Perinatal Period Anxiety Disorders

1. What every clinician should know

Clinical features and incidence

Clinical features

Core features of anxiety disorders include excessive worry or concern that impacts the functioning of the patient’s life. The specific features of the anxiety disorder depend on which disorder (such as generalized anxiety, panic, etc.) is being described. In pregnancy, presenting features of anxiety may involve persistent concerns about the health of the pregnancy or infant. Other physical symptoms, such as persistent nausea/vomiting, may include an associated contribution of anxiety. An anxiety disorder should always be considered when a pregnant woman presents with multiple physical complaints which appear to have no physical basis after thorough evaluation. Some common anxiety disorders seen in this population include:

Generalized anxiety disorder: Characterized by at least 6 months of persistent and excessive anxiety and worry that is difficult to control, causes difficulty in functioning and is accompanied by other symptoms such as restlessness, fatigue, difficulty concentrating, irritability, muscle tension and sleep disturbance.

Panic disorder (with or without agoraphobia): The presence of recurrent panic attacks accompanied by persistent fear of having another panic attack or of the consequences of having an attack, or significant changes in behavior in an effort to avoid having a panic attack.

Specific phobias: Clinically significant anxiety provoked by exposure to a specific object or situation.

Obsessive-compulsive disorder: The presence of obsessions (which are persistent ideas, thoughts, impulses or images that are experienced as intrusive and cause marked anxiety or distress) and/or compulsions (repetitive behaviors or mental acts) that patients engage in to reduce anxiety related to obsessions. Common themes of obsessions include fears of contamination, repeated doubts (i.e., about whether the door is locked), a rigid need for order, or aggressive impulses (i.e., ideas or images of harming one’s children). These obsessions are experienced as intrusive and distressing, and patients are typically aware that they are in excess of reality.

Social phobia: Anxiety triggered by exposure to certain types of social or performance situations that is excessive and causes marked distress or efforts to avoid these situations.

Post-traumatic stress disorder: Symptoms that occur in the aftermath (acute or chronic) of a traumatic event, characterized by re-experiencing (such as nightmares, flashbacks or intrusive thoughts), hyper-arousal (sleep problems, irritability, concentration problems, exaggerated startle and hypervigilance), and avoidance of situations or activities that remind one of the trauma (avoidance of thoughts and activities, memory loss around the trauma, decreased interest, feelings of detachment, decreased emotional range).

Some women may have clinically significant anxiety that does not strictly meet criteria for any of the above disorders, but which nevertheless may cause impairment in functioning, may have implications for pregnancy and transition to motherhood, and may require treatment in some form.

Clinical incidence

Anxiety affects a significant portion of women in the perinatal period. One study by Heron et al demonstrated that 21% of pregnant women in a large community sample had clinically significant anxiety symptoms. Of these patients, 64% had significant anxiety in the postpartum period. As with mood disorders, rates of anxiety tend to increase in the postpartum period as compared to the antenatal period.

Risk factors

Risk factors for anxiety in pregnancy or the postpartum include a pre-existing anxiety disorder or major depressive disorder, a family history of affective or anxiety disorders and the presence of acute stressors, such as complication in the pregnancy, significant adverse life events (i.e. loss of a loved one), or difficult or traumatic delivery.

2. Diagnosis and differential diagnosis

A. Establishing the diagnosis

The diagnosis of an anxiety disorder in the perinatal period is similar to the diagnosis outside of this period. In general, the clinical psychiatric interview is used to make the assessment. Diagnostic tests are often useful to exclude medical causes of anxiety or panic symptomatology, such as, for example, assessment of thyroid function, complete blood count to rule out anemias, and urine toxicology. Other tests that might prove useful include tests that assess cardiac function (such as an electrocardiogram, Holter monitoring and/or an echocardiogram) and pulmonary function.

B. Differential diagnosis

The differential diagnosis of anxiety includes anxiety disorders, medical disorders and substance abuse disorders. Clinically significant anxiety disorders include the following:

Generalized anxiety disorder. This disorder includes at least six months of excessive anxiety and worry (more than would be expected for a particular situation), significant difficulty in controlling the anxiety, associated symptoms such as restlessness, fatigue, difficulty with concentration and significant impairment in functioning in everyday life.

Panic disorder, which is characterized by recurrent panic attacks and their sequelae, including concern about their return, change in behavior in relation to the attacks, and worry about the implications of the panic. The early postnatal period in particular may be a time of increased vulnerability to new-onset panic disorder, with an incidence of around 1%.

Post-traumatic stress disorder (PTSD) involves exposure to a traumatic event and a characteristic set of subsequent symptoms from three clusters, including re-experiencing (such as flashbacks), numbing/avoidance (such as efforts to avoid discussing the trauma), and hyperarousal (such as insomnia or irritability). A trauma is defined as an event that involves actual or threatened death or injury or a threat to physical integrity, and includes intense fear, helplessness or horror. PTSD related to medical procedures surrounding pregnancy and childbirth has been debated in the literature, although the data are limited.

Obsessive-compulsive disorder. Patients with this disorder have both obsessions (unwanted and repeated thoughts, feelings, ideas, or sensations) and compulsions (behaviors that make them feel driven to action). Data suggest that the perinatal period is a time of high risk for the onset of OCD, with some studies suggesting that up to 40% of women have the onset of this disorder during their childbearing years.

Other disorders that have anxiety symptoms at the core of the presentation are also relevant to the perinatal period. Hypochondriasis, which is the persistent worry or fear that physical symptoms are a sign of serious illness despite reassurance to the contrary, should be considered. Patients who have an acutely stressful event, such as a miscarriage or difficult childbirth or pregnancy complication, may develop an adjustment disorder with anxiety (or depression, or both). This may be diagnosed if a patient has an identifiable acute stress and has symptoms that occur within 3 months of the stress, such as nervousness or worry, that is either more excessive than what one would expect from such a stressor, or that causes significant impairment in occupational or social functioning.

Medical disorders that can mimic anxiety in the perinatal period should always be ruled out. These can include but are not limited to the following:

• Thyroid disorders, particularly hyperthyroidism.

• Cardiac disorders, especially arrhythmias.

• Respiratory disorders, such as asthma or pulmonary embolism.

• Rare disorders such as pheochromocytoma.

Last, substance abuse disorders should always be included as part of the evaluation of anxiety in the perinatal period. Both intoxication (such as with cocaine or methamphetamines) and withdrawal (such as from alcohol) can present with clinically significant anxiety.

3. Management

Antepartum

The management of anxiety disorders in the perinatal period comprises both nonpharmacologic and pharmacologic methods. Many pregnant women opt to treat anxiety with nonpharmacologic methods first and will consider medication only if symptoms are unresponsive to behavioral interventions. Cognitive-behavioral therapy (CBT) and interpersonal psychotherapy (IPT) have both demonstrated efficacy in the perinatal period. Clinicians can also teach relaxation methods, such as breathing techniques, which may be helpful in mitigating anxiety. Additionally, anxiety disorder patients often benefit from education about the illness. Reading materials are available from the Anxiety Disorders Association of America website: www.adaa.org.

In terms of psychotropic medications, selective serotonin reuptake inhibitors (SSRIs) remain the first choice for treatment of both anxiety and depression in this population. While SSRIs have been shown to be effective for anxiety disorders in general, there are not specific controlled studies examining the efficacy of these medications in pregnancy. Tricyclic antidepressants (TCAs) also have proven efficacy to mitigate anxiety. Clinicians can also opt to use benzodiazepines, especially with anxiety that is episodic in nature or unresponsive to SSRIs. However, data regarding the use of benzodiazepines in this population are still somewhat limited.

4. Complications

Complication arising as a consequence of anxiety in pregnancy

Anxiety in pregnancy can result in adverse pregnancy, maternal and fetal outcomes. Evidence links a high degree of maternal anxiety with pregnancy outcomes, such as preeclampsia, preterm birth and low birth weight. For example, one recent study of almost 2,000 women suggests that pregnancy-related anxiety-specific worries or concerns related to the pregnancy is a risk factor for preterm birth, even after controlling for other psychosocial factors.

Perinatal anxiety is linked to adverse maternal outcomes as well. In particular, antepartum anxiety is a significant risk factor for postpartum depression. One large longitudinal study found that anxiety during pregnancy predicts postpartum depression at 8 weeks and 8 months, even after controlling for antepartum depression.

Perinatal anxiety also may have adverse effects on the offspring of these women. Significant stress and anxiety during pregnancy may affect the in utero environment, and therefore fetal “programming” and development, by pathways that have not been fully characterized but likely involve stress hormones, the autonomic nervous system and immune function.

There are data that link prenatal stress and anxiety with delays in infant development, impaired academic achievement and greater emotional dysregulation through childhood and adolescence. The Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective longitudinal study of more than 7,000 pregnant women and their offspring, found that patients with higher anxiety levels had children who were at increased risk at age 4 to have emotional and behavioral problems, and also, for boys, at increased risk of hyperactivity and inattention. This was independent of maternal mood. Another study found anxiety during pregnancy predicted attention deficit hyperactivity disorder (ADHD) in offspring at 8-9 years.

Complications of management

Non-pharmacologic interventions

Complications from nonpharmacologic interventions such as psychotherapy or relaxation strategies have not been clearly described and are likely to be minimal.

Antidepressants (selective serum reuptake inhibitors)

Full discussion of all the known and possible risks of psychiatric medications in pregnancy is beyond the scope of this article (see references below for more detailed information). Virtually all the data about risks of antidepressant medications in pregnancy are based on epidemiolgic research and pregnancy registeries, thus raising important questions about possible confounding factors.

For example, it is often difficult to control for the role of the underlying depressive illness and its biologic and behavioral correlates (i.e. elevated cortisol, higher rates of alcohol and tobacco use among the cohort on antidepressants, etc.) from the effects of the medications. Unfortunately, precise risk stratification of pharmacologically treated vs. untreated depression is not possible with the data available at this time.

Below is a summary of the current knowledge base regarding antidepressant exposure in pregnancy. Because selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants and a significant number of women are exposed to these medications during pregnancy, most of the data below are based on studies looking at SSRI exposure.

Miscarriage: Some but not all studies have found higher rates of early pregnancy loss in women taking SSRIs. Data are still inconclusive at this point.

Congenital malformations: Most studies have not found that SSRIs as a class are associated with higher rates of birth defects. However, there are some epidemiologic data linking exposure to some SSRIs in the first trimester to certain malformations. Specific defects found by some groups include ventricular outflow defects, craniosynostosis and omphalocele; however these risks are extremely small and not consistently replicated between studies.

Delivery outcomes: Several studies have found an association between SSRI exposure in pregnancy and lower birth weight and earlier delivery, with a trend towards preterm birth. As noted, though, no causal link has been established.

Neonatal Adaptation Syndrome: SSRI exposure in late pregnancy has been associated with a neonatal syndrome consisting of CNS, motor, respiratory and gastrointestinal signs. Symptoms most commonly consist of crying, jitteriness, tremor, feeding problems, reflux, sneezing and sleep dysregulation. The syndrome may be identified in up to 30% of babies exposed to SSRIs in the third trimester, but the symptoms are generally mild and resolve with supportive care within 48 hours to 2 weeks of age.

Persistent pulmonary hypertension of the newborn (PPHN): Several studies have linked exposure to SSRI medication, particularly in the second half of gestation (after 20 weeks) to an increased risk for PPHN. The baseline risk for PPHN in the general population is 0.5-2 per thousand live births. According to the case control studies that identified this potential association, the risk increases to 3-6 per thousand with exposure after 20 weeks. However, a number of epidemiologic studies have not confirmed this increased risk. The FDA recently updated its warning about this potential risk, stating that there is currently insufficient evidence to definitively link SSRI exposure to elevated risk for PPHN in the neonate.

Neurodevelopmental outcomes: Most studies that have looked at neurodevelopmental outcomes of children longitudinally after in utero exposure to SSRI or other antidepressants have not found an association with adverse cognitive or behavioral outcomes. However, the data are limited at this time. There is evidence that there may be an association with SSRI exposure and mild motor delays, although data indicate that these delays are still within the normal range and that the differences normalize over the course of development (i.e. by 18-24 months).

Although there is one retrospective case-control study suggesting a possible link between SSRI exposure in utero with increased risk for a diagnosis of autism spectrum disorders, this is a single study with multiple methodological limitations; other previous studies have associated untreated depression in mothers with higher risk of autism as well. The data are not strong enough to alter clinical practice at this time. Similarly, there are animal studies that have suggested altered brain and behavioral outcomes in animals exposed to SSRIs at critical periods of development, but the relevance for human illness and treatment are not clear at this time.

Benzodiazepines

Risk of the use of benzodiazepines include the risk of cleft lip/palate, which is estimated to be in the range of about 0.7%. Since this risk is specific to the first trimester, benzodiazepines can be used without risk of this malformation in the second/third trimesters. Intrapartum risks of benzodiazepines include symptoms of toxicity (including neonatal sedation, floppiness and respiratory compromise). There can also be withdrawal syndromes including irritability, sleep disruptionand (rarely) seizures.

5. Prognosis and outcome

As above (see “Complications”), untreated anxiety disorders during pregnancy are associated with negative neonatal and obstetric outcomes (i.e. preterm delivery, pre-eclampsia, low birthweight), as well as negative maternal outcomes (i.e.postpartum depression).

6. What is the evidence for specific management and treatment recommendations

Davis, EP, Glynn, LM, Schetter, CD, Hobel, C, Chicz-Demet, A. “Prenatal Exposure to Maternal Depression and Cortisol Influences Infant Temperament”. J Am Acad Child Adolesc Psychiatry. vol. 46. 2007. pp. 737-46. (This study highlights the relationshipo between maternal stress and infant temperament.)

Glover, V, O’Connor, TG. “Effects of antenatal stress and anxiety: implications for development and psychiatry”. British Journal of Psychiatry. vol. 180. 2002. pp. 389-91. (This article summarizes data from both animal models and humans to illustrate the impact of stress and anxiety on pregnancy.)

Heron, J, O’Connor, TG. “The course of anxiety and depression through pregnancy and the postpartum in a community sample”. J Affect Disord. vol. 80. 2004. pp. 65-73. (This article followed a large community sample of women through pregnancy and postpartum and demonstrated a high prevalence of anxiety symptoms in this population.)

Lanza, di Scalea, Wisner, KL. “Antidepressant medication use during breastfeeding”. Clin Obstetr Gynecol. vol. 52. 2009. pp. 483-97. (This article is a review of commonly-used antidepressants and breastfeeding.)

Neziroglu, F, Anemone, R, Yaryura-Tobias, JA. “Onset of obsessive-compulsive disorder in pregnancy”. Am J Psychiatry. vol. 149. 1992. pp. 947-50. (This article highlights the increased risk of the onset of obsessive-compulsive disorder in women of childbearing age.)

O’Connor, TG, Heron, J, Glover, V. “The ALSPAC Study Team Antenatal anxiety predicts child behavior/emotional problems independently of postnatal depression”. J Am Acad Child Adolesc Psychiatry. vol. 41. 2002. pp. 1470-7.

Orr, ST, Reiter, JP, Balzer, DG, James, SA. “Maternal prenatal pregnancy-related anxiety and spontaneous preterm birth in Baltimore, Maryland”. Psychosom Med. vol. 69. 2007. pp. 566-70. (This is a prospective study examining more than 1,800 women with pregnancy-related anxiety and found an increased risk of preterm birth in this population even after controlling for other psychosocial variables related to preterm birth.)

Ross, LE, McLean, LM. “Anxiety disorders during pregnancy and the postpartum period: a systematic review”. J Clin Psychiatry. vol. 67. 2006. pp. 1285-98. (This systematic review examines the overall literature on anxiety disorders in pregnancy.)

Van den Bergh, BR, Marcoen, A. “High antenatal maternal anxiety is related to ADHD symptoms, externalizing problems and anxiety in 8-9 year olds”. Child Dev. 75. pp. 1085-97.

Vythilingum, B. “Anxiety disorders in pregnancy and the postnatal period”. Curr Psychiatry Rep. vol. 10. 2008. pp. 331-5. (This readable article succinctly describes the clinical aspects of anxiety disorders in pregnancy.)

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