn and your pediatrician are in communication with each other will minimize differences of opinion and maximize treatment outcomes for you and your baby.

The benefits of breastfeeding for the baby are well documented. The American Academy of Pediatrics currently recommends breastfeeding through the first six months of life. However, since most psychotropic medications pass readily into breast milk, it is important to be aware of the potential effects on your baby. As noted above, it often does not make sense to switch the medication to which the infant was exposed in utero so the mother can more safely breastfeed. But there are some exceptions to this rule: 1) if the mother’s depression or other psychiatric illness has relapsed and the current medication regimen is not working; 2) if the mother is on a medication that has a risk of severe side effects with continued exposure for the infant; 3) if the baby appears to be having side effects or medical complications related to the medication exposure during breastfeeding.

A common side effect for many psychiatric medications is sedation, so the baby should be monitored for excessive sleepiness and decreased feeding, particularly during the feeding after the mother takes the medication.

If the medication regimen needs to be changed during breastfeeding, the mother, 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:

• Switching to a new class of medications (for example, going from an exposure to an antidepressant in utero to a mood stabilizer while breastfeeding)
• Exposure to several new medications while breastfeeding
• There has been an addition of a medication that may require blood tests to monitor the effect in the infant.

Again, there are no definite rules — each mother and her baby will have unique circumstances and feelings that will need to be considered.

As noted, it is important to involve your 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 through blood tests, 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, so 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 best choice is to do what makes the mother the most comfortable.

Here are our recommendations for minimizing exposure to medications during breastfeeding:

• If possible, take the medication in one dose, at the same time of day.
• Take the medication after the baby has been fed and just before the longest time the baby sleeps.
• “Pump and dump” for the next feeding and use either stored breast milk or formula for that feeding.
• Resume breastfeeding for the next meal.

While there is not much research in this area, common sense suggests 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). Always discuss the guidelines with your doctor, as it may put your mind at ease to know that you can actively do something to minimize exposure for your child.

Prescription drug use during pregnancy is common. One study found that about 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, and most of these (97%) were not in the FDA Pregnancy Category A (i.e., “safest”). A doctor’s choice of whether or not to prescribe a medication during pregnancy is challenging, but he or she should take into account not only the potential risks and benefits for the unborn infant but also for the mother.

When in doubt, the best choice is to do what makes the mother the most comfortable.

The amount of study needed to categorize each medication varies from medication to medication, as does the level of risk actually imposed by a particular drug. Therefore, medications in the same category may 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 the best information regarding clinical care.

Overall there does not appear to be an increased risk of major malformations of the fetus with exposure to antidepressants in utero, though not all drugs have data available. The one exception is paroxetine (Paxil) which has been associated with a small increased risk of cardiac defects (2 out of 1000) with exposure during the first trimester, and should, therefore, be used only if there are no other choices for that particular patient.

In general, many doctors prescribe SSRI medications for major depression during pregnancy since they are well tolerated. Of the SSRI medications, both fluoxetine (Prozac) and sertraline (Zoloft) have more data regarding safety than the newer SSRIs such as escitalopram (Lexapro). The older tricyclic antidepressants should also be considered for use during pregnancy, though their common side effects, particularly constipation and low blood pressure or faintness upon standing (orthostatic hypotension), may be exacerbated by pregnancy.

Although there are less data on the use of serotonin-norepinephrine reuptake inhibitors (SNRIs), bupropion (Welbutrin), mitazapine (Remeron) and monoamine oxidase inhibitors (MAOIs), any of these agents may be appropriate in a particular patient. One study reported there was no increased risk of major malformations in infants exposed to venlafaxine (Effexor) in utero. Similarly, there does not seem to be an increased risk of malformations for infants exposed to bupropion in utero, and one study indicated that it could be helpful for pregnant women who are trying to quit smoking. Finally, another study reported that there did not seem to be an increased risk for developmental problems when the mothers were taking mirtazepine.

Most antidepressants appear to be relatively safe during breastfeeding, and again, SSRIs are generally well tolerated. Fluoxetine (Prozac) has the longest history of use during lactation, but also has a long half-life (meaning it stays in the system longer), which can in theory lead to higher levels, even toxicity, in the young infant. Similarly, citalopram (Celexa) is found in the breast milk in higher concentrations and therefore has a higher risk of toxicity. Therefore, it’s important to be cautious about these medications, and discuss with your doctor about whether it is advised to continue using them during pregnancy.

Tricyclic antidepressants also have a well-established history of use during lactation. Blood levels may be tracked in the mother and the baby, and the baby should be 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 MAOIs, but what does exist is generally reassuring (despite one case report of a seizure in an infant exposed to buproprion).

Even if we assume that SSRIs increase the odds of PPHN by six times (compared to women who do not take SSRIs while pregnant), still only 6-12 infants out of 1000 (or 0.6-1.2%) will develop PPHN.

Studies on the association between SSRIs and PPHN in the newborn have led to mixed results.

Some have found a slightly higher risk of PPHN for the infants of mothers who took SSRIs while pregnant, while other studies have not found such a link. One issue that complicates the picture 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 major depression and psychiatric disorders in general. Future studies that take these factors into consideration are needed in order to fully understand the connection between SSRIs and the development of PPHN in the newborn.

It is also important to keep the in mind the rarity of PPHN overall. The condition only occurs in 1-2 infants out of 1000 in the general population. Even if we assume that SSRIs increase the odds of PPHN by six times (compared to women who do not take SSRIs while pregnant), still only 6-12 infants out of 1000 (or 0.6-1.2%) will develop PPHN. In other words, 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.

Despite the limitations in the available literature in this area., 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.

As a result of the FDA action, many doctors have recommended tapering antidepressants off prior to labor and delivery, even though it is unclear if tapering decreases the risk for the syndrome and whether it might increase the risk for postpartum depression. It should be noted that most cases of the neonatal syndrome appear to be very mild and go away by themselves, ,and they do not appear to be associated with any lasting effects.(45)

Pregnancy is probably not the time to deal with deep-seated psychological issues, as the general goal at that time should be to minimize stress and the triggering of anxiety or depressive symptoms.

There are other questions that complicate the decision as to whether to continue or taper antidepressants, including: 1) What effect does breastfeeding have on the risk for the neonatal syndrome? 2) What is the contribution of maternal psychiatric illness? and 3) What is the value of multiple psychotropic agents during pregnancy?

Some studies suggest that approximately one-third of exposed infants will have at least mild symptoms of the syndrome and that the risk increases when multiple medications, particularly benzodiazepines, are used. Still, we need larger studies on neonatal withdrawal syndrome along with ways to minimize its likelihood, as there isn’t currently enough information to recommend tapering of antidepressants in the third trimester, particularly in cases of moderate to severe maternal depression.

Psychotherapy – for instance, talk therapy or cognitive behavior therapy – for pregnant women is an important part of any treatment plan for depression or other psychiatric illness. Supportive therapy that focuses on coping skills, stress reduction, conflicts about becoming a parent, and improving relationship skills can all be important parts of treatment. That said, pregnancy is probably not the time to deal with deep-seated psychological issues, as the general goal at that time should be to minimize stress and the triggering of anxiety or depressive symptoms.

Depression, anxiety and other psychiatric disorders likely respond to psychotherapy during pregnancy in the same way that they respond at other times of a woman’s life. although there is not a huge amount of data showing “proof” that talk therapy works for pregnant women. Still, psychotherapy is often beneficial to patients, and should be considered either as either alongside medication, or instead of it, for pregnant women with major depression who wish to discontinue medications during pregnancy.

Given the fact that Roberta has a history of recurrent depression and that her last episode of depression was severe, she is at high risk of recurrence if her antidepressant medication is discontinued. However, though there is currently no evidence that escitalopram is associated with developmental problems in an exposed infant, it is a newer antidepressant and less information is available about its safety. Since Roberta has not been treated with other antidepressants in the past, one option would be to change her antidepressant to a medication with which we have a longer experience such as sertraline (Zoloft) or fluoxetine (Prozac).

If Roberta remains stable on the new medication, ideally for at least three months, she could then proceed with pregnancy. We discuss with her the risks and benefits of treatment during pregnancy, the risks of no treatment, the option of switching medications, and 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 has to be made by Roberta and her husband, as they will need to be satisfied that they made the right decision for their family.

Since there is no clear history of major depressive episodes for Brenda, and the fluoxetine was originally prescribed for premenstrual symptoms, we suggest tapering off the fluoxetine. Before trying to get pregnant, Brenda should wait for at least three months after ending fluoxetine to make sure that she is stable and does not have any new symptoms of depression.

Many women with major depression need medication management during pregnancy due to the severity of their illness, the high rate of relapse when medications are stopped, and the poor outcomes associated with untreated major depression during pregnancy to both the mother and her child. It is important to be aware, ideally before pregnancy, of both the risks and the benefits of medication use, as well as the potential risks of untreated illness.

The goal of psychiatric management during pregnancy should be to limit the number of exposures to the baby, and it’s important to remember that psychiatric illness is also considered an exposure. As a class, antidepressant medications are generally not associated with major organ malformations, with the exception of paroxetine (Paxil), 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 (PPHN) and poor neonatal adaption syndrome. While studies are conflicting regarding PPHN, the relative risk is less than 1% of those exposed to antidepressants. 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 consequences of this syndrome remain unclear and much more work needs to be done to better understand this syndrome and what can be done to minimize its occurrence.

Overall, the evidence is relatively reassuring regarding the use of antidepressants for major depression during pregnancy, though every case should be considered individually and the risks and benefits fully explored with your doctor.