Assisted reproduction and risk of depressive relapse: Considerations for treatment
Perinatal and Reproductive Psychiatry Program, Massachusetts General Hospital, Boston, Massachusetts, USA
Vincent In Vitro Fertilization Unit, Massachusetts General Hospital, Boston, Massachusetts, USALee S. Cohen, MD
Perinatal and Reproductive Psychiatry Program, Massachusetts General Hospital, Boston, Massachusetts, USA
BACKGROUND: At present, there is a lack of systematic data regarding the risk of relapse of psychiatric disorders in women undergoing infertility treatment. Clinicians would benefit from a systematic study of the biological sequelae of stress and the clinical implications for women with histories of depression or anxiety disorders undergoing treatment for infertility. Women with histories of major depressive disorder may be vulnerable to the stress involved in the process of assisted reproduction, and treatment changes during this time in anticipation of a pregnancy may affect relapse rates.
METHODS: We have highlighted the elements important to the care of women undergoing assisted reproduction with histories of depression in the following case report and review of the relevant literature.
RESULTS: No clinical guidelines currently exist for prevention of depressive relapse in women seeking infertility treatment. Due to concerns about medication exposure during a potential pregnancy, many women will avoid antidepressants.
CONCLUSIONS: The profession needs to identify women at risk of depressive relapse and create evidence-based treatment guidelines for their management. Similarly, among patients who may be pregnant, providers should monitor mood, psychotherapeutic approaches, and collaborative decision-making about medication use carefully.
KEYWORDS: infertility, pregnancy, antidepressants, depression
ANNALS OF CLINICAL PSYCHIATRY 2013;25(4):283-288
Women often are diagnosed and treated with major depressive disorder (MDD) during the reproductive years, and those who have histories of depression often find themselves evaluating treatment choices in anticipation of a pregnancy or soon after becoming pregnant. Women who have difficulty conceiving represent an especially complicated patient population. The chronic stress of infertility treatments and the unknown time course and outcomes for a potential pregnancy may pose challenges in the maintenance treatment of MDD. Women often view unsuccessful attempts to conceive as a loss. At present, we do not fully understand how infertility treatment affects the course of mood and anxiety disorders, as well as how untreated psychiatric disorders may impact conception. In this case presentation and discussion, we review the elements that contribute to decision-making regarding MDD treatment.
Ms. A, a 38-year-old teacher, and her husband tried to conceive shortly after their wedding. She had a history of MDD and panic disorder with agoraphobia. She had experienced 3 major depressive episodes in the past, each with moderate severity of about 6 months’ duration. Before trying to conceive, she was treated successfully to remission for MDD and anxiety with fluoxetine, 40 mg/d, which she had been on as maintenance treatment for 4 years before trying to conceive. She used lorazepam, 1 mg as needed, for acute panic attacks, which she rarely experienced while on fluoxetine. She stopped fluoxetine just before starting to try to conceive. She started cognitive-behavioral therapy (CBT) before discontinuing the antidepressant.
After 1 year without becoming pregnant, she and her husband sought consultation around infertility. After assessment by a reproductive endocrinologist, they planned to start a course of in vitro fertilization (IVF).
Ms. A preceded though an unsuccessful course of IVF with her anxiety under reasonable control, optimistic and slightly anxious, but without panic attacks or agoraphobic symptoms. She used her CBT skills on a regular basis, and attended booster sessions of CBT after an initial course of weekly treatment. She noted decreased sleep and appetite after embryo transfer as she awaited the result of the cycle, and was disappointed when she had a negative pregnancy test, but did not become depressed. She and her husband planned another course of IVF.
As the second course of IVF approached, Ms. A was again optimistic about conceiving. However, she experienced a fluctuating course of anxious thoughts that contributed to initial insomnia. Several days prior to egg retrieval, her mother was diagnosed with breast cancer and planned to undergo a mastectomy and start chemotherapy. Ms. A proceeded though the IVF cycle, with worsening insomnia as she awaited the results of her cycle. Her pregnancy test was again negative.
Ms. A began to feel increasingly overwhelmed, sad, and anxious, and became socially withdrawn. She and her husband considered taking several months off from trying to conceive. She was an only child and wanted to support her mother as she had a mastectomy and began chemotherapy. Her mother’s prognosis was good, but on several occasions her mother stated that she wanted to have grandchildren soon in case she died, and encouraged Ms. A to start another cycle of IVF as soon as possible. Also, Ms. A’s colleague, another teacher at the school who taught in the same grade, announced that she was pregnant.
Ms. A and her husband began to plan for a third attempt with IVF. As the time neared to start treatment, Ms. A experienced progressively worsening sadness, difficulty sleeping, decreased appetite, interest, and motivation. She began having panic attacks and agoraphobic symptoms severe enough to prevent her driving, which interfered with her work and social functioning. She became unsure about whether to proceed with infertility treatment because of worsening depression and anxiety. After the psychiatric consultation, Ms. A restarted fluoxetine. She used lorazepam as needed for acute panic attacks, until approximately 4 weeks after starting fluoxetine, when her depressive symptoms and panic attacks improved. She proceeded with the IVF cycle, continuing on medication. Ms. A continued treatment with fluoxetine and discontinued as needed use of lorazepam after the embryo transfer. She successfully conceived a viable pregnancy, confirmed by vaginal ultrasound.
Prevalence of infertility, public health significance, and implications for mental health
Infertility affects up to 17% of women age 20 to 44 who are married or in consensual partnerships, and in developed countries, 42% to 76% of those affected seek treatment for infertility.1 Considering the prevalence of depression in women, many women pursuing infertility treatment will have histories of MDD. Risk factors for the relapse of mood disorders have not been studied systematically in women undergoing infertility treatment, but are likely to be highly relevant for treatment considerations. Untreated depression affects the woman, her relationships, and her functioning at a time when she needs optimal functioning and support from significant others.
A woman going through infertility treatment may be experiencing infertility as a chronic stressor, while facing the physical and emotional demands of engagement in infertility treatment. We do not fully understand the impact of untreated depression, or the anxiety that often accompanies it, on the outcome of successful conception. Untreated MDD and anxiety experienced by women undergoing infertility treatment may affect fertility rates secondary to HPA axis dysregulation and/or the interplay between HPA function and hypothalamic–pituitary gonadal (HPG) function.2 Depression and/or anxiety may adversely affect overall health, nutrition, appetite, engagement in health care services, tobacco and alcohol use, or other substances, ambivalence about or decreased motivation for pursuing infertility treatments in the face of unsuccessful attempts, increased individual distress, and distress in intimate relationships. All these factors in turn may impair fertility. In addition to these potential effects of depression and anxiety on fertility, hormones used during infertility treatment have not been studied systematically with respect to their impact on the course of mood and anxiety disorders.
Biological relationships affecting MDD, stress, and infertility
Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is associated with the stress response and MDD.3 The context of infertility treatment is an intriguing and clinically compelling context for the study of perceived stress, biomarkers of stress physiology, and risk for major depression. The biomarkers of the stress response include cortisol and HPA axis dysregulation, and inflammation, with potential markers including C-reactive protein (CPK) and interleukin 6 (IL-6). Considering that the menstrual cycle is known to be a strong modulator of the stress response, one can reasonably expect that the stress response and cortisol levels may be affected by the hormonal interventions and physiologic changes across cycles of IVF.4 As the nature of stress has been shown to modulate stress response,5,6 it is also reasonable to assume that the different stressors posed in different phases of the IVF cycle or other courses of assisted reproduction would be associated with differing risk of MDD relapse or symptom burden (FIGURE). A meta analysis of human studies demonstrates that acute stress elevates salivary or serum cortisol and HPA axis dysregulation,7 with modulation including duration of the stressor, nature of the stressor, the individual’s perceived control over the stressor, and the emotional reaction of the individual evoked by the stressor. Certainly many women will experience infertility as a prolonged stressor with a major emotional valance and feel varying degrees of lack of control.
FIGURE: Phases of the in vitro fertilization cycle
I: insemination; IVF: in vitro fertilization; PT: pregnancy test; R: egg retrieval; T: embryo transfer.
Maintenance or discontinuation of antidepressant treatment may influence strongly the stress response in individuals with MDD, as antidepressants have been shown to attenuate HPA axis response in MDD.8,9 Patients with depression have been found to have an over-active immune response.10-12 Therefore, MDD biomarkers may help identify women most at risk for relapse as they proceed through infertility treatment, which can be a challenging emotional process. With this research in mind, clinicians need to identify women most at risk of depressive relapse throughout the infertility treatment process.
Bloch and colleagues recently demonstrated that women with histories of depressive and anxiety disorders are especially vulnerable for worsening symptoms during infertility treatment and may experience an altered hormonal stress response compared to women without such a history.13 Women with and without histories of mood and anxiety disorders experienced elevation in cortisol levels across the cycle, but those with a history of psychopathology had blunted cortisol increases in comparison to the more continuously elevated cortisol levels across the cycle in women without such histories. The symptomatic worsening in women at risk and the differences in stress responses between groups suggest that clinicians need to carefully monitor patients during infertility treatment.
Treatment considerations throughout the course of infertility treatment
Importantly, untreated depression and anxiety carry risks for pregnancy outcomes. Both have been cited as risk factors for preterm birth and low birth weight. Investigators have found it difficult to disentangle the risks from antidepressants and depression and anxiety when studies have been done. A major limitation of the literature to date is to account for depression and anxiety severity as related to pregnancy and developmental outcomes of exposed children.
Approximately 3% to 4% of all pregnancies in the United States involve congenital malformations (birth defects). In most cases, we do not know the causes of these defects. Decision making around the treatment of psychiatric disorders in pregnancy requires consideration of what is known about the medications in pregnancy, the disorder being treated, and exposures to the baby of both untreated maternal illness and of medication. The mother’s wellbeing also is paramount to the health of a pregnancy. The CDC Recommendations for Women of Reproductive Age advises women to take folic acid, maintain a healthy diet and weight, get regular physical activity, quit/abstain from tobacco use, alcohol and drugs, and plan with their providers around treatment decisions for chronic medical conditions (Centers for Disease Control and Prevention, http://www.cdc.gov/reproductivehealth/UnintendedPregnancy/index.htm).14
MDD and infertility: bidirectional considerations
A complicated bidirectional relationship between MDD and fertility outcomes likely exists. Untreated MDD could negatively impact fertility rates, either due to distress and the impact on hormonal dysregulation, or in terms of willingness to continue with treatment after experiencing a negative fertility outcome. Also, some women are concerned that taking antidepressants could decrease the chances for conception. At this time, there is no evidence to suggest that selective serotonin reuptake inhibitors (SSRIs) decrease fertility rates in women undergoing infertility treatment. For example, in one review of 950 women who underwent IVF, researchers observed no difference in pregnancy rates or live birth rates between women who were using SSRIs, representing about 4% of the sample, and those who were not.15 Maternal depressive symptoms were not controlled for in the sample. In another study, investigators found that women undergoing IVF with higher depression and anxiety scores had lower pregnancy rates.16 Efficacy of MDD treatments in the context of infertility also are understudied, and the roles of psychotherapies and medication need to be delineated. For example, in 1 study of women undergoing infertility treatment, CBT was superior to placebo and fluoxetine in the treatment of acute mild to moderate MDD.17
Depressive relapse associated with discontinuation of antidepressant
As women undergoing infertility treatment may wish to avoid any medication exposure to the fetus should the cycle be successful, many will discontinue medication in anticipation of a course of infertility treatment.
In general, multiple studies have demonstrated a high risk of relapse with antidepressant discontinuation in patients treated with a maintenance antidepressant, with relapse rates as high as 78% with placebo substituted for medication, compared with 20% relapse rates for those who continue medication.18-21 There have not been previous studies to determine relapse rates of MDD specifically among women who are going through infertility treatment. We do know, however, that during pregnancy, prevalence rates of moderate and severe depressive symptoms range from 7% to 20%,23-25 rates similar to non-pregnant women in the same age group. Data demonstrate higher rates of relapse when antidepressants are discontinued for pregnancy, when compared with patients who continue to take them.22 Cohen et al found that 43% of pregnant women with a history of MDD experienced a major depressive episode during pregnancy, with significantly higher relapse rates among women who discontinued antidepressants.22 Among women who discontinued medication, 68% experienced a depressive relapse, similarly high when compared with non-pregnant patients with MDD who discontinue medication. It is unclear if similar relapse rates would be found in women pursuing infertility treatment. It is likely that relapse rates would be equal or greater, considering the fact that infertility is a major life stressor.
To discontinue? And when?
Because of the protocols involved in assisted reproduction, a woman going through an IVF cycle or another type of infertility treatment will know very early if she is pregnant. Therefore, she might have a different treatment plan while she is trying to conceive, when compared with the 1 she may plan to have after she achieves a successful pregnancy. Others may not plan to change treatment regimens at all. Regardless, medications that are reasonable to consider during early pregnancy should be first line treatments for women undergoing infertility treatment.
Importance of non-medication treatments
Psychotherapy is an extremely important treatment option for women trying to conceive via assisted reproduction. Experts recommend psychotherapy as a primary treatment for relatively mild depression in pregnancy,26 and indeed it is an important part of the treatment plan regardless of depression severity in women during a pregnancy or during infertility treatment. In 1 review of psychosocial interventions for women undergoing infertility treatment, treatment was found to reduce negative emotional states, with clearer benefit from psycho-education and relaxation training than from more open-ended psychosocial interventions. Both women and their partners benefited in terms of distress. There appears to be a clear role for psychosocial and psychotherapeutic interventions in helping women and partners with the experience of the stressors and uncertainties that occur during assisted reproduction. We do not know, however, if there is a direct outcome of psychosocial interventions on the outcomes of successful conception and live births after infertility treatment.27
Overview: SSRI and benzodiazepine exposure in early pregnancy
SSRIs in early pregnancy. The safety of SSRIs has been well studied in pregnancy. Most studies do not show any increased risk of birth defects with SSRIs or tricyclics, although some have shown rare and inconsistent reports of malformations. Among the SSRIs, fluoxetine is the best characterized. Several meta-analyses combining studies with exposures to tricyclics and SSRIs have not found an increase in risk of congenital malformation in children exposed to either class of drugs.26 The comprehensive data regarding exposure to antidepressants have been reported elsewhere, but when clinically warranted, SSRIs are a well characterized and reasonable choice of treatment for moderate to severe MDD.26
Lorazepam and other benzodiazepines in early pregnancy. Benzodiazepines have been studied across pregnancy, and generally there have been few reports of any consistent risk. One concern with early pregnancy exposure to benzodiazepines is oral clefting, reported inconsistently after first trimester exposure.28 Therefore, recommendations typically advise benzodiazepines be used sparingly during the first trimester, and only when clinically indicated.
Overview of IVF treatment
During a typical IVF cycle, women are treated with hormones to stimulate follicle maturation, assist with implantation of the embryo, and support a pregnancy until the placenta is producing sufficient progesterone.
Considerations for partners
In 1 study, married couples were assessed regarding perspectives and distress around infertility. Upon seeking treatment for infertility, women reported more distress regarding infertility than men, although they also sought more psychosocial support. Men were less likely to confide in others about emotional aspects related to infertility.29 In another study of married couples going through IVF or intracytoplasmic sperm injection, both wives and husbands had similar emotions throughout the process, including emotional distress, from oocyte retrieval, fertilization, embryo transfer and in reaction to the pregnancy test.30,31 Therefore, the partner’s well being and health is a crucial consideration as well.
To date, there have been no specific studies to identify predictors of relapse among women undergoing IVF who have mood and anxiety disorders. Delineation of such factors would inform the care of a large number of reproductive-age women. In the meantime, clinicians should carefully monitor symptoms during infertility treatment. There are many variables that may contribute to exacerbation of psychiatric symptoms during IVF or other infertility treatment. These include treatment decisions made by each individual (such as continuation or discontinuation of psychotropic medication), the impact of exogenous hormonal therapies, which may have highly variable effects on mood and anxiety, and the amount of perceived stress and support. Decisions around medication use should take into account potential fetal exposure.
DISCLOSURES: Dr. Freeman receives grant/research support from GlaxoSmithKline; is a consultant to Johnson and Johnson, Otsuka, Takeda/Lundbeck, and Genentech. Dr. Toth reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. Dr. Cohen receives research support from AstraZeneca, Bristol-Myers Squibb, Cephalon, GlaxoSmithKline, the National Institute on Aging, the National Institute of Mental health, Ortho-McNeil, Janssen, and Sunovion; and is a consultant to Noven Pharmaceutical.
- Boivin J, Bunting L, Collins JA, et al. International estimates of infertility prevalence and treatment-seeking: potential need and demand for infertility medical care. Hum Reprod. 2007;22:1506–1512.
- Young EA, Korszun A. The hypothalamic-pituitary-gonadal axis in mood disorders. Endocrinol Metab Clin North Am. 2002;31:63–78.
- Pariante CM, Lightman SL. The HPA axis in major depression: classical theories and new developments. Trends Neurosci. 2008;31:464–468.
- Kirschbaum C, Kudielka BM, Gaab J, et al. Impact of gender, menstrual cycle phase, and oral contraceptives on the activity of the hypothalamus-pituitary-adrenal axis. Psychosom Med. 1999;61:154–162.
- Kiecolt-Glaser JK, Newton T, Cacioppo JT, et al. Marital conflict and endocrine function: are men really more physiologically affected than women? J Consult Clin Psychol. 1996;64:324–332.
- Stroud LR, Salovey P, Epel ES. Sex differences in stress responses: social rejection versus achievement stress. Biol Psychiatry. 2002;52:318–327.
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- Schüle C, Baghai T, Zwanzger P, et al. Attenuation of hypothalamic-pituitary-adrenocortical hyperactivity in depressed patients by mirtazapine. Psychopharmacology (Berl). 2003;166:271–275.
- Nikisch G, Mathé AA, Czernik A, et al. Long-term citalopram administration reduces responsiveness of HPA axis in patients with major depression: relationship with S-citalopram concentrations in plasma and cerebrospinal fluid (CSF) and clinical response. Psychopharmacology (Berl). 2005;181:751–760.
- Smith RS. The macrophage theory of depression. Med Hypotheses. 1991;35:298–306.
- Maes M, Stevens WJ, Declerck LS, et al. Significantly increased expression of T-cell activation markers (interleukin-2 and HLA-DR) in depression: further evidence for an inflammatory process during that illness. Prog Neuropsychopharmacol Biol Psychiatry. 1993;17:241–255.
- Maes M, Delange J, Ranjan R, et al. Acute phase proteins in schizophrenia, mania and major depression: modulation by psychotropic drugs. Psychiatry Res. 1997;66:1–11.
- Zaig I, Azem F, Schreiber S, et al. Psychological response and cortisol reactivity to in vitro fertilization treatment in women with a lifetime anxiety or unipolar mood disorder diagnosis. J Clin Psychiatry. 2013;74:386–392.
- . Center for Disease Control and Prevention. Unintended pregnancy prevention. http://www.cdc.gov/reproductivehealth/UnintendedPregnancy/index.htm. Accessed August 20 2013.
- Friedman BE, Rogers JL, Shahine LK, et al. Effect of selective serotonin reuptake inhibitors on in vitro fertilization outcome. Fertil Steril. 2009;92:1312–1314.
- Gürhan N, Akyüz A, Atici D, et al. Association of depression and anxiety with oocyte and sperm numbers and pregnancy outcomes during in vitro fertilization treatment. Psychol Rep. 2009;104:796–806.
- Faramarzi M, Alipor A, Esmaelzadeh S, et al. Treatment of depression and anxiety in infertile women: cognitive behavioral therapy versus fluoxetine. J Affect Disord. 2008;108:159–164.
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- Wisner KL, Zarin DA, Holmboe ES, et al. Risk-benefit decision making for treatment of depression during pregnancy. Am J Psychiatry. 2000;157:1933–1940.
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- Hjelmstedt A, Andersson L, Skoog-Svanberg A, et al. Gender differences in psychological reactions to infertility among couples seeking IVF- and ICSI-treatment. Acta Obstet Gynecol Scand. 1999;78:42–48.
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CORRESPONDENCE: Marlene P. Freeman, MD Perinatal and Reproductive Psychiatry Program Massachusetts General Hospital 185 Cambridge Street, 2nd Floor Boston, MA 02114 USA E-MAIL: email@example.com
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