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Using Antidepressants During Pregnancy


Using Antidepressants During Pregnancy

Depression is particularly common among women and it is one of the most encountered conditions in primary care. Depression could be the most common medical condition that affects pregnant women.

Lifetime prevalence rates of depression in women are more than two times greater than those reported in men. In the perinatal period, women suffer from depression more than they suffer from gestational diabetes or preeclampsia. But despite all this, women’s health care providers feel unprepared to detect or manage depression. The management of depression has become even more complex due to recent reports of neonatal complications associated with the use of some commonly used antidepressants.

 

PHYSIOLOGIC CHANGES IN PREGNANCY:

In the development or worsening of depression during pregnancy and postpartum, changes in the brain chemistry have been theorized to be the underlying trigger. Mood disorders are associated with abnormal thyroid function; because of this, changes in thyroid function are of concern. During the first year postpartum, overt thyroid dysfunction seems to be more common than in pregnancy. Over the course of pregnancy, other hormones such as progesterone, estrogen and prolactin also increase significantly, but then decline precipitously postpartum. Estrogen has been theorized to sensitize the brain to neurotransmitters and to cause significant fluctuations in their release. The degradation of monamine oxidase also seems to be affected by estrogen, which increases the number of serotonin receptors, catabolizes serotonin, and affects the transport and uptake of serotonin. It is though that estrogen is a serotonin agonist.

 

Elevated levels of cortisol and cortisol-releasing factor also occur in pregnancy, which are thought to lead to dysregulation of the HPA axis in cases of depression. Several comprehensive literature reviews concluded that studies haven’t consistently demonstrated a correlation between changes in gonadal hormones, thyroid levels, or cortisol and postpartum mood disorders, in spite of profound changes in the hormonal milieu during pregnancy and the early postpartum period. A more recent study concurred that women with major depression at birth didn’t differ from healthy controls in the magnitude of the decline in estrogen and progesterone from postpartum day1 to day 3, and had significantly higher levels of estrogen on day 3.

 

As a matter of fact, it seems that pregnant women and non-pregnant women have the same triggers for depression, including undue stress in vulnerable women. Recent studies have shown that the risk of depression is higher in individuals with certain variations in the serotonin transporter gene (5-HTTLPR) who are subjected to stressful life events than those without these variations. Similar results were found by Schid et al. in pregnant women.

 

SAFETY OF ANTIDEPRESSANTS IN PREGNANCY:

When a pregnant woman needs medications for depression, there are a number of available antidepressants that she could choose from. Some of the most commonly used medications for treating depression include:

 

  • SSRIs (selective serotonin reuptake inhibitors)
  • NDRIs (norepinephrine/dopamine reuptake inhibitors)
  • SNRIs (serotonin/norepinephrine reuptake inhibitors).

 

These drugs work by inhibiting the reuptake of the neurotransmitters in the synaptic cleft. Some of the other available but less commonly used medications are TCAs (tricyclic antidepressants) and MAOIs (monoamine oxidase inhibitors). The MAOIs inhibit the degradation of monoamine oxidase, while TCAs block the presynaptic reuptake of serotonin and increase the sensitivity of postsynaptic neurons to serotonin, thus increasing the availability of norepinephrine. The TCAs and MAOIs have poorer safety and side effect profiles, and so they are usually reserved for use by individuals with refractory depression.

 

The bad news is that there’s only limited available evidence to guide providers in choosing among the different kinds of antidepressants. Considering delaying medication use until after birth is quite tempting due to the insufficiency of information. However, untreated depression in pregnancy could pose risks for both the mother and the infant, so delaying the medication use may not be in the best interest of either the mother or the fetus. It seems that one of the protective factors against suicide is being pregnant and having children, however, there are other factors or stressors that may offset the benefits of having children in the household, such as experiencing multiple stressful events, poverty, and lower educational attainment. The suicide rate in pregnant women is quite rare, but always a possibility.

 

Poor self-care, preterm birth, abnormal neurochemical changes in offspring, and poorer behavioral and mental health outcomes in children are some of the other problems that are associated with untreated depression as reported by the literature. Preterm birth seems to be the stronger and most consistently associated factor. However, interpretation of the literature is hampered by widespread methodologic issues including:

 

  • Small sample sizes
  • Use of different definitions of stress and depression
  • Varying length of follow-up
  • Lack of a similarly impaired control group, which is the most important factor.

 

Many studies compare the safety of antidepressants in treated depressed women to healthy, nondepressed women; because of this, when the safety of antidepressant use is being evaluated in pregnancy, the last mentioned problem is particularly problematic. Only a few studies have included in their designs both treated and untreated women. A prospective longitudinal study of depressed pregnant women taking antidepressants (49 women), pregnant women with depression receiving either no or partial treatment with antidepressants (22 women), and healthy, non-depressed pregnant women (19 women), found significantly higher rates of preterm birth in those who received antidepressants (about 14.3%), when compared to women with no or partial treatment (0%) and healthy women (5.3%). 279 depressed and non-depressed pregnant women were followed by Wisner et al. from mid-pregnancy until birth. These women were assigned to five mutually exclusive groups:

 

  • 131 women weren’t depressed and so didn’t use SSRIs
  • 48 women were depressed and used SSRIs throughout pregnancy
  • 14 women were depressed but didn’t use SSRIs
  • 23 women were depressed and were using SSRIs partially
  • 22 women were partially depressed but didn’t use SSRIs.

 

The maternal assessments were completed at four time points; 20, 30, 36 weeks, and then at birth. When compared with infants who were born to pregnant women who were partially treated with SSRIs or those with healthy control, infants who were exposed to either the continuous use of SSRIs throughout pregnancy or untreated depression were at significantly higher risk of being born preterm. In the latter mentioned two groups, the rate of preterm birth was more than 20% compared with the 4% to 9% in the other groups. These findings suggest that preterm birth is associated with medication use and maybe even depression itself.

 

When compared with other studies, the most recent study to date has a very large sample size and includes 329 pregnant women with depression using SSRIs, 4902 women with a psychiatric history but no SSRI use in pregnancy, and 51,770 pregnant healthy women.

 

The severity and duration of current or past depression wasn’t measured, and there wasn’t any available information about the duration or dose of the antidepressant being used by women in this study, because the data were collected with a questionnaire. Different kinds of SSRIs were used by these women, such as escitalopram (Lexapro), sertraline (Zoloft) and fluoxetine (Prozac), while some of them also used paroxetine (Paxil), different antidepressant regimens, and/or combined the use of an SSRI with other medications, such as tricyclics, benzodiazepine, and/or antipsychotics. When compared with healthy control group, women who were using SSRIs in pregnancy had a higher risk of giving birth before 37 weeks’ gestation (adjusted odds ratio [OR], 1.89; 95% CI, 1.29-3.16). In women taking SSRIs, the rate of preterm birth was reported to be 8.8%, in women with a psychiatric history 5.0%, and in healthy women 4.9%. Here, it should be noted that gestational age at birth in exposed pregnancies was only 5 days shorter (95% CI, -6 to -3 days).

 

In SSRI-exposed pregnancies, the preterm birth rate appears to be significantly higher, but this finding suggests that the risk may be increased by the matter of a few days only. Unfortunately, the authors did not break down the risk of preterm birth by category, namely extreme prematurity (<28 weeks' gestation), very preterm (28–31 weeks' gestation), and mild preterm (32–36 weeks' gestation). This is quite important because to what degree do antidepressants increase the risk of preterm birth is one of the clinical questions that have remained unanswered. The consequences for the fetus will be quite different if it is only slightly and the risk is concentrated in the mild preterm birth category, than if the preterm birth occurs earlier in the pregnancy.

 

It has been suggested by the evidence to date that the safety of antidepressants could vary by trimester of exposure, duration of use, dose, class of antidepressant, and specific agent. The adverse effects of antidepressants could be both short-term and long-term. More data are available about the safety of the newer antidepressants, especially the SSRIs than for many other classes of antidepressants; because of this, authorities usually recommend these newer antidepressants in pregnancy and lactation as first-line treatment agents. For instance, very little data are available about the safety of bupropion (Wellbutrin), despite the fact that this medication is commonly prescribed for smoking cessation and has been categorized as a pregnancy category B medication by the FDA. The evidence to date doesn’t suggest that bupropion is associated with any increased risks.

 

MISCARRIAGE:

An increased risk of miscarriage seems to be associated with the use of antidepressants in the first trimester by two meta-analyses. The studies that investigated birth outcomes following exposure to SSRIs in pregnancy published between 1990 and 2005 were identified by Rahimini et al.; the studies that didn’t include a control group were excluded. In SSRI-exposed pregnancies, the summary OR for spontaneous abortion for the nine studies that met inclusion criteria was 1.7 (95% CI, 1.28–2.24). In a large meta-analysis of six studies comprised of 3567 women, in which 1534 were exposed to antidepressants in pregnancy and 2033 weren’t exposed, Hemels et al. reported a miscarriage rate of 12.4% in those who used antidepressants, and 8.7% in those who didn’t (relative risk, 1.45; 95% CI, 1.19 – 1.77). But the authors noted that it may be that underlying depression, not antidepressant exposure, increases the risk of miscarriage, because the miscarriage rate didn’t vary by antidepressant class. An association between untreated depression and higher risk of spontaneous abortion was reported by other studies.

 

CONGENITAL ANOMALIES:

There’s mixed evidence on whether SSRIs increase the risk of congenital anomalies. The overall risk of congenital anomalies was found by earlier studies not to be increased with exposure to SSRIs as a class during pregnancy. But among SSRIs, the use of paroxetine (Paxil) could be of concern. A higher risk of cardiac defects with the use of paroxetine was reported by several studies. This resulted in a change in its status to a pregnancy category D medication according to the FDA. An increased risk of cardiac defects associated with the use of paroxetine in the first trimester was also found by later studies, but other studies didn’t find this increased risk.

 

Paroxetine use was reported by a recent meta-analysis of six studies to be significantly associated with increased risk of cardiac defects when compared with other antidepressants (OR, 1.72; 95% CI, 1.22-2.42). However, because of the widespread use of fetal echocardiograms in exposed pregnancies in these studies, the authors noted that their results could be influenced by detection error. In addition to this, the rate of cardiac defects in exposed infants was significantly higher than in unexposed infants, but the impact seems to be small; cardiac defects were reported in just under 2% of exposed infants when compared with the 1% in non-exposed infants. The incidence of congenital anomalies was found by one of the largest studies to date in more than 3000 infants exposed to paroxetine (Paxil) during pregnancy to be approximately 1%, which is the same as that found in the general population.

 

NEONATAL EFFECTS:

Other adverse neonatal complications including preterm birth, pulmonary hypertension and poor neonatal adaption after birth are also associated with SSRI use. Persistent pulmonary hypertension is a rare complication, estimated to occur in less than 1% of births, but it is a potentially fatal one. Higher rates have been reported by several studies after exposure to SSRIs in late pregnancy, but other studies haven’t reported these higher rates. The association between antidepressant exposure and persistent pulmonary hypertension is found to hold in future studies, but the absolute risk is probably small. It has been estimated by Chambers et al. that even with the adjusted odds ratio (AOR) of 6.1 (95% CI, 2.2-16.8) reported in their study, that 99% of infants exposed to SSRIs in pregnancy won’t be affected by persistent pulmonary hypertension.

 

Even though the results of the newest and largest study published to date are compelling, but whether the use of SSRIs in pregnancy increases the risk of prematurity or low birth weight is still controversial. Controlling the severity of maternal depression; maternal self-care activities such as nutrition, drug and alcohol use, and smoking; and exposure variables including the specific medication(s) used, timing and duration of use in pregnancy, and dosage, could be difficult and could explain why studies have come to opposite conclusions. In contrast, the evidence appears to constantly show that in the first few days after birth following in utero exposure to SSRIs, newborns can have transient difficulties. Jitteriness, irritability, feeding difficulties, and respiratory distress after birth have been reported to be experienced by neonates who were exposed to SSRIs in late pregnancy. These symptoms respond to supportive care; they are self-limited and don’t last long. It has been estimated that the overall risk ratio of developing poor neonatal adaption after exposure to SSRIs in late pregnancy is 3.0 (95% CI, 2.0-4.4).

 

LONG-TERM EFFECTS:

It is still unclear whether using antidepressants in pregnancy has negative long-term health consequences for exposed infants. The evidence is reassuring until now. Way concluded in an extensive literature review that was published in 2007 that the preponderance of the literature confirms the conclusion that exposure to SSRIs in pregnancy doesn’t affect the future health of exposed children adversely. In children whose mothers used antidepressants during pregnancy, no significant differences were found in language development, mood, intelligence, distractibility, temperament, or behavior problems. Subtle changes were found by only one study in fine motor control of children exposed to SSRIs in utero, and slight delays in their psychomotor development; however, the clinical implications of this finding are still not known.

 

The functioning of the HPA axis in infants seems to be affected by exposure to SSRIs in pregnancy and exposure to untreated maternal depression. A small study was done, in which the salivary cortisol levels in 31 infants of mothers receiving SSRIs in pregnancy were compared with that of 45 nonexposed infants; and significantly lower evening basal salivary cortisol levels were found in SSRI-exposed infants, even when the results were controlled for both feeding status and maternal mood. Levels of cortisol also seem to be affected by stress during pregnancy in untreated women; this has been linked with higher cortisol levels and poorer performance on Bayley Scales of Infant Development in infants aged three months. The studies done till now are relatively few and of short duration, so to determine the safety of antidepressant exposure in pregnancy and lactation, more data are needed about the comparative impact of treated and untreated maternal depression on infant temperament, neurocognition, and stress reactivity.

 

TREATMENT:

A health provider will need to manage two different clinical scenarios during pregnancy:

 

  • Starting medications, either for a woman with new-onset depression or for a woman experiencing a relapse of depression
  • Management of a woman with current depression who is already receiving antidepressants.

 

The health provider will need to confirm the diagnosis, asses the acuity of the situation, identify any comorbidity that may complicate management, and decide on a treatment plan in each of the cases mentioned above. The woman, after an in-depth discussion of available choices may choose to use antidepressants, receive counseling, or use a combination of options. She may either prefer to be referred to a mental health specialist, or she may decide to have some or all of her care managed by her health provider. Health providers should carefully evaluate women for other coexisting medical conditions, drug use, or psychiatric conditions that can mimic depression or complicate management when considering treatment options and before initiating antidepressants. The discussion below will focus primarily on the medication management specifically for pregnant and lactating women because the principles of management are similar in pregnant and non-pregnant women.

 

STARTING MEDICATION:

It is ideal to wait before starting antidepressant use until after the first trimester if the maternal condition permits, because this minimizes the potential risk of miscarriage and teratogenesis associated with the use of antidepressant. Remission is the goal of treatment in pregnancy, and using subtherapeutic doses of an antidepressant increases the risk of poor maternal self-care and it hasn’t shown to reduce neonatal risks. As a matter of fact, during pregnancy, especially in the third trimester when drug serum levels fall secondary to the increased plasma volume and dilutional effects in pregnancy, higher doses of antidepressants may be needed. Because of this, the approach recommended by the ACOG (American College of Obstetricians and Gnyecologists) and the American Psychiatric Association, is starting an antidepressant at a low dose and titrating slowly upward until remission is achieved. Treating depression with a single agent and using antidepressants with few active metabolites, lower placental transfer, and minimal interactions with other medications is also recommended by the ACOG. SSRIs and tricyclic antidepressants have the largest amount of data on their safety in pregnancy. Because of the problematic side effect profile of tricyclic antidepressants and their lethality in overdose, they are rarely used. Because of this, they aren’t used in pregnancy as first-line agents. SSRIs are much more commonly used in treating depression, and among them, the most studied are sertraline (Zoloft), fluoxetine (Prozac) and paroxetine (Paxil).

 

Even though sertraline (Zoloft) isn’t risk-free, but some authorities recommend it as the preferred first-line agent in pregnancy. Although the absolute risk seems to be small, but Zoloft seems to increase the risk of cardiac septal defects (OR, 2.0; 95% CI, 1.2-4). It has been noted by Louik et al. that the risk of having an affected child would only be 0.2% if the risk increases by a factor of four. There are several advantages for using sertraline in pregnancy. First of all, it has lower maternal serum levels than other SSRIs, and second, the serum levels of sertraline in breastfed infants are almost undetectable. However, paroxetine (Paxil) isn’t recommended for use in pregnancy because it has been reported to be associated with higher risks of congenital anomalies in some studies, despite the fact that serum levels of women taking paroxetine in pregnancy and during lactation have also been found to be significantly lower than in those whose mothers are taking fluoxetine (Prozac). The safety data on other commonly used agents such as NNRIs and atypical antidepressants are much more limited, but they appear to be safe. So, in pregnant women who are considering breastfeeding, using sertraline could be especially helpful.

 

In the case of women who have used antidepressants in the past, a thorough review of the medication history is needed. A woman may have a more refractory depression or other comorbid psychiatric conditions in case she has needed multidrug regimens or has used TCAs, MAOIs, or mood stabilizers. Women with a more complex psychiatric history may benefit from consulting a psychiatrist to determine the most effective and safe regimen, but beginning with sertraline (Zoloft) could be a good first approach.

 

WOMEN CURRENTLY TAKING MEDICATION:

A careful review of psychiatric and medication histories are needed for women who are currently taking medication for depression. Treatment will need to be individualized. Some women may prefer to change their medication regimen to products for which safety data are more abundant, or they may prefer to stop taking their medications if their depression is in remission. The risk of cardiac defects may be increased with the use of paroxetine (Paxil) in early pregnancy; because of this, women who have taken this medication in early pregnancy should be offered a fetal echocardiogram.

 

Deciding whether to change or stop the medications is quite complex. The risk of relapse is high, and women should be cautioned about it. Cohen et al. has found that in women who chose to stop the antidepressants in their first trimester had a significantly higher risk of relapse than those who continued using antidepressants throughout pregnancy (hazard ration, 5.0; 95% CI, 2.8-9.1; P < .001). In yet another similar study, Cohen et al. found that 42% of women who stopped taking antidepressants at conception started taking them again later in pregnancy; and 50% of them restarted their medications again in the first trimester. In case a woman decides to stop her medication to minimize the chance of a relapse, she will be weaned slowly. Until the woman is completely off the medication, the health provider shouldn’t reduce the dose by more than 25% every two weeks. In this case, careful and regular follow-ups are warranted.

 

The risk of adverse effects in pregnancy is thought to be low with most of the commonly used antidepressants; because of this, medications usually aren’t changed if the depression is controlled well. Changing medications may also lead to relapse; because of this, if a woman wants to change her medication regimen to products for which safety data are more abundant, she has to do it under the guidance of a psychiatrist.

 

To minimize neonatal problems, some professionals suggest weaning off medications at the end of pregnancy. But not only is the risk of maternal relapse high, but also the response to medication after it is reintroduced may not be as positive as it would be if the medication had been continued. A small study of 104 depressed individuals suffering from a relapse of depression found that as the number of previous depressive episodes increased, the respond rate to medication declined.

 

POSTPARTUM CONSIDERATIONS:

Treating postpartum depression with supplemental estrogen would seem to be a biologically plausible option because of the steep decline in the levels of many hormones immediately postpartum. But there’s an insufficient number and quality of studies available to evaluate the effectiveness of this approach. Only one randomized trial has been conducted till now. 61 women with major depression that began within 3 months of childbirth were randomly assigned by Gregoire et al. to either an active treatment group (n = 34; 3 months of transdermal 17b-oestradiol 200 mg daily alone, then 3 months with added cyclical dydrogesterone 10 mg daily for 12 days each month) or placebo (n = 27; placebo patches and tablets according to the same regimen). Women completed monthly self-ratings of depressive symptoms using the Edinburgh Postnatal Depression Scale. When compared with the women in the control group, women receiving estrogen improved rapidly. The estimated overall treatment effect of estrogen was a reduction of Edinburgh Postnatal Depression Scale of 4.38 points (95% CI, 1.89–6.87). Before treatment with estrogen can be recommended, more studies of sufficient size are needed to confirm these findings. Consequently, counseling, medication, or both are the postpartum treatment options, which are the same as those recommended for women in pregnancy.

 

LACTATION:

Whether a woman is breastfeeding or not is the only specific consideration during the postpartum period. Only little data are available about the safety of antidepressants during lactation, but SSRIs and TCAs are considered compatible with breastfeeding. Due to the reports of adverse neonatal effects with the use of some SSRIs such as citalopram (Celexa) and fluoxetine (Prozac), they are thought by some professionals not to be first-line options. Because paroxetine (Paxil) and sertraline (Zoloft) have been found to have lower serum levels and are considered acceptable for use during lactation, their use may be more appropriate.

 

CONCLUSION:

The appropriate treatment of depression is critical to both the short- and long-term health of women and their children. Higher rates of spontaneous abortion, preterm birth, poor maternal responsiveness to infant cues, suicidal attempts, and postpartum depression are found to be associated with untreated maternal depression during pregnancy, in addition to significantly higher rates of psychopathology in children as old as 18 years of age who were born to mothers with untreated depression during pregnancy.

 

Women have inappropriately stopped taking antidepressants without counsel from their health care provider due to concerns about the safety of antidepressants in pregnancy. But the lives of both mothers and their children can be improved with treatment. It has been reported that the remission rates of individuals receiving appropriate care are as high as 76%. Children of mothers who have received appropriate care also see improvements in their mental health. It has been found by a prospective study of 151 mother-child pairs that children of women who were treated with medication to remission had fewer new psychiatric diagnoses over the course of the study and when compared with children whose mothers didn’t experience remission, those with psychiatric diagnosis at baseline had significantly higher remission rates. With appropriate counsel and care from their health care provider, women can receive care that will enhance the well-being of both themselves and their families; so they shouldn’t fear treatment.

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Prepared By: Dr. Mehyar Al-khashroum
Edited By: Miss Araz Kahvedjian


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