Preconception counseling components.
Evaluation of psychological defensive functioning and psychological reactions to the infertility diagnosis
The fertility counselor has a unique role in the infertility treatment team, as this clinician can help identify patients who may be at risk for psychological disturbances as well as mood and anxiety disorders during infertility treatment. While studies have not shown higher rates of personality disorders in women with infertility [2], the stress of the infertility process may lead to psychological problems in women with personality disorders, and even women without personality disorders may demonstrate psychological defenses that will interfere with their treatment. Consequently, preconception counseling should include an evaluation of psychological functioning to clarify for both the patient and the treatment team whether the complex and stressful process of infertility treatment will be associated with extreme distress. For example, patients with personality disorders can be especially challenging for medical staff and could be identified in preconception counseling sessions, particularly borderline personality disorder, narcissistic personality disorder and histrionic personality disorder. Patients with these disorders may be at a greater risk for creating “drama” during the treatment process, including setting up “splitting” between infertility doctors and nurses, excessive phone calls due to fears of abandonment or lack of compliance due to devaluation of members of the treatment team. Patients with obsessive-compulsive personality disorder, or strong traits, will be at risk for perseveration over the details of the infertility treatments, and extreme indecisiveness regarding future treatment planning. Recognition of these personality disorders and traits early on will help all members of the treatment team continue to work collaboratively. For instance, psycho-education about personality styles and support from the fertility counselor on the treatment will enable the team to plan which patients might be best seen at the end of the clinic, so as not to disrupt the flow of other patients; which patients will need more frequent scheduled follow-up phone calls, or which patients may need extra instruction in procedures.
The fertility counselor also plays an important role in evaluating the patient’s psychological reaction to the infertility diagnosis. Recent research has demonstrated that infertility patients often suffer from profound feelings of external shame, a sense that others are judging them harshly as inadequate, as well as internal shame, the sense of negative self-judgment, often based on past events, such as a previous abortion, or desire to delay childbearing [3]. Since shame has been found to be risk factor for the development of mood and anxiety disorders [4,5], and the character trait of neuroticism has been found to predict depression and anxiety in infertility patients [6], exploration of the patient’s reaction to the infertility diagnosis and treatment during the preconception counseling session will help identify patients who may need to be followed more closely by the fertility counselor, or referred for more in-depth therapy.
Evaluation of hormonal sensitivity
The preconception counseling session should include an in-depth review of the patient’s history of hormonal sensitivity. No large prospective studies have yet been completed that compare rates of new onset or recurrence of major depression or anxiety disorders in women in infertility treatment with or without a history of mood and anxiety symptoms. Nonetheless, it is recommended that clinicians determine a baseline understanding of reproductive hormone sensitivity prior to infertility treatment, as some women do appear to be especially sensitive to the effects of hormones. One example of a reproductive-cycle-oriented interview is the Composite International Diagnostic Interview for Women, which focuses upon the interaction of psychiatric symptoms and reproductive events and stages [7]. At the very minimum, the preconception therapy session should include:
1. Psychiatric history – special attention to history of affective and anxiety disorders, including bipolar disorders.
2. Review of psychological symptoms at the following times:
puberty
oral contraceptive pills
ovulation and luteal phase
pregnancy and postpartum.
3. Family history of reproductive-related psychiatric symptoms:
premenstrual dysphoric disorder
postpartum depression
perimenopausal depression.
4. Family history of major depression and bipolar disorder.
Evaluation and treatment of behaviors with potential effects on fertility/pregnancy
The fertility counselor is poised to be a very helpful member of the infertility treatment team for the evaluation and treatment of conditions that may affect fertility and pregnancy, such as eating disorders, smoking and alcohol cessation, healthy eating habits in both men and women (see Figure 6.2). The gynecologist or reproductive endocrinologist may identify these problems in the history and physical examination, but it is the MHP who can provide a more complex and nuanced evaluation and treatment plan. To date, there are no specific evidence-based treatments for eating disorders or substance use disorders in infertility patients, and treatment guidelines are usually based on treatments for patients in the general population [8]. Motivational interviewing will be an extremely important component of treatment for this population as it is in the general population [9]. Overweight and obese patients should be educated about studies that have shown increased rates of fertility in women and men who have been able to reduce their BMI through diet and exercise [10,11].
Example of options for behavior related to infertility.
Cigarette smoking has been shown to have deleterious affects on both male and female fertility. In women, cigarette smoking may have multiple routes of fertility disruption, including altered hormonal milieu, disruption of ovarian transport in the fallopian tubes, and negative effects on the uterine environment, as women undergoing ovum donor assisted ART who smoke more than ten cigarettes per day have lower pregnancy rates than women who do not smoke [10]. In men, cigarette smoking is associated with reduced sperm motility, sperm count and fertilizing capacity; and it may be associated with an increased risk of sex chromosome abnormalities and disomies. Cessation of smoking for three months was associated with improvement in sperm concentration, motility and vitality in one study [10]. Because of this increasing research that cigarette smoking has negative effects on both male and female reproductive health, fertility counselors should identify this modifiable fertility factor, provide education about its effects on infertility treatment and aid patients in choosing and implementing a smoking cessation treatment plan.
Infertility medication-emergent side effects
For many infertility patients, review of potential medication-emergent side effects of treatment should be a standard part of the preconception counseling. Patients with prior history of hormonal sensitivity will be especially concerned about the potential central nervous effects of infertility medications, and they should be counseled regarding the current research, the implications of this research for their personal story and current gaps in knowledge.
Oral contraceptives
Many women are concerned about taking oral contraceptives (OCPs), a standard phase of early infertility treatment, because of the common belief that oral contraceptives are associated with mood changes. However, while earlier studies with higher dose estrogen and progesterone preparations suggested increased depressive symptoms in normal women [12] more recent studies evaluating pills with lower doses show most women do not experience mood changes with OCPs [13,14]. One side effect of OCPs that may occur in all women, though, is decreased libido. Oral contraceptives increase sex hormone-binding globulin that decrease free testosterone levels, which is associated with decreased libido in some women [14].
Gonadotropin releasing hormone agonists
Gonadotropin Releasing Hormone Agonists (GnRH agonists) are used frequently at the beginning of an infertility cycle. These medications lead to decreases in luteinizing (LH) and follicular stimulating (FSH) by negative feedback, and this hypogonadal state is similar to the hormonal milieu of menopause. Consequently, women taking GnRH agonists will frequently complain of hot flashes and sleep disturbance [15]. To date, studies of psychiatric symptoms with GnRH agonists have been small and involved women without mood disorders [16,17]. In general these medications have the potential to cause the side effects of irritability, depressed mood, anxiety, problems with memory and concentration [18]. Women in infertility treatment are likely to only be exposed to these medications for a few weeks, at most. A recent study of short-term GnRH use in healthy women failed to confirm early reports of significant memory and concentration changes [19] and another showed that depression and anxiety increased in women exposed to GnRH agonists not in the hypogonadal phase (i.e., the follicular phase), but later in the IVF cycle [20]. If these medications are required for extended period of time for treatment of fibroids, for instance, and if major depression emerges, sertraline (Zoloft) has been found to be a useful treatment [21].
Clomiphene citrate (Clomid)
Women with unexplained subfertility or polycystic ovarian syndrome (PCOS) are frequently prescribed clomiphene citrate as an infertility treatment. Clomiphene citrate is a synthetic estrogen receptor modulator with mixed agonist–antagonist properties. It is taken orally days 3–7 of menstrual cycle and creates a central perception of low estradiol [22]. Many women and their partners have reported that clomiphene citrate is associated with mood lability, often characterized as “super]PMS” [23,24]. While these symptoms appear to be most pronounced during the time that the medication is taken, it also has a long half-life, so these symptoms could theoretically persist beyond the time of oral intake.
Clomiphene citrate has even been associated with case reports of psychosis, occurring in patients with and without previous psychiatric history. In these case reports, there is a forewarning of sleeplessness and agitation progressing to auditory hallucinations, paranoia, delusions and ideas of reference. Notably, the onset of symptoms was within 48 hours of initiation of medication and neuroleptics and/or ECT resolved the symptoms [25–29].
Human menopausal gonadotropins
Women who are undergoing IVF (or in some cases intrauterine insemination) will use human meno-pausal gonadotropins, which are synthetic peptides similar in structure to GnRH that are delivered via injection.
These medications increase the number of ovarian follicles and are associated with extremely high serum estradiol levels. As in the case of clomiphene citrate, women exposed to these medications frequently describe mood lability [24].
In summary, detailed studies of women undergoing IVF with gonadotropins and progesterone supplementation showed increased depressive symptoms as they moved from the estrogen dominant phase (follicular) to the progesterone dominant phase (luteal phase), suggesting that changing levels of estrogen, rather than absolute levels of estrogen, were associated with changing symptoms [30]. Furthermore, women who had a previous Axis I diagnosis of anxiety or depression had even greater elevations in mood symptoms [31].
Psychopharmacology considerations for infertility patients
Infertility patients represent a unique population when psychiatric medications are being considered. As described in other chapters of this book, psychotherapy, with both individuals and couples, remains the first-line treatment of depression and anxiety disorders. If patients do require the addition of psychotropic medications to their psychotherapy, several important issues must be addressed, including impact of psychiatric medications on the menstrual cycle and ovulatory function, risk of spontaneous abortion, risk of congenital malformations and other perinatal complications.
Impact of antidepressants on the menstrual cycle
In general, antidepressants have not been commonly associated with menstrual cycle dysfunction. While typical and atypical antipsychotics are most commonly associated with increased prolactin levels, SSRIs have been associated with moderate increases as well, and hyperprolactinemia is associated with menstrual cycle abnormalities, including amenorrhea and oligomenorrhea [32]. Antidepressants that do not affect serotonin levels, such as Bupropion, are not associated with increases in prolactin. If a patient describes significantly increased breast size or pain, or nipple discharge or change in menstrual cycle length after initiation of an SSRI, they should be evaluated for elevated prolactin levels and consideration should be made to switch to another antidepressant if possible, such as Bupropion, and prolactin level rechecked.
Impact of antidepressants on spermatogenesis
The impact of SSRIs on sperm concentration, morphology and mobility remains controversial. Only a few small studies have been completed to investigate this question, but all have shown that treatment with SSRIs is associated with decreased sperm concentration and mobility, and increased DNA fragmentation [33,34]. Men who are taking SSRIs for premature ejaculation should be referred to behavior therapy for this problem since it has been shown to be effective in several studies and is without the potential risks to sperm [35].
Impact of antidepressants on IVF outcome
To date, there are only three small studies comparing reproductive outcome in women undergoing IVF who are either on or not on SSRIs. One study randomized women who had normal anxiety levels at baseline to either Fluoxetine (Prozac) or folic acid during the IVF cycle. In both groups, anxiety increased significantly over the IVF cycle, and Fluoxetine was no more effective than placebo in treating the anxiety. There was no significant difference in IVF outcome between the two groups – no difference in quality of embryos, number of embryos transferred, pregnancy rate, spontaneous abortion rate or live birth rate [36]. Two retrospective chart reviews comparing women taking SSRIs to women not taking antidepressants also did not find significant differences in IVF outcomes [37,38]; although one study did report that women on antidepressants had a lower ongoing pregnancy rate [38]. In summary, to date, antidepressant exposure does not appear to affect egg quality or embryo development, but it is still not clear whether it has an effect on risk of spontaneous abortion.
Antidepressants and miscarriage
All antidepressants, regardless of class, have been associated with an increased rate of spontaneous abortion in individual studies and meta-analyses [39–41]. The causes of this possible increased rate of miscarriage remain unclear. Most studies have compared women with depression on antidepressants to women without depression not on antidepressants; consequently, the increased rate of spontaneous abortion may be due to the underlying condition of depression. To date, the studies examining antidepressants and the risk of spontaneous abortion are limited by methodological problems. When discussing this finding with patients, it is important to point out this limitation in the studies, as well as other confounding variables, such as the fact that no studies controlled for Body Weight Index (BMI), occult thyroid or medical illnesses commonly associated with infertility, or ovarian reserve. Furthermore, in several of the studies the significantly higher rate of miscarriage was still within the general population background rate, for instance 13% spontaneous abortion rate in antidepressant users, compared to 8% in nonusers [42]. Nevertheless, all fertility patients should be counseled about the potential increased risk of spontaneous abortion with use of antidepressants immediately prior to and during pregnancy because this is such an important consideration for this group.
Antidepressants and congenital malformation risks
All patients who are attempting to become pregnant will be concerned about whether antidepressants are associated with an increased risk of major congenital malformations. After several decades of research and thousands of children exposed worldwide to antidepressants, general consensus is that commonly used antidepressants, including serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs) and Bupropion are not major teratogens, that is adversely affecting the embryo [42]. To date, the associations between individual antidepressants and congenital malformations are based on very small numbers of cases, and no consistent, single type of malformation has been found across all classes of antidepressants, so currently it appears that the risk of a unifying teratogenicity is low. However, patients should be counseled about the conflicting reports of increased risk of cardiac defects with Paroxetine (Paxil) and it is not currently considered a first choice SSRI in perinatal patients [42].
Antidepressants and perinatal complications
While antidepressants do not appear to be highly associated with an increased risk of congenital malformations, they may be associated with perinatal complications such as persistent pulmonary hypertension, increased rates of preterm labor, neonatal adaptation syndrome and unknown long-term neurodevelopmental outcomes.
Persistent pulmonary hypertension
Persistent pulmonary hypertension (PPHN) is a rare condition occurring in term or near-term newborns associated with severe respiratory failure. It occurs when there is failure of the newborn to move from a high pulmonary vascular resistance to low pulmonary vascular resistance state at birth. The most recent, largest study of PPHN, a multinational cohort study (n = 1 618 255) of 17 053 SSRI exposed infants in early pregnancy and 11 014 later than week 20, found that exposure to SSRIs in late pregnancy was associated with approximately twice the rate of PPHN in newborns. Since PPHN is very rare, occurring in 1–3/1000 births, the highest rate in SSRI-exposed infants would be 1–6/1000 [43]. Other known risk factors for PPHN include Caesarian section and use of nonsteroidal anti-inflammatory agents (NSAIDs) [44], so patients who are likely to need these interventions should be counseled about possible additive risks.
Preterm labor and delivery
Preterm labor and delivery are defined as labor and delivery before 37 weeks. Some studies have reported higher rates of preterm delivery in women with depression on antidepressants in pregnancy compared to those who are not [42]. Currently, the relationship between antidepressant use and preterm labor and delivery remains controversial, but patients should be counseled that medication may confer additional risk and, consequently, patients should be even more conscientious about modifying other known risk factors for preterm labor, such as smoking, drinking and illicit drug use.
Neonatal adaptation syndrome
Maternal use of SSRIs and SNRIs in the third trimester of pregnancy has been associated with neonatal adaptation syndrome. This syndrome has included both signs of serotonin withdrawal and serotonin toxicity. The most common symptoms include restlessness, autonomic nervous system disturbances, respiratory distress, tremors, myoclonus and rarely seizures. The syndrome is common, affecting up to 30% of infants exposed to SSRIs and SNRIs in the last trimester, but to do date is not associated with mortality. All women taking SSRIs or SNRIs in pregnancy should be warned about this potential perinatal complication, and since it may be dose related it is yet another reason to encourage that all pregnant patients on antidepressants be treated with the lowest effective dose [42].
Long-term neurodevelopment
The long-term neurodevelopmental effects of antidepressant exposure in utero remain unknown. Infertility patients should be cautioned that SSRIs have been associated with developmental differences in fine and gross motor development, but the clinical significance of these differences is not yet known. For instance, in one of the earliest follow-up studies of infants of depressed mothers, infants exposed to depression during pregnancy and antidepressants had subtle fine motor abnormalities, including tremor [45]. These children have not been re-evaluated, so it is not known whether these were lasting changes beyond the age of 3 and if they were clinically significant. These neurodevelopmental follow-up studies have many methodological problems, and several have not controlled for critical confounding variables, such as familial history of neurodevelopmental problems [46]. While an early study of children exposed to SSRIs in utero reported a higher rate of autism spectrum disorders in exposed children [47], a later study, which controlled for autism in siblings, failed to find this association [48].
While antidepressants in pregnancy have been associated with the risks described above, it is important to point out that untreated major depression and anxiety disorders in pregnancy have also been associated with increased risk of perinatal complications, such as preterm labor and delivery, small for gestational age infants and newborn irritability [49].
Case discussion
Ms. G. underwent preconception counseling, following the guidelines outlined in this chapter. She was found to have strong personality traits of obsessionality, but she did not meet criteria for obsessive-compulsive personality disorder, or obsessive-compulsive disorder. She did have perfectionistic tendencies, and desire for her schedule to be predictable and all her “ducks in a row.” When things were out of order, or unexpected, it caused a great deal of distress and anxiety. The fertility counselor helped Ms. G. and the treatment team identify ways that she could feel more in control and less anxious about her upcoming IVF procedure. She was given a detailed printed schedule of the medications, including a daily calendar. She was given the opportunity to attend as many injection-teaching classes as she needed, and the MHP normalized this process. Ms. G.’s husband was provided education as well, and he agreed to talk with his supervisor about decreasing his work schedule during the IVF cycle in order to provide extra household and emotional support. This intervention was extremely important to Ms. G., because she was also working outside the home, and it enabled her to have “fewer loose ends to worry about” and a predictable time for the injections.
Ms. G.’s depressive symptoms did meet criteria for major depression, moderate. She had no suicidal ideation and, at first, she said she was too busy to begin psychotherapy. Ms. G. confided to the fertility counselor that she felt she should “snap out of it,” and that she should be grateful that she had at least one child, since many women in the infertility clinic had none. The MHP educated her about the increased risk of major depression in women after a miscarriage, and that women with recurrent miscarriages are at even greater risk [50]. The fertility counselor educated Ms. G. that her current symptoms were like other medical illnesses, and that major depression has well-established treatments, which include evidence-based psychotherapies, such as cognitive-behavioral therapy (CBT), interpersonal psychotherapy and brief dynamic psychotherapies. She explained to Ms. G. that therapy is the first-line approach to the treatment of anxiety and depression in infertility patients, but that at times medications may be needed as well.
She was advised to begin psychotherapy and be followed closely through the IVF cycle, because recent research has suggested that women with current or past anxiety and depressive symptoms do in fact have greater psychiatric distress during the complex hormonal manipulations of IVF, compared to women who are not currently depressed or anxious and who have no such history [31]. The fertility counselor explained that currently there is very little literature comparing antidepressants and psychotherapy in patients with infertility and depression, such as Ms. G., but that the available evidence suggested that either one alone or in combination could be very helpful [51,52]. Ms. G. was not currently suicidal, and was functioning well despite the distress, and she was very concerned about the safety of antidepressants in pregnancy. Since she was not in any sort of current treatment, and appeared to be an insightful, motivated and an excellent psychotherapy candidate, the fertility counselor and she chose to begin weekly psychotherapy. The MHP also referred Ms. G. to a mindfulness-based group therapy (MBSR) that was offered at night at the infertility clinic, since there is emerging evidence that MBSR is also effective in decreasing psychological distress associated with infertility diagnosis and treatment [53].
Ms. G. began weekly cognitive-behavioral psychotherapy with the fertility counselor, as well as MBSR group on Tuesday nights. Ms. G.’s husband followed through on his commitment to change his schedule, and he was home each night at 6:30 pm, which enabled Ms. G. to attend all MBSR meetings, to rely on him for her injections and to feel a greater sense of predictability in the nightly routine. Despite these interventions, Ms. G. experienced increased anxiety, irritability and obsessionality during the week after embryo transfer. She had noted increasing anxiety and insomnia as her estradiol levels increased during the cycle, but after the transfer, she felt even worse. Ms. G.’s depression had been clearly improving over the 8 weeks since the initial consult with the fertility counselor, despite the exposure to oral contraceptive for a month, and the week of GnRH flare. Ms. G. was referred to a cognitive-behavior therapy for insomnia therapist (CBT-I) and she was confused by the referral because she “thought she already was in CBT.” The fertility counselor explained that CBTI-I is a specialized form of CBT. Ms. G. agreed to begin CBT-I because, she admitted, she had suffered on and off from insomnia throughout her life, but she insisted on a medication for immediate relief because she was so agitated, anxious and distressed at night because of inability to fall asleep or sustain sleep. Given the overall clear improvement in depression and anxiety and the acute onset of her symptoms, it was decided to treat her insomnia and anxiety symptomatically for a few days, with an antihistamine for sleep and a benzodiazepine on an as-needed basis.
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