The Intertwining Effect of Mood Disorders and Infertility

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Psychiatric Times, Vol 37, Issue 12, Volume 37, Issue 12

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.

CATEGORY 1 CME

Premiere Date: December 20, 2020

Expiration Date: June 20, 2022

This activity offers CE credits for:

1. Physicians (CME)

2. Other

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

ACTIVITY GOAL

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

LEARNING OBJECTIVES:

• 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

TARGET AUDIENCE

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 Psychiatric TimesTM. 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.

OFF-LABEL DISCLOSURE/DISCLAIMER

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.

HOW TO CLAIM CREDIT

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 (Figure). Some form of infertility was reported by 9% of men aged 25 to 44 years. In about 35% of couples surveyed, infertility was due to both male and female factors.1

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 (Table 1). 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,2 but other studies have found that self-reported levels of stress do impact hormone levels.3 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.4

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 Donarelli and colleagues5 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.6

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.7 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.8 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 affective disorder.

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 (Table 2). Menstrual 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.9

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.9

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 demonstrated similar rates of successful pregnancy in women with a history of an eating disorder compared with women in the general population.10 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.11

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.12

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.13 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.14

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.15 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.16 Women who perceived infertility as central to their identity, and who were resistant to realigning their goals, reported greater distress during fertility treatment.17 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.16 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).15 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.15

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.19 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).20 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.21

Recent research also suggests that both women and men with a history of major depressive disorder (MDD) are more likely to experience depressive symptoms during ART.22 In a prospective observational study of 25 women with a history of MDD 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.23

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.24

Clinical vignette

“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.

Clinical recommendations

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 National Infertility Association), 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 (Table 3). 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 associated with prenatal benzodiazepine exposure, more recent reports have shown no increase in the overall risk of malformations in children exposed to benzodiazepines during pregnancy.26

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 increase in risk of miscarriage in women treated with SSRIs, although this is not a universal finding.27 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.28

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.29 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.

Concluding thoughts

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, eating disorders can also affect fertility.

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.


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References

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2. Prasad A, Schisterman EF, Schliep KC, et al. Depressive symptoms and their relationship with endogenous reproductive hormones and sporadic anovulation in premenopausal women. Ann Epidemiol. 2014;24(12):920-924.

3. Roney JR, Simmons ZL. Elevated psychological stress predicts reduced estradiol concentrations in young women. Adapt Human Behav Physiol. 2015;1(1):30-40.

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. Am J Reprod Immunol. 2018;79(4).

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? Reprod Biomed Soc Online. 2016;(3):16-23.

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? Arch Womens Ment Health. 2012;15(5):353-359.

7. Crawford NM, Hoff HS, Mersereau JE. Infertile women who screen positive for depression are less likely to initiate fertility treatments. Hum Reprod. 2017;32(3):582–587.

8. Pedro J, Sobral MP, Mesquita-Guimarães J, . Couples’ discontinuation of fertility treatments: a longitudinal study on demographic, biomedical, and psychosocial risk factors. J Assist Reprod Genet. 2017;34(2):217-224.

9. Kimmel MC, Ferguson EH, Zerwas S, Bulik CM, Meltzer-Brody S. Obstetric and gynecologic problems associated with eating disorders. Int J Eat Disord. 2016;49(3):260-275.

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 sistersInt J Eat Disord. 2018;51(2):102–111.

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12. Lania A, Gianotti L, Gagliardi I, Bondanelli M, Vena W, Ambrosio MR. Functional hypothalamic and drug-induced amenorrhea: an overview. J Endocrinol Invest. 2019;42(9):1001-1010.

13. Sansone A, Di Dato C, de Angelis C, et al. Smoke, alcohol and drug addiction and male fertility. Reprod Biol Endocrinol. 2018;16(1):3.

14. de Angelis C, Nardone A, Garifalos F, et al. Smoke, alcohol and drug addiction and female fertility. Reprod Biol Endocrinol. 2020;18(1):21.

15. Zurlo MC, Cattaneo Della Volta MF, Vallone F. Predictors of quality of life and psychological health in infertile couples: the moderating role of duration of infertility. Qual Life Res. 2018;27(4):945-954.

16. Peterson BD, Pirritano M, Christensen U, et al. The longitudinal impact of partner coping in couples following 5 years of unsuccessful fertility treatments. Hum Reprod. 2009;24(7):1656-1664.

17. Neter E, Goren S. Infertility centrality in the woman’s identity and goal adjustment predict psychological adjustment among women in ongoing fertility treatments. Int J Behav Med. 2017;24(6):880-892.

18. Benyamini Y, Gozlan M, Weissman A. Normalization as a strategy for maintaining quality of life while coping with infertility in a pronatalist culture. Int J Behav Med. 2017;24(6):871-879.

19. Peterson BD, Sejbaek CS, Pirritano M, Schmidt L. Are severe depressive symptoms associated with infertility-related distress in individuals and their partners? Hum Reprod. 2013;29(1):76-82.

20. Joelsson LS, Tydén T, Wanggren K, et al. Anxiety and depression symptoms among sub-fertile women, women pregnant after infertility treatment, and naturally pregnant women. Eur Psychiatry. 2017;45:212-219.

21. Milazzo A, Mnatzaganian G, Elshaug AG, et al. Depression and anxiety outcomes associated with failed assisted reproductive technologies: a systematic review and meta-analysis. PLoS ONE. 2016;11(11): e0165805.

22. Holley SR, Pasch LA, Bleil ME, et al. Prevalence and predictors of major depressive disorder for fertility treatment patients and their partners. Fertil Steril. 2015;103(5):1332-1339.

23. Freeman MP, Lee H, Savella GM, et al. Predictors of depressive relapse in women undergoing infertility treatment. J Womens Health. 2018;27(11):1408-1414.

24. Zaig I, Azem F, Schreiber S, et al. Psychological response to cortisol reactivity to in vitro fertilization treatment in women with a lifetime anxiety or unipolar mood disorder diagnosis. J Clin Psychiatry. 2013;74(4):386-92.

25. Frederiksen Y, Farver-Vestergaard I, Skovgård NG, et al. Efficacy of psychosocial interventions for psychological and pregnancy outcomes in infertile women and men: a BMJ Open. 2015;5(1):e006592.

26. Andersen JT, Andersen NL, Horwitz H, et al. Exposure to selective serotonin reuptake inhibitors in early pregnancy and the risk of miscarriage. Obstet Gynecol. 2014;124(4):665-61.

27. Grigoriadis S, Graves L, Peer M, et al. Benzodiazepine use during pregnancy alone or in combination with an antidepressant and congenital malformations: systematic review and meta-analysis. J Clin Psychiatry. 2019;80(4).

28. Jarde A, Morais M, Kingston D, et al. Neonatal outcomes in women with untreated antenatal depression compared with women without depression: a systematic review and meta-analysis. JAMA Psychiatry. 2016;73(8):826-837.

29. Wu P, Velez Edwards DR, Gorrindo P, et al. Association between first trimester antidepressant use and risk of spontaneous abortion. Pharmacotherapy. 2019;39(9):889-898. ❒