Ruta Nonacs, MD, PhD

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

The goal of this activity is to inform readers about the possible connections between infertility and mental health disorders.

• Understand the prevalence of mood and anxiety disorders in women experiencing infertility and undergoing infertility treatment

• Identify patients who may need psychiatric support during infertility treatment

• Appreciate factors that may modulate vulnerability to stress, anxiety, and depression in the context of infertility and its treatment

• Identify appropriate treatment options for mood and anxiety disorders in women undergoing infertility treatment

This continuing medical education (CME) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve the care of patients with mental health disorders.

ACCREDITATION/CREDIT DESIGNATION/FINANCIAL SUPPORT

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Physicians’ Education Resource®, LLC and 

. Physicians’ Education Resource®, LLC is accredited by ACCME to provide continuing medical education for physicians.

Physicians’ Education Resource®, LLC designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This activity is funded entirely by Physicians’ Education Resource®, LLC. No commercial support was received.

This CME activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME activity is for continuing medical education purposes only and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic or treatment options for a specific patient’s medical condition.

The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of Physicians’ Education Resource®, LLC.

FACULTY, STAFF, AND PLANNERS’ DISCLOSURES

Elizabeth Clayton, Ruta Nonacs, MD, PhD, Linda L.M. Worley, MD, FACLP (external reviewer), the staff members of Physicians’ Education Resource®, LLC, and Psychiatric TimesTM have no relevant financial relationships with commercial interests.

Once you have read the article, please use the following URL to evaluate and request credit 

https://education.gotoper.com/activity/ptcme20dec

. If you do not already have an account with PER® you will be prompted to create one. You must have an account to evaluate and request credit for this activity.

Ms Clayton is an MD candidate (class of 2021) at Tufts University School of Medicine. Dr Nonacs is clinical assistant professor in the Department of Psychiatry at Massachusetts General Hospital and editor in chief at the MGH Center for Women’s Mental Health.

Difficulty with conceiving can have many psychological repercussions. Infertility is defined as the inability of a couple to conceive after 12 months of regular intercourse without the use of contraception in women aged 35 years or younger, or after 6 months in women aged 36 years or older. The Centers for Disease Control and Prevention (CDC) reports that 12% of women aged 15 to 44 years have difficulty getting pregnant or carrying a pregnancy to term (

). Some form of infertility was reported by 9% of men aged 25 to 44 years. In about 35% of couples 

, infertility was due to both male and female factors.

Infertility can have a profound impact on psychological well-being for both the individual and the couple. A woman may find herself feeling betrayed by her body and may be overcome by emotions, ranging from profound despair to anger and resentment, when a friend announces a pregnancy. Sexual intimacy can morph from an expression of closeness to a demand for conception. Each failed cycle is a multifaceted burden. In vitro fertilization (IVF) is rarely covered by insurance. Some individuals may even become suicidal with recurrent loss of pregnancy.

While we acknowledge that infertility and its treatment are physically and psychologically challenging, there is a paucity of research into the association between psychiatric illness and infertility (

). Additionally, we know little about the psychological impact of infertility and prolonged exposure to infertility treatment on mood and well-being. As the current research stands, it is unclear how mood and anxiety disorders impact fertility and if infertility and its treatment may lead to mood and anxiety disorders.

Impact of affective disorders on fertility and its treatment

There are conflicting data regarding the impact of depression and anxiety on the reproductive cycle. In one study, it was observed that depressive symptoms were not associated with changes in reproductive hormone levels,

 but other studies have found that self-reported levels of stress do impact hormone levels.

 In a group of young women aged 17 to 20 years,higher ratings of stress were associated with lower estradiol (but not testosterone or progesterone) concentrations. This finding is consistent with previous studies suggesting that prolonged perceived stress may lower overall estradiol production, thus inhibiting ovulation and suppressing reproduction.

Inflammation may also play an important role in infertility, and current research suggests that chronic inflammation may affect fertility and pregnancy outcomes. Chronic stress, depression, and anxiety have all been associated with inflammation and, therefore, may interfere with attempts to conceive. In a study of women and men undergoing infertility treatment, higher stress levels were associated with various markers of inflammation, including higher cervicovaginal inflammatory cytokines. These inflammatory markers were, in turn, associated with a decreased likelihood of achieving pregnancy through IVF.

It is likely that high levels of cumulative stress associated with recurrent depression and/or anxiety may affect multiple stages of fertilization. That said, normal levels of stress related to infertility treatment probably have minimal effects. A prospective study from 

 examined anxiety and stress levels in women and men pursuing infertility treatment before undergoing ovarian stimulation. The researchers found that neither partner’s level of treatment-related stress had an impact on the number of ovarian follicles greater than 16 mm, with ovarian follicle size being a predictor of IVF success.

Health care providers can reassure patients that neither partner’s situational stress will impact follicle stimulation. Additionally, it has been speculated that chronic stress impedes successful implantation, but difficulty with implantation can be overcome using IVF. Although more research is needed, IVF may be a reasonable recommendation for women with mood disorders who are experiencing infertility.

Although it is unclear whether depression affects fertility, it may have an impact on treatment with assisted reproductive technology (ART). Health care providers should be aware that women with depression are less likely to pursue infertility treatment. A recent prospective study of patients attending a fertility clinic found that women who screened positive for depression were about half as likely to initiate treatment for infertility compared with their nondepressed counterparts.

 Additionally, depression in women has been associated with higher ART dropout rates. One study found that couples with a clinically depressed female partner were 5 times more likely to discontinue treatment than couples with a nondepressed partner.

 Screening for depression is therefore important in couples pursuing infertility treatment, and extra care should be taken to provide appropriate support to patients seeking infertility treatment who screen positive for an 

Eating disorders and infertility treatment

Infertility and subfertility may occur in women with anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED). In women with active illness, amenorrhea and oligomenorrhea can compromise the likelihood of conception (

 irregularities occur most commonly in women with AN, with 39% to 42% experiencing amenorrhea (an absence of menstruation) and an additional 6% to 11% reporting oligomenorrhea (infrequent menstruation); however, 7% to 40% of women with BN report amenorrhea and 36% to 64% experience oligomenorrhea.

The strongest predictors of amenorrhea in women with eating disorders are low body mass index (BMI), low caloric intake, and higher levels of exercise. Weight restoration is the primary intervention for amenorrhea in women with eating disorders, although amenorrhea may persist even after normal weight has been restored. In addition, polycystic ovarian syndrome (PCOS) may be another factor contributing to menstrual irregularity in this population, as PCOS is common among women with BN and BED. In fact, one study reported polycystic ovaries in 75% of women with BN.

Women with a current eating disorder may experience fertility problems, especially if they have a low BMI and experience menstrual irregularity. However, data regarding the fertility of women with a history of an eating disorder have yielded mixed results. Many studies, including 2 large, population-based cohort studies, have 

 similar rates of successful pregnancy in women with a history of an eating disorder compared with women in the general population.

 At the same time, prospective data from the Avon Longitudinal Study of Parents and Children (ALSPAC) indicate that women with a history of AN or BN were more likely to take longer than 6 months to conceive and were more likely to have conceived with the aid of fertility treatment.

While we do not have detailed information on the impact of other psychiatric disorders (such as bipolar disorder and schizophrenia) on fertility, it should be noted that certain medications used to treat these disorders may cause menstrual irregularities, including amenorrhea, and may thus negatively affect fertility. For example, antipsychotic agents with strong antagonism of the dopamine D2 receptor, such as risperidone and older antipsychotics, increase levels of prolactin, causing hypogonadotropic hypogonadism and subsequent menstrual dysfunction.

Finally, drug and alcohol use disorders have well-documented effects on the fetus, but the effects on conception and implantation of an embryo are unclear. Studies have suggested that substance use disorder has a negative impact on female and male fertility, but more research is needed in this area.

 The majority of data have come from animal models. Studies in humans have been observational and are complicated by participants who use multiple substances and different routes of administration. Explicit associations between substance use and fertility is further confounded by lifestyle factors that often accompany substance use, such as overall unhealthy lifestyle, poor decision-making, and comorbid physical and mental health disorders.

Psychological impact of fertility treatment

The decision to begin ART can be very stressful for couples, and research has shown that stress may increase with each subsequent fertility treatment.

 However, distress can manifest at any point during ART. In a large Dutch study following couples experiencing infertility (who reported undergoing an average of 4.3 fertility treatments over 5 years), a passive-avoidant method of coping (eg, hoping for a miracle) was linked with psychological distress in women, and this effect increased over time. For men, this coping style led to increased marital distress.

 Women who perceived infertility as central to their identity, and who were resistant to realigning their goals, reported greater distress during fertility treatment.

 On the other hand, meaning-based coping strategies, learning to grow from a negative experience, and/or finding other goals in life were associated with decreased distress in women, but not in men. A woman’s use of meaning-based coping strategies also decreased marital stress for both partners.

 It is important to note that these studies are based in countries where fertility treatment is covered by insurance, which is rare in the United States. American couples undergoing ART have additional stressors, although they would also likely benefit from these coping strategies.

Protective factors have also been identified. For a woman, having a higher level of education and adequate social supports decreases distress during ART. For men, a problem-solving coping strategy was linked to a higher self-reported quality of life (QOL).

 In a study from Israel, where there is a social emphasis on having children, researchers observed that maintaining daily routines and making efforts to feel normal led to a higher QOL and better adjustment to fertility treatment.18 In another study, the Dyadic Adjustment Scale (DAS), a tool that measures relationship distress, was administered to couples currently undergoing fertility treatment. Higher dyadic adjustment was associated with better QOL and less psychological distress in both men and women undergoing ART. However, this protective effect was diminished when infertility persisted for longer than 3 years.

Although multiple studies have assessed psychological distress in couples undergoing treatment for infertility, far fewer have assessed the prevalence of clinically significant anxiety and depressive symptoms in this population. A large Danish study of couples undergoing ART found severe depressive symptoms in 11.6% of women and 4.3% of men.

 These symptoms correlated to an increase in infertility-related distress. However, there is considerable variation among studies with regard to rates of depression and anxiety in couples pursuing infertility treatment, which may reflect differences in type of ART, duration of infertility, number of failed cycles, cultural considerations, and methods used to assess symptoms.

According to another study, women who conceived through ART showed no difference in anxiety and depressive symptoms compared with pregnant women who conceived naturally. However, rates of depression and anxiety were higher in subfertile, nonpregnant women (57.6% and 15.7%, respectively).

 Comparisons between women undergoing repeated IVF cycles and first-time participants have suggested that ongoing treatment may lead to an increase in depressive symptoms, which may persist for 6 months after a failed ART trial.

Recent research also suggests that both women and men with a history of major depressive disorder (MDD) are more 

 to experience depressive symptoms during ART.

 In a prospective observational study of 25 women with a history of 

 undergoing ART, 44% of the women experienced a depressive relapse; rates of relapse were similar among women who maintained antidepressant use compared with those who discontinued treatment.

In another study, researchers observed that among 108 women undergoing IVF for the first time, those with a history of unipolar depression or anxiety disorder reported more depressive symptoms than controls without these disorders. The group without psychiatric illness responded to fertility treatment with elevated cortisol levels (compared to baseline), whereas women with a history of mood or anxiety disorder had a blunted cortisol response. These results may indicate that infertile women with Axis I disorders may have chronically elevated levels of cortisol, even before entering into infertility treatment.

“Angela,” a 35-year-old nurse practitioner, was referred to a perinatal psychiatrist to discuss the reproductive safety of escitalopram. Angela had a long history of recurrent major depression and generalized anxiety disorder dating back to high school. She had benefited from supportive psychotherapy during high school and college, but she experienced a severe episode of depression in her first year of graduate school. She resumed psychotherapy and eventually initiated treatment with escitalopram. Angela responded well to escitalopram and continued with medication and psychotherapy. She had no further episodes of depressive illness during graduate school or in the early years of her career. About a year after she married, Angela tapered off her medication because she and her husband were planning a pregnancy. At this point, she was meeting with her therapist every other month and felt very positive about her current situation. It had been nearly a decade since her last episode of depression. About 6 months after discontinuing the medication, she noticed an increase in her anxiety, mostly related to getting pregnant. Most of her friends were pregnant or had young children at home. Angela and her husband had been trying to conceive for the past 6 months, but had not had any luck. She started worrying that she would not be able to have a child of her own. She was not sure that they could afford infertility treatment, if that was required. She felt guilty that they had waited for a few years to get married and to start a family.

Shortly after her 35th birthday, Angela and her husband met with a fertility specialist. Although Angela left the appointment feeling optimistic about their chances of conceiving, Angela’s anxiety continued to worsen over the next few months. Most of the testing came back normal; however, a few weeks before Christmas, Angela found out that she might have a uterine abnormality and might need surgery.

Christmas was difficult for Angela. Her younger sister just had a baby, and everybody in her large extended family kept asking Angela why she was not pregnant. She felt ashamed, but also angry that her family was so insensitive and intrusive. Angela wanted to talk to her sister about the infertility issue; however, her sister was so focused on the new baby that the conversation went nowhere.

When she returned home, Angela continued to deteriorate. She could not stop thinking about trying to get pregnant. She felt that there was something wrong with her and that she was defective. She had always wanted to have a family but started to think that maybe this was some sort of sign that she was not meant to be a mother. She started to worry that her infertility would drive her husband away and that he would find somebody else to have a family with.

She experienced difficulty falling asleep and left for work in the morning feeling totally depleted. Normally, work was enjoyable for her and was a place where she felt confident, but Angela found herself questioning her clinical decisions. It was difficult to concentrate, and she spent much more time at the end of the day reviewing and rewriting her notes. After coming home, if she was not thinking about getting pregnant, she was worrying about her patients and worrying that she had done something wrong.

The next time she met with her fertility specialist, Angela told him that she was feeling much more anxious, maybe even a little depressed, and wondered if it would be OK to resume treatment with escitalopram. The doctor reassured her that anxiety was a normal response to fertility problems. He stated that they try to avoid medications that are not necessary and recommended that Angela meet with a social worker.

Angela left the office feeling despondent. She wanted to tell her doctor how badly she felt, but she was worried that he might think less of her. What kind of woman would ever consider taking medications during pregnancy? And if she could not handle a little anxiety, how would she ever manage being a mother? And what if something bad did happen? She could never forgive herself.

Angela wondered, if she felt this bad, how was she going to push ahead with the infertility treatment? Angela felt like she was a ball of nerves. She wanted to talk to her husband but felt ashamed about the way she felt. She felt weak and inept and not at all up for this challenge.

Steps should be taken to screen couples, not just women, for psychiatric disorders and chronic stress prior to beginning infertility treatment, as well as throughout treatment. Although depressive symptoms and anxiety occur frequently in women experiencing infertility, many women do not seek treatment. In fact, many women resist disclosing their mental health status to their reproductive endocrinologist for fear that they would be deemed bad candidates for infertility treatment. Effectively treating eating disorders, substance use disorders (including alcohol and tobacco use), and bipolar disorder from the initiation of infertility treatment will aid in a healthy pregnancy, if conception is successful.

Although there is no evidence to suggest that antidepressants or anxiolytic medications negatively affect fertility or infertility treatment, many women are reluctant to use medication in this setting. Women undergoing infertility treatment may not engage in treatment of anxiety and depression because they already feel overburdened by the demands of infertility treatment on their time and financial resources. In addition, having to pursue psychiatric treatment in this setting may accentuate the shame and stigma many women with infertility often feel.

Providing couples with information normalizes the psychological effects of infertility and its treatment may help patients adjust to and tolerate the process. Clinicians should give guidance when psychological symptoms are more than a normal reaction to a common reaction to failed ART. Counseling patients on the importance of self-care, healthy coping strategies, and improving communication may have a positive impact on both the individual and couple. Patient support can include connecting them with community support resources, such as RESOLVE (a network of groups affiliated with the 

), and recommending a consultation with a sex therapist to help the couple maintain a positive connection with each other.

Additionally, targeted psychological interventions may help alleviate the adverse psychological outcomes associated with infertility and its treatment, including anxiety, depressive symptoms, and marital stress (

. According to a recent meta-analysis25 that included 39 studies and a total of 3064 women and 347 men, psychological interventions, most commonly cognitive behavioral therapy (CBT) or mind-body interventions (MBI), may be effective for reducing anxiety (25 studies), as well as depressive symptoms (21 studies). These interventions also appeared to improve rates of pregnancy; in this meta-analysis, women treated with CBT or MBI were about twice as likely to achieve pregnancy compared with women receiving usual care. Of note, larger reductions in anxiety were associated with greater improvements in pregnancy rates.

To date, there is no research that specifically looked at the pharmacologic treatment of depression or anxiety in women with infertility. Thus, the same principles that guide the treatment of women during pregnancy should inform the treatment of women undergoing infertility treatment. There are sufficient data to support the use of selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRIs and SNRIs), bupropion, and tricyclic antidepressants. Other factors that may influence the selection of an antidepressant include prior response to a particular antidepressant, comorbidity of anxiety symptoms, and adverse effect profile.

Benzodiazepines, including lorazepam and clonazepam, may be helpful for the management of anxiety disorders, treatment-emergent anxiety, and sleep disturbance. Althoughearlier reports suggested an increased risk of cleft lip and palate 

 prenatal benzodiazepine exposure, more recent reports have shown no increase in the overall risk of malformations in children exposed to benzodiazepines during pregnancy.

Many women question whether the use of these medications may affect fertility or the success of infertility treatment. Although there is no evidence to indicate that antidepressants or benzodiazepines have deleterious effects on fertility, this has not been studied systematically. There have been reports suggesting a small but statistically significant 

 in risk of miscarriage in women treated with SSRIs, although this is not a universal finding.

 It is also important to note that women who suffer from mood and anxiety disorders probably carry a slightly higher risk of miscarriage. In fact, women with a history of depression who stop treatment with an antidepressant 3 to 12 months prior to conception have the same risk of miscarriage as women who continue treatment with an antidepressant.

Although avoiding treatment with a medication may seem like the safest option, untreated anxiety and/or depression in the mother has been associated with negative pregnancy outcomes, including increased risk of preterm birth, low birth weight, and other complications.

 In addition, depression during pregnancy is a robust predictor of postpartum depression. Numerous somatic complaints are treated with medication during pregnancy; psychological complaints can be just as detrimental and should be treated, as well.

Infertility is a common and psychologically distressing experience, both for the individual and the couple. Although there is a dearth of research examining the association between infertility and psychiatric illness, preliminary research indicates that depression, anxiety, and chronic stress may contribute to inflammation and alterations in hormone levels, factors which may affect the likelihood of successful pregnancy outcomes. Additionally, ongoing infertility treatment has been linked to increased depressive symptoms and anxiety and may hinder couples’ ability to pursue and continue with infertility treatment. As noted, 

Increased psychological support during infertility treatment would be beneficial for this population and may improve the chances of a successful pregnancy. The patient undergoing infertility treatment should be given the same plan of care as any patient with anxiety or depression. Support should include expectation management around the psychological effects of infertility treatment, as well as promotion of healthy coping strategies, such as taking time for self-care. If needed, pharmacotherapy with SSRIs or benzodiazepines is unlikely to have an adverse effect on conception and may decrease ART dropout. However, more research is needed to establish the connection between psychological illness and depression in order to create effective targeted therapies.

Posttest, credit request forms, and activity evaluations must be completed online at 

 (requires free account activation), and participants can print their certificate or statement of credit immediately. This website supports all browsers. For PER’s privacy policy, please visit https://www.gotoper.com/privacy.

PLEASE NOTE THAT THE POSTTEST IS AVAILABLE ONLINE ONLY ON THE 20TH OF THE MONTH OF ACTIVITY ISSUE AND FOR 18 MONTHS AFTER.

1. Reproductive Health: Infertility FAQs. Centers for Disease Control and Prevention. Updated January 16, 2019. Accessed November 7, 2019. 

https://www.cdc.gov/reproductivehealth/infertility/index.htm

2. Prasad A, Schisterman EF, Schliep KC, et al. Depressive symptoms and their relationship with endogenous reproductive hormones and sporadic anovulation in premenopausal women. 

3. Roney JR, Simmons ZL. Elevated psychological stress predicts reduced estradiol concentrations in young women. 

4. Haimovici F, Anderson JL, Bates GW, et al. Stress, anxiety, and depression of both partners in infertile couples are associated with cytokine levels and adverse IVF outcome. 

5. Donarelli Z, Lo Coco G, Gullo S, et al. 

Infertility-related stress, anxiety and ovarian stimulation: can couples be reassured about the effects of psychological factors on biological responses to assisted reproductive technology?

6. Zaig I, Azem F, Schreiber S, et al. Women’s psychological profile and psychiatric diagnoses and the outcome of in vitro fertilization: is there an association? 

7. Crawford NM, Hoff HS, Mersereau JE. Infertile women who screen positive for depression are less likely to initiate fertility treatments. 

8. Pedro J, Sobral MP, Mesquita-Guimarães J, . Couples’ discontinuation of fertility treatments: a longitudinal study on demographic, biomedical, and psychosocial risk factors.

9. Kimmel MC, Ferguson EH, Zerwas S, Bulik CM, Meltzer-Brody S. Obstetric and gynecologic problems associated with eating disorders. 

10. Tabler J, Utz RL, Smith KR, Hanson HA, Geist C.

 Variation in reproductive outcomes of women with histories of bulimia nervosa, anorexia nervosa, or eating disorder not otherwise specified relative to the general population and closest-aged sisters

11. Schmidt U, Sharpe H, Bartholdy S, et al. Treatment of anorexia nervosa: a multimethod investigation translating experimental neuroscience into clinical practice. 

12. Lania A, Gianotti L, Gagliardi I, Bondanelli M, Vena W, Ambrosio MR. Functional hypothalamic and drug-induced amenorrhea: an overview.

13. Sansone A, Di Dato C, de Angelis C, et al. Smoke, alcohol and drug addiction and male fertility. 

14. de Angelis C, Nardone A, Garifalos F, et al. Smoke, alcohol and drug addiction and female fertility. 

Articles

Matters around child-bearing bring up emotions ranging from joy and elation to profound despair, anger, and resentment. Psychiatrists are trained to recognize such issues.

The Intertwining Effect of Mood Disorders and Infertility

Mood disorders are common in women and typically emerge during the childbearing years.

 While pregnancy has traditionally been considered a time of emotional well- being, recent data indicate that about 10% to 15% of women experience clinically significant depressive symptoms during pregnancy.

 The risk is particularly high in women with recurrent major depression who discontinue antidepressant medication proximate to conception; 68% of those women experience a depressive relapse.

The clinician faces certain challenges in making recommendations regarding treatment for depression during pregnancy. While psychotherapy is an attractive option, not all women respond to this intervention and many require pharmacotherapy. All antidepressant medications readily diffuse across the placenta, and no psychotropic drug has yet been approved by the FDA for use during pregnancy. Although data accumulated during the past 30 years suggest that certain medications, including SSRIs, may be used safely during pregnancy,

 knowledge regarding the risks of prenatal exposure to psychotropic medications remains incomplete.

While most reports do not indicate that antidepressants increase the risk of miscarriage, several reports have suggested small increases in rates of spontaneous abortion among women treated with SSRIs during the first trimester of pregnancy.

 In these individual reports, the observed differences have not reached statistical significance, and in all cases, reported rates of miscarriage in exposed women have never exceeded the rate of spontaneous abortions observed in the general population (12% to 15%). Findings from a recent meta-analysis that included 3567 women showed that the miscarriage rate was 1.43-fold higher in women who had been exposed to antidepressants than in those who had not (12.4% vs 8.7%, respectively).

 The authors concluded that while maternal exposure to antidepressants may be associated witha small increase in risk of miscarriage, depression itself also may be a contributing factor and that further studies are needed to clarify this issue.	

The baseline incidence of major congenital malformations in newborns born in the United States is estimated to be between 2% and 3%. A teratogen is an agent that interferes with organ formation and that produces some type of organ malformation or dysfunction. Data on the overall teratogenicity of SSRIs come from relatively small prospective observational studies, larger international birth registries, and managed health care databases; these data have cumulatively supported the reproductive safety of fluoxetine and certain other SSRIs.

Although SSRIs share a common mechanism of action, their chemical structures are distinct; whether they have similar effects on pregnancy outcomes is not known. Of the antidepressants, fluoxetine is the best charac- terized with regard to its use during pregnancy; prospective studies complemented by postmarketing surveillance studies indicate no increase in risk of major congenital malformation in infants exposed to it.

 Information regarding the reproductive safety of other SSRIs is accumulating but is more limited in terms of sample size.

 In a recent meta-analysis that included 1774 antidepressant-exposed infants, first-trimester exposure to SSRIs was not associated with an increased risk of major malformations above the baseline level of 2% to 3%.

On the basis of these data, SSRIs are not generally thought to be major te- ratogens; however, concerns about the potential teratogenicity of SSRIs were first raised in 2005 when several studies suggested that paroxetine may be associated with a small increase in risk of congenital abnormalities. A preliminary analysis of data derived from an HMO-claims database demonstrated a 1.8-fold increase in overall risk of malformations in infants exposed to paroxetine and showed a trend toward increased risk of cardiovascular malformation (odds ratio [OR], 1.54).

 Data from the Swedish Medical Birth Registry, which included 882 paroxetine-exposed children, demonstrated a 1.78-fold increased risk of cardiovascular malformation; the majority of these defects were ventricular or atrial septal defects. Infants exposed to other SSRIs did not have an increased risk of cardiac defects.

Two recent retrospective case-control studies evaluated the risks of early exposure to SSRIs.

 analyzed data from the National Birth Defects Prevention study, comparing 9622 infants who had selected major birth defects with 4092 controls who had no defects. After delivery, the mothers of these infants were interviewed regarding drug exposures during pregnancy and other possible risk factors for major malformations. The investigators found an association between exposure to an SSRI during the first trimester and an increased risk of omphalocele (OR, 2.8). The strongest effect was observed with paroxetine, which accounted for 36% of all SSRI exposures and which was associated with an 8.1-fold increase in risk of omphalocele. SSRI exposure during the first trimester also was associated with craniosynostosis (OR, 2.5) and anencephaly (OR, 2.4).

Using a similar study design, researchers from the Slone Epidemiology Center at Boston University analyzed 9849 infants with identified birth defects and 5860 infants without such defects.

 In contrast to the previous study, they found that overall use of SSRIs was not associated with significantly increased risks of craniosynostosis, omphalocele, or heart defects. However, when they looked for associations between the use of specific SSRIs and specific defects, they observed significant associations between first-trimester exposure to sertraline and both omphalocele (OR, 5.7) and septal defects (OR, 2.0) and between exposure to paroxetine and right ventricular outflow tract obstruction defects (OR, 3.3).

This volley of conflicting reports has left many clinicians confused and uncertain about how to counsel their patients regarding the safety of SSRIs during pregnancy. For example, while earlier reports suggested a link between paroxetine and septal defects, the 2 most recent studies show no such association. While one of the case-control studies suggests that paroxetine may increase the risk of omphalocele, the other does not and, instead, links sertraline exposure to this defect. The differences in the results from the available studies and the diversity in the types of abnormalities reported make it difficult to definitively draw a causal link between SSRI exposure and any particular congenital abnormality.

While there is clearly a need for more thorough analysis of the existing data, taken together, these reports may signal an increase in risk of malformations in children exposed to SSRIs. However, it is important to put these risks into perspective. Even if we assume the associations from these case-control studies to be true, the absolute risk of malformations remains low. For example, an 8.1-fold increase in risk of omphalocele translates into an absolute risk of only 0.2% (approximately 2 of every 1000 births). Absolute risk is of far greater clinical value than relative risk and should be taken into consideration before patients are arbitrarily counseled to discontinue antidepressants during pregnancy.

Multiple studies have suggested that exposure to SSRIs proximate to the time of delivery may be associated with poor perinatal outcomes. Using a variety of methodologies, studies have indicated that children who had been exposed to SSRIs in the third trimester are more likely to have had decreased gestational age, lower Apgar scores, and lower birth weight.

 However, many other studies have observed no differences between infants who had been exposed to SSRIs and those who had not.

 Thus, the clinical relevance of these findings is unclear. In general, the magnitude of the differences has been small. For example, the differences in Apgar scores between exposed and nonexposed infants have typically been less than 1 point and average Apgar scores in the exposed children have remained high (above 7); clinically, a score of 7 or greater suggests that the infant's condition is good to excellent.

In October 2005, the FDA ordered drug manufacturers to include warnings in the packaging inserts regarding the use of certain antidepressants during pregnancy. What prompted these label changes were postmarketing adverse event reports submitted to the FDA, as well as a number of controlled studies, suggesting a constellation of symptoms associated with third-trimester exposure to SSRIs. The symptoms most commonly reported include tremor, restlessness, jitteriness, increased muscle tone, increased crying, feeding difficulties, and respiratory distress.

 Whether these symptoms represent a direct effect of exposure to the antidepressant (ie, increased serotonergic activity) or a discontinuation syndrome is not yet clear. One report has suggested that neonatal symptoms may be more common in infants who had been exposed to agents with shorter half-lives, such as paroxetine.

 It should also be noted that infants born to mothers with untreated depression are at higher risk for adverse neonatal outcomes than those born to mothers who are not depressed, suggesting that it may be the underlying illness-rather than the medications used to treat the disorder-that is associated with poor neonatal outcomes.

While these reports have raised concerns regarding the use of SSRIs in pregnancy, it is important to put these findings into a larger context. Reassuringly, the vast majority of reported adverse events appear to be mild and relatively short-lived; they rarely require any type of medical intervention and typically resolve spontaneously within 1 to 4 days. Furthermore, there is no indication of longer-term problems in children who had been exposed to SSRIs.

A recent study linked SSRI use during late pregnancy to an increased risk of persistent pulmonary hypertension of the newborn (PPHN).

 PPHN is a cardiovascular syndrome that typically occurs in full-term infants and causes severe respiratory distress. Using a case-control design to evaluate risk factors for PPHN, investigators identified 377 infants with PPHN and a control group of 836 women and their infants. The use of an SSRI after the 20th week of gestation was significantly associated with PPHN (PPHN developed in 14 SSRI-exposed infants but in only 6 controls; adjusted OR, 6.1). Neither the use of SSRIs before the 20th week of gestation nor the use of other antidepressants any time during pregnancy was associated with PPHN. To date, this is the only study that reveals a link between SSRI exposure and the risk of PPHN.

It is difficult to reconcile these findings with other studies investigating neonatal outcomes in infants exposed to antidepressants in utero. There have been reports of respiratory distress (usually tachypnea or rapid breathing); however, the observed symptoms were relatively mild and transient and did not require specific medical intervention, suggesting that these cases were not PPHN, a more serious complication with significant morbidity. Nonetheless, these findings must be taken into consideration when deciding whether an SSRI should be used during pregnancy. While PPHN is a potentially serious complication, the absolute risk is still relatively small; the risk is estimated to be less than 1% in infants exposed to SSRIs.

Because neuronal migration and differentiation occur throughout pregnancy and into the early years of life, the CNS remains particularly vulnerable to toxic agents throughout pregnancy. However, insults that occur after neural tube closure produce changes in behavior and function as opposed to gross structural abnormalities. In a landmark study, Nulman and colleagues

 followed until preschool age a cohort of children who had been exposed to either tricyclic antidepressants (TCAs) (n = 80) or fluoxetine (n = 55) during pregnancy (most commonly during the first trimester), and compared these children with a cohort of children who had not been exposed to SSRIs (n = 84). Results indicated no significant differences in IQ, temperament, behavior, reactivity, mood, distractibility, or activity level. A more recent report from the same group followed a cohort of children exposed to fluoxetine (n = 40) or TCAs (n = 47) for the 

 The authors concluded that their findings support the hypothesis that fluoxetine and TCAs are not behavioral teratogens.

 prospectively examined the relationship between prenatal antidepressant exposure and behavior in a group of 4-year-old children. In this study, outcomes were compared between children with prenatal exposure to SSRIs (n = 22) and children of healthy, non- depressed mothers with no medication exposure (n = 14). Levels of internalizing behaviors (eg, depression, anxiety, withdrawal), as reported by parents and other caregivers and as rated by a clinician, did not differ significantly between the children exposed to SSRIs and those without prenatal SSRI exposure. Similarly to the 2 previous studies from the Motherisk program, these findings support the hypothesis that in utero exposure to SSRIs has no long-term negative effects on the child. Although the studies are reassuring, these data are preliminary. Furthermore, it should be noted that effects of antidepressant exposure may appear later in a child's life. Clearly, further investigation into the long-term neurobehavioral effects of prenatal exposure to antidepressants is warranted.

While clinicians are appropriately concerned about the known and unknown risks associated with fetal exposure to psychiatric medications, the potential negative effect of untreated psychiatric illness on fetal well-being has frequently been overlooked. Depression not only increases the risk of self-injurious or suicidal behaviors in the mother but also may contribute to inadequate self-care and poor compliance with prenatal care. Women with depression often present with decreased appetite and consequently lower than expected weight gain in pregnancy, factors that have been associated with negative pregnancy outcomes.

 In addition, pregnant women with depression are more likely to smoke and to use alcohol or illicit drugs.

 Furthermore, current research suggests that maternal depression itself may adversely affect the developing fetus and may be associated with higher rates of preterm birth, lower birth weight, smaller head circumference, and lower Apgar scores.

Clinicians faced with the decision of whether to treat depression during pregnancy should weigh the risks and benefits of antidepressant use versus the risks of untreated psychiatric disorder. While there is a tendency to withdraw or withhold psychiatric medications, for many women this may not be the best option; treatment decisions must be made on a case-by-case basis. Ideally, decisions regarding treatment should be discussed before conception. In patients with less severe depression, it is appropriate to consider discontinuation of pharmacological therapy during pregnancy. In this setting, psychotherapy may be helpful and may eliminate the need for medications. In contrast, women who have a more recurrent or refractory depressive illness and who are at significant risk for relapse in the setting of medication discontinuation may decide that the safest option is to continue pharmacological treatment during pregnancy.

In choosing an antidepressant for use during pregnancy, the clinician should attempt to select a medication that has a well-characterized reproductive safety profile. Fluoxetine, with the most extensive literature supporting its reproductive safety, is a first-line choice. There is growing literature on the reproductive safety of the newer SSRIs. Although SSRIs are the antidepressants most commonly used in this setting, there are data that support the use of TCAs.

 While several studies outlined here suggest that there may be a small increase in the risk of certain malformations, it is felt that the absolute risk is low and that treatment is warranted when the risks of depression are thought to outweigh the risks associated with drug exposure.

Recent reports of adverse neonatal events in infants who had been exposed to SSRIs have led to changes in the package labeling of SSRIs, advising physicians to "carefully consider the potential risks and benefits of treatment" in patients and suggesting that clinicians consider tapering or discontinuing SSRIs late in the third trimester before labor and delivery. This approach may not be the most prudent, given that the women who most commonly take antidepressants during pregnancy are those who have histories of severe or recurrent depression and who have not been able to successfully taper their medications. In this situation, discontinuing antidepressant therapy proximate to delivery would probably place them at significant risk for relapse of depression.

While there may be a risk of neonatal symptoms associated with exposure to SSRIs near the time of delivery, it is important to note that these symptoms are generally mild and short-lived. Furthermore, there are no data to suggest that drug taper before delivery reduces the risk of the symptoms described in the newborn. Therefore, it is recommended that babies born to mothers taking SSRIsbe observed after delivery so that any neonatal symptomscan be recognized early and, if necessary, treated. Currently, affectedinfants are typically treated conservatively and may be admitted to a special care nursery for observation.

In a recent editorial, Michael F. Greene, MD, of the division of maternal and fetal medicine at Massachusetts General Hospital in Boston, noted that these newer-and often conflicting-studies clearly have made it more difficult to make decisions regarding the treatment of depression during pregnancy. He noted further that "patients and physicians alike would prefer it if there were clear lines separating risk and no risk and if all studies gave consistent results pointing in the same direction."

 While these more recent reports have raised concerns, the data, taken as a whole, are reassuring and indicate that the risks associated with SSRI exposure during pregnancy are low.

 Kessler RC, McGonagle KA, Swartz M, et al. Sex and depression in the National Comorbidity Survey. I: lifetime prevalence, chronicity and recurrence. 

 O'Hara MW. Social support, life events, and depression during pregnancy and the puerperium. 

 Evans J, Heron J, Francomb H, et al. Cohort study of depressed mood during pregnancy and after childbirth. 

 Gotlib IH, Whiffen VE, Mount JH, et al. Prevalence rates and demographic characteristics associated with depression in pregnancy and the postpartum. 

 Flynn HA, Blow FC, Marcus SM. Rates and predictors of depression treatment among pregnant women in hospital-affiliated obstetrics practices. 

 Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. 

 Altshuler L, Cohen L, Moline ML, et al. The Expert Consensus Guidelines Series. Treatment of depression in women. 

 Ryan D, Milis L, Misri N. Depression during pregnancy. 

 Pastuszak A, Schick-Boschetto B, Zuber C, et al. Pregnancy outcome following first-trimester exposure to fluoxetine (Prozac). 

 Kulin N, Pastuszak A, Sage SR, et al. Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors: a prospective controlled multicenter study. 

 Einarson A, Fatoye B, Sarkar M, et al. Pregnancy outcome following gestational exposure to venlafaxine: a multicenter prospective controlled study. 

 Einarson A, Bonari L, Voyer-Lavigne S, et al. A multicentre prospective controlled study to determine the safety of trazodone and nefazodone use during pregnancy. 

 Djulus J, Koren G, Einarson TR, et al. Exposure to mirtazapine during pregnancy: a prospective, comparative study of birth outcomes. 

 Hemels ME, Einarson A, Koren G, et al. Antidepressant use during pregnancy and the rates of spontaneous abortions: a meta-analysis. 

 Hallberg P, Sjöblom V. The use of selective serotonin reuptake inhibitors during pregnancy and breast-feeding: a review and clinical aspects. 

 Chambers CD, Johnson KA, Dick LM, et al. Birth outcomes in pregnant women taking fluoxetine. 

 Goldstein DJ. Effects of third trimester fluoxetine exposure on the newborn. 

Mood disorders are common in women and typically emerge during the childbearing years. While pregnancy has traditionally been considered a time of emotional well- being, recent data indicate that about 10% to 15% of women experience clinically significant depressive symptoms during pregnancy.

Ruta Nonacs, MD, PhD

Articles

The Intertwining Effect of Mood Disorders and Infertility

SSRIs and Pregnancy: Putting the Risks Into Perspective